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1.  The Greater Cincinnati Pediatric Clinic Repository: A Novel Framework for Childhood Asthma and Allergy Research 
Allergic disorders, including asthma, allergic rhinitis, atopic dermatitis, eosinophilic esophagitis, and food allergy, are a major global health burden. The study and management of allergic disorders is complicated by the considerable heterogeneity in both the presentation and natural history of these disorders. Biorepositories serve as an excellent source of data and biospecimens for delineating subphenotypes of allergic disorders, but such resources are lacking.
In order to define subphenotypes of allergic disease accurately, we established an infrastructure to link and efficiently utilize clinical and epidemiologic data with biospecimens into a single biorepository called the Greater Cincinnati Pediatric Clinic Repository (GCPCR). Children with allergic disorders as well as healthy controls are followed longitudinally at hospital clinic, emergency department, and inpatient visits. Subjects' asthma, allergy, and skin symptoms; past medical, family, social, diet, and environmental histories; physical activity; medication adherence; perceived quality of life; and demographics are ascertained. DNA is collected from all participants, and other biospecimens such as blood, hair, and nasal epithelial cells are collected on a subset.
To date, the GCPCR has 6,317 predominantly Caucasian and African American participants, and 93% have banked DNA. This large sample size supports adequately powered genetic, epidemiologic, environmental, and health disparities studies of childhood allergic diseases.
The GCPCR is a unique biorepository that is continuously evaluated and refined to achieve and maintain rigorous clinical phenotype and biological data. Development of similar disease-specific repositories using common data elements is necessary to enable studies across multiple populations of comprehensively phenotyped patients.
PMCID: PMC3377950  PMID: 22768387
2.  Cognitive functioning in young children with type 1 diabetes 
To assess cognitive functioning in children with type 1 diabetes (T1D) and examine whether glycemic history influences cognitive function.
Research Design and Methods
Neuropsychological evaluation of 216 children (healthy controls, n = 72; T1D, n = 144) ages 4-10yrs across five DirecNet sites. Cognitive domains included IQ, Executive Functions, Learning and Memory, and Processing Speed. Behavioral, mood, parental IQ data and T1D glycemic history since diagnosis were collected.
The cohorts did not differ in age, gender or parent IQ. Median T1D duration was 2.5yrs and average onset age was 4yrs. After covarying age, gender, and parental IQ, the IQ and the Executive Functions domain scores trended lower (both p = .02, not statistically significant adjusting for multiple comparisons) with T1D relative to controls. Children with T1D were rated by parents as having more depressive and somatic symptoms (p < 0.001). Learning and memory (p = 0.46) and processing speed (p = 0.25) were similar. Trends in the data supported that the degree of hyperglycemia was associated with Executive Functions, and to a lesser extent, Child IQ and Learning and Memory.
Differences in cognition are subtle in young children with T1D within 2 years of onset. Longitudinal evaluations will help determine whether these findings change or become more pronounced with time.
PMCID: PMC4123061  PMID: 24512675
cognition; early onset; T1DM; hyperglycemia; hypoglycemia; children
3.  Regulation of IL-4 Receptor Signaling by STUB1 in Lung Inflammation 
Rationale: IL-4Rα, the common receptor component for IL-4 and IL-13, plays a critical role in IL-4– and IL-13–mediated signaling pathways that regulate airway inflammation and remodeling. However, the regulatory mechanisms underlying IL-4Rα turnover and its signal termination remain elusive.
Objectives: To evaluate the role of STUB1 (STIP1 homology and U-Box containing protein 1) in regulating IL-4R signaling in airway inflammation.
Methods: The roles of STUB1 in IL-4Rα degradation and its signaling were investigated by immunoblot, immunoprecipitation, and flow cytometry. The involvement of STUB1 in airway inflammation was determined in vivo by measuring lung inflammatory cells infiltration, mucus production, serum lgE levels, and alveolar macrophage M2 activation in STUB1−/− mice. STUB1 expression was evaluated in airway epithelium of patients with asthma and lung tissues of subjects with chronic obstructive pulmonary disease.
Measurements and Main Results: STUB1 interacted with IL-4Rα and targeted it for ubiquitination-mediated proteasomal degradation, terminating IL-4 or IL-13 signaling. STUB1 knockout cells showed increased levels of IL-4Rα and sustained STAT6 activation, whereas STUB1 overexpression reduced IL-4Rα levels. Mice deficient in STUB1 had spontaneous airway inflammation, alternative M2 activation of alveolar macrophage, and increased serum IgE. STUB1 levels were increased in airways of subjects with asthma or chronic obstructive pulmonary disease, suggesting that up-regulation of STUB1 might be an important feedback mechanism to dampen IL-4R signaling in airway inflammation.
Conclusions: Our study identified a previously uncharacterized role for STUB1 in regulating IL-4R signaling, which might provide a new strategy for attenuating airway inflammation.
PMCID: PMC3919125  PMID: 24251647
IL-4R signaling; STUB1; airway inflammation
4.  Neuroanatomical Correlates of Dysglycemia in Young Children With Type 1 Diabetes 
Diabetes  2013;63(1):343-353.
Studies of brain structure in type 1 diabetes (T1D) describe widespread neuroanatomical differences related to exposure to glycemic dysregulation in adults and adolescents. In this study, we investigate the neuroanatomical correlates of dysglycemia in very young children with early-onset T1D. Structural magnetic resonance images of the brain were acquired in 142 children with T1D and 68 age-matched control subjects (mean age 7.0 ± 1.7 years) on six identical scanners. Whole-brain volumetric analyses were conducted using voxel-based morphometry to detect regional differences between groups and to investigate correlations between regional brain volumes and measures of glycemic exposure (including data from continuous glucose monitoring). Relative to control subjects, the T1D group displayed decreased gray matter volume (GMV) in bilateral occipital and cerebellar regions (P < 0.001) and increased GMV in the left inferior prefrontal, insula, and temporal pole regions (P = 0.002). Within the T1D group, hyperglycemic exposure was associated with decreased GMV in medial frontal and temporal-occipital regions and increased GMV in lateral prefrontal regions. Cognitive correlations of intelligence quotient to GMV were found in cerebellar-occipital regions and medial prefrontal cortex for control subjects, as expected, but not for the T1D group. Thus, early-onset T1D affects regions of the brain that are associated with typical cognitive development.
PMCID: PMC3868050  PMID: 24170697
5.  Relationship between Daily Mood and Migraine in Children 
Headache  2013;53(10):1624-1634.
Retrospective and cross-sectional studies have suggested a bidirectional relationship between migraine and mood disturbance.
The present prospective daily diary study examined the prevalence and temporal associations between migraine and daily mood, mood and next-day headache, and headache and next-day mood.
Sixty-nine children (50 females, 19 males) between the ages of 7–12 years and their parents attending neurology clinic appointments and having a diagnosis of migraine as defined by ICHD-II criteria completed measures on quality of life, headache disability, child emotions and child behaviors. Children and parents then recorded children’s headache occurrence, headache duration, headache severity, mood, daily hassles, and medication use on paper diaries once a day for two consecutive weeks. “Mood” was defined using the facial affective scale, which is a visual representation of negative and positive affect. Data were analyzed using multilevel models.
Controlling for age, sex, quality of life, headache disability, and medication use, worse mood was associated with same-day occurrence, longer duration and more severe headache in both child and parent report. Today’s mood was not consistently associated with next-day headache and today’s headache was not associated with next-day mood in either child or parent report.
Results of this study lend support for a complex relationship between mood and headache in children with migraine. More research is needed to further elucidate the temporal nature of this relationship within a given day and over an extended period of time.
PMCID: PMC4270347  PMID: 24102349
children; migraine; mood; daily hassles; daily diary
7.  IL-13Rα2 Has a Protective Role in a Mouse Model of Cutaneous Inflammation 
IL-13 is expressed in lesions of atopic dermatitis (AD) and has been associated with increased disease severity. IL-13 has two cognate receptors: IL-13Rα1 and IL-13Rα2. Although IL-13Rα2 expression is known to be induced in response to IL-13 in keratinocytes, its function in AD has never been evaluated. We characterized the loss of skin barrier function and the development of cutaneous inflammation in IL-13Rα2–null versus wild-type BALB/c mice following an epicutaneous allergen-sensitization/challenge model that shares similarities with human AD. Mice lacking IL-13Rα2 had significantly increased transepidermal water loss, cutaneous inflammation, peripheral eosinophilia, and IgG1 and IgE levels compared with wild-type mice. The rate of resolution of the cutaneous inflammation was not significantly altered in the IL-13Rα2–null mice. IL-13 induced expression of IL-13Rα2 in keratinocyte cell lines and primary human keratinocytes. Depletion of IL-13Rα2 in a keratinocyte cell line resulted in increased STAT6 signaling in response to IL-13. In conclusion, IL-13Rα2 serves a protective role in the pathogenesis of allergic inflammation and loss of skin barrier function in a mouse model of AD, suggesting that it may be an important endogenous regulator of IL-13–induced cutaneous inflammation in humans.
PMCID: PMC4251801  PMID: 20971924
8.  Principles of Translational Control: An Overview 
Translational control plays an essential role in the regulation of gene expression. It is especially important in defining the proteome, maintaining homeostasis, and controlling cell proliferation, growth, and development. Numerous disease states result from aberrant regulation of protein synthesis, so understanding the molecular basis and mechanisms of translational control is critical. Here we outline the pathway of protein synthesis, with special emphasis on the initiation phase, and identify areas needing further clarification. Features of translational control are described together with numerous specific examples, and we discuss prospects for future conceptual advances.
The control of protein synthesis defines the proteome and maintains homeostasis in the cell and the organism. Regulation occurs at different steps of translation; the initiation step is the most common target.
PMCID: PMC3504442  PMID: 23209153
9.  Quality of Life and Emotional Functioning in Youth with Chronic Migraine and Juvenile Fibromyalgia 
The Clinical journal of pain  2013;29(12):10.1097/AJP.0b013e3182850544.
Chronic pain in children is associated with significant negative impact on social, emotional, and school functioning. Previous studies on the impact of pain on children's functioning have primarily used mixed samples of pain conditions or single pain conditions (e.g., headache, abdominal pain) with relatively small sample sizes. As a result, the similarities and differences in the impact of pain in sub-groups of children with chronic pain have not been closely examined.
To compare pain characteristics, quality of life, and emotional functioning among youth with pediatric chronic migraine (CM) and juvenile fibromyalgia (JFM).
We combined data obtained during screening of patients for two relatively large intervention studies of youth (ages 10-18) with CM (N = 153) and JFM (N = 151). Measures of pain intensity, quality of life (Pediatric Quality of Life; PedsQL™, child and parent-proxy), depressive symptoms (Children's Depression Inventory; CDI), and anxiety symptoms (Adolescent Symptom Inventory-4 - Anxiety subscale) were completed by youth and their parent. A multivariate analysis of co-variance (MANCOVA) controlling for effects of age and gender was performed to examine differences in quality of life and emotional functioning between the CM and JFM groups.
Youth with JFM had significantly higher anxiety and depressive symptoms, and lower quality of life in all domains. Among children with CM, overall functioning was higher but school functioning was a specific area of concern.
Results indicate important differences in sub-groups of pediatric pain patients and point to the need for more intensive multidisciplinary intervention for JFM patients.
PMCID: PMC3675174  PMID: 23446072
Pediatric pain; chronic migraine; pediatric headache; juvenile fibromyalgia; quality of life
10.  Altered Cortical Activation in Adolescents With Acute Migraine: A Magnetoencephalography Study 
To quantitatively assess cortical dysfunction in pediatric migraine, 31 adolescents with acute migraine and age- and gender-matched controls were studied using a magnetoencephalography (MEG) system at a sampling rate of 6,000 Hz. Neuromagnetic brain activation was elicited by a finger-tapping task. The spectral and spatial signatures of magnetoencephalography data in 5 to 2,884 Hz were analyzed using Morlet wavelet and beamformers. Compared with controls, 31 migraine subjects during their headache attack phases (ictal) showed significantly prolonged latencies of neuromagnetic activation in 5 to 30 Hz, increased spectral power in 100 to 200 Hz, and a higher likelihood of neuromagnetic activation in the supplementary motor area, the occipital and ipsilateral sensorimotor cortices, in 2,200 to 2,800 Hz. Of the 31 migraine subjects, 16 migraine subjects during their headache-free phases (interictal) showed that there were no significant differences between interictal and control MEG data except that interictal spectral power in 100 to 200 Hz was significantly decreased. The results demonstrated that migraine subjects had significantly aberrant ictal brain activation, which can normalize interictally. The spread of abnormal ictal brain activation in both low- and high-frequency ranges triggered by movements may play a key role in the cascade of migraine attacks.
This is the first study focusing on the spectral and spatial signatures of cortical dysfunction in adolescents with migraine using MEG signals in a frequency range of 5 to 2,884 Hz. This analyzing aberrant brain activation may be important for developing new therapeutic interventions for migraine in the future.
PMCID: PMC3844550  PMID: 23792072
Migraine; magnetoencephalography (MEG); pediatric; high-frequency oscillations; wavelet
11.  Glycemic extremes in youth with T1DM: Effects on the developing brain's structural and functional integrity 
Pediatric diabetes  2013;14(8):10.1111/pedi.12088.
Hypoglycemia and hyperglycemia are rare occurrences in normal individuals, but they occur commonly in patients with type 1 diabetes mellitus (T1DM) due to a dysfunction of peripheral glucose-insulin-glucagon responses and non-physiologic doses of exogenous insulin, which imperfectly mimic normal physiology. These extremes can occur more frequently in children and adolescents, due to events leading to the diagnosis of T1DM (prolonged untreated hyperglycemia, diabetic ketoacidosis), and to behavioral factors interfering with optimal treatment. Given that these events are occurring at a time of dynamic changes in brain structure and metabolic demand, it has been hypothesized that glycemic extremes could alter normal brain developmental trajectories depending on the age and severity at which these extremes are experienced. Researchers have attempted to determine the impact of diabetes, hypoglycemia, and hyperglycemia on brain structure and function in vivo using various neuroimaging techniques although few studies have examined these questions in children and youth with T1DM within a neurodevelopmental context. In this article, we review the current neuroimaging techniques available, describe the limited data in youth that address whether exposure to glycemic extremes in T1DM has any long-lasting consequences on the brain and its functions within a developmental perspective, and provide commentary on future directions for this field.
PMCID: PMC3857606  PMID: 24119040
brain; type 1 diabetes mellitus; children; neuroimaging; cognition
12.  Use of Social Media Across US Hospitals: Descriptive Analysis of Adoption and Utilization 
Use of social media has become widespread across the United States. Although businesses have invested in social media to engage consumers and promote products, less is known about the extent to which hospitals are using social media to interact with patients and promote health.
The aim was to investigate the relationship between hospital social media extent of adoption and utilization relative to hospital characteristics.
We conducted a cross-sectional review of hospital-related activity on 4 social media platforms: Facebook, Twitter, Yelp, and Foursquare. All US hospitals were included that reported complete data for the Centers for Medicare and Medicaid Services Hospital Consumer Assessment of Healthcare Providers and Systems survey and the American Hospital Association Annual Survey. We reviewed hospital social media webpages to determine the extent of adoption relative to hospital characteristics, including geographic region, urban designation, bed size, ownership type, and teaching status. Social media utilization was estimated from user activity specific to each social media platform, including number of Facebook likes, Twitter followers, Foursquare check-ins, and Yelp reviews.
Adoption of social media varied across hospitals with 94.41% (3351/3371) having a Facebook page and 50.82% (1713/3371) having a Twitter account. A majority of hospitals had a Yelp page (99.14%, 3342/3371) and almost all hospitals had check-ins on Foursquare (99.41%, 3351/3371). Large, urban, private nonprofit, and teaching hospitals were more likely to have higher utilization of these accounts.
Although most hospitals adopted at least one social media platform, utilization of social media varied according to several hospital characteristics. This preliminary investigation of social media adoption and utilization among US hospitals provides the framework for future studies investigating the effect of social media on patient outcomes, including links between social media use and the quality of hospital care and services.
PMCID: PMC4260061  PMID: 25431831
social media; Internet; health information
13.  Using a mobile app and mobile workforce to validate data about emergency public health resources 
Emergency medicine journal : EMJ  2013;10.1136/emermed-2012-202095.
Social media and mobile applications that allow people to work anywhere are changing the way people can contribute and collaborate.
We sought to determine the feasibility of using mobile workforce technology to validate the locations of automated external defibrillators (AEDs), an emergency public health resource.
We piloted the use of a mobile workforce application, to verify the location of 40 AEDs in Philadelphia county. AEDs were pre-identified in public locations for baseline data. The task of locating AEDs was posted online for a mobile workforce from October 2011 to January 2012. Participants were required to submit a mobile phone photo of AEDs and descriptions of the location.
Thirty-five of the 40 AEDs were identified within the study period. Most, 91% (32/35) of the submitted AED photo information was confirmed project baseline data. Participants also provided additional data such as business hours and other nearby AEDs.
It is feasible to engage a mobile workforce to complete health research-related tasks. Participants were able to validate information about emergency public health resources.
PMCID: PMC3883991  PMID: 23666486
14.  A Comparison of D2 Receptor Specific Binding in Obese and Normal-weight Individuals Using PET with (N-[11C]methyl)benperidol 
Synapse (New York, N.Y.)  2013;67(11):748-756.
Previous PET imaging studies have demonstrated mixed findings regarding dopamine D2/D3 receptor availability in obese relative to non-obese humans. Nonspecific D2/D3 radioligands do not allow for separate estimation of D2 receptor (D2R) and D3 receptor (D3R) subtypes of the D2 receptor family, which may play different roles in behavior and are distributed differently throughout the brain. These radioligands are also displaceable by endogenous dopamine, confounding interpretation of differences in receptor availability with differing levels of dopamine release. The present study used PET imaging with the D2R-selective radioligand (N-[11C] methyl)benperidol ([11C]NMB), which is non-displaceable by endogenous dopamine, to estimate D2R specific binding (BPND) and its relationship to body mass index (BMI) and age in 15 normal-weight (mean BMI = 22.6 kg/m2) and 15 obese (mean BMI = 40.3 kg/m2) men and women. Subjects with illnesses or taking medications that interfere with dopamine signaling were excluded. Striatal D2R BPND was calculated using the Logan graphical method with cerebellum as a reference region. D2R BPND estimates were higher in putamen and caudate relative to nucleus accumbens, but did not differ between normal-weight and obese groups. BMI values did not correlate with D2R BPND. Age was negatively correlated with putamen D2R BPND in both groups. These results suggest that altered D2R specific binding is not involved in the pathogenesis of obesity per se and underscore the need for additional studies evaluating the relationship between D3R, dopamine reuptake, or endogenous dopamine release and human obesity.
PMCID: PMC3778147  PMID: 23650017
dopamine; obesity; NMB
15.  White Matter Integrity and Executive Abilities Following Treatment with Tetrahydrobiopterin (BH4) in Individuals with Phenylketonuria 
Molecular genetics and metabolism  2013;110(3):10.1016/j.ymgme.2013.07.010.
Tetrahydrobiopterin (BH4) lowers blood phenylalanine (Phe) in individuals with PKU who are responders, but its effects on the brain and cognition have not been explored thoroughly. We examined blood Phe, microstructural white matter integrity, and executive abilities in 12 BH4 responders before (i.e., baseline) and after (i.e., follow-up) six months of treatment with BH4. Compared with baseline, Phe in these responders decreased by 51% during a 4 week screening period after initiation of treatment and remained lowered by 37% over the 6 month follow-up period. Significant improvements in white matter integrity, evaluated by mean diffusivity from diffusion tensor imaging, were also found following six months of treatment. Improvements in executive abilities were not identified, although six months may have been a period too brief for changes in cognition to follow changes in brain. To our knowledge, our study is the first to explore relationships among Phe, white matter integrity, executive abilities, and BH4 treatment within a single study.
PMCID: PMC3832288  PMID: 23928118
phenylketonuria; tetrahydrobiopterin; sapropterin; white matter; diffusion tensor imaging; executive
16.  Diesel exhaust particle induction of IL17A contributes to severe asthma 
The Journal of allergy and clinical immunology  2013;132(5):10.1016/j.jaci.2013.06.048.
IL-17A has been implicated in severe forms of asthma. However, the factors that promote IL-17A production during the pathogenesis of severe asthma remain undefined. Diesel exhaust particles (DEP) are a major component of traffic related air pollution and are implicated in asthma pathogenesis and exacerbation.
To determine the mechanism by which DEP exposure impacts asthma severity using human and mouse studies.
Balb/c mice were challenged with DEP +/− house dust mite extract (HDM). Airway inflammation and function, BALF cytokine levels, and flow cytometry of lung T cells were assessed. The impact of DEP exposure on frequency of asthma symptoms and serum cytokine levels was determined in children with allergic asthma.
In mice, exposure to DEP alone did not induce asthma. DEP and HDM co-exposure markedly enhanced AHR compared to HDM alone and generated a mixed Th2 and Th17 response, including IL-13+IL-17A+ double producing T-cells. IL-17A neutralization prevented DEP-induced exacerbation of AHR. Among 235 high DEP-exposed children with allergic asthma, 32.2% had more frequent asthma symptoms over a 12 month period, compared to only 14.2% in the low DEP-exposed group (p=0.002). Additionally, high DEP-exposed children with allergic asthma had nearly six times higher serum IL-17A levels compared with low DEP-exposed children.
Expansion of Th17 cells contributes to DEP-mediated exacerbation of allergic asthma. Neutralization of IL-17A may be a useful potential therapeutic strategy to counteract the asthma promoting effects of traffic related air pollution especially in highly exposed severe allergic asthmatics.
PMCID: PMC3845500  PMID: 24060272
allergic asthma; house dust mite; diesel exhaust particle; IL17A; Treg
17.  Upf1 Phosphorylation Triggers Translational Repression during Nonsense-Mediated mRNA Decay 
Cell  2008;133(2):314-327.
In mammalian cells, nonsense-mediated mRNA decay (NMD) generally requires that translation terminates sufficiently upstream of a post-splicing exon junction complex (EJC) during a pioneer round of translation. The subsequent binding of Upf1 to the EJC triggers Upf1 phosphorylation. We provide evidence that phospho-Upf1 functions after nonsense codon recognition during steps that involve the translation initiation factor eIF3 and mRNA decay factors. Phospho-Upf1 interacts directly with eIF3 and inhibits the eIF3-dependent conversion of 40S/Met-tRNAiMet/mRNA to translationally competent 80S/Met-tRNAiMet/mRNA initiation complexes to repress continued translation initiation. Consistent with phospho-Upf1 impairing eIF3 function, NMD fails to detectably target nonsense-containing transcripts that initiate translation independently of eIF3 from the CrPV IRES. There is growing evidence that translational repression is a key transition that precedes mRNA delivery to the degradation machinery. Our results uncover a critical step during NMD that converts a pioneer translation initiation complex to a translationally compromised mRNP.
PMCID: PMC4193665  PMID: 18423202
18.  IL-13 Receptor Alpha 2 Contributes to Development of Experimental Allergic Asthma 
The Journal of allergy and clinical immunology  2013;132(4):10.1016/j.jaci.2013.04.016.
IL-13 receptor alpha2 (IL-13Rα2) binds IL-13 with high affinity and modulates IL-13 responses. There are soluble and membrane forms of IL-13Rα2 generated by alternative splicing in mice but humans express only the membrane form (memIL-13Rα2).
We determined the role of memIL-13Rα2 in development of allergic inflammation in mouse models of asthma.
IL-13Rα2-deficient and memIL-13Rα2 lung epithelium-specific transgenic mice were challenged with house dust mite (HDM). Airway hyperresponsiveness (AHR) and inflammation were assessed by airway pressure time index, bronchoalveolar lavage (BAL) cell counts and lung histology. The mucus production was determined by periodic acid-Schiff (PAS) staining of lung sections, western blot analysis of chloride channel calcium activated 3 (CLCA3) expression in lung homogenates, and ELISA of Muc5ac in BAL fluid (BALF). The expression of cytokines and chemokines was determined by RT-quantitative PCR.
In IL-13Rα2-deficient mice, AHR and airway inflammation were attenuated compared to wild type mice following HDM challenge. Lung epithelium overexpression of memIL-13Rα2 in the IL-13Rα2-deficient mice reconstituted AHR and inflammation to levels similar to those observed in HDM-challenged wild type mice. Mucus production was attenuated in lungs from HDM-treated IL-13Rα2-deficient mice while lung epithelium overexpression of memIL-13Rα2 increased mucus production. Lung epithelium overexpression of memIL-13Rα2 had no effect on the levels of sIL-13Rα2 in the serum or BALF and did not affect IL-13-dependent STAT6 activation in the lungs.
These data collectively support a distinct role for memIL-13Rα2 in lung, and suggest that memIL-13Rα2 may contribute to allergic inflammation.
PMCID: PMC3836839  PMID: 23763980
IL-13; IL-13 receptor; lung; airway hyperresponsiveness; airway inflammation
19.  Exacerbation of allergen-induced eczema in TLR4 and TRIF deficient mice is mediated by TRIF 
Despite its presence on resident skin cells, the role of TLR4 in skin diseases remains poorly understood. This is highly significant since the skin biome is rich with potential TLR4 agonists. We aimed to establish the contribution of TLR4 to atopic dermatitis and determine the mechanism by which TLR4 acts in an experimental model of atopic dermatitis (AD). MyD88, TLR4, or TRIF-deficient and wild type (WT) mice were epicutaneously exposed to Aspergillus fumigatus allergen over three weeks. Impaired skin barrier function was assessed by measuring transepidermal water loss (TEWL). Skin levels of innate and adaptive genes were quantified. In an experimental model of AD, TEWL, allergic sensitization and epidermal thickness were increased following cutaneous allergen exposure and these were further enhanced in the absence of TLR4. Increased allergen-induced skin levels of innate (S100A8/A9, IL1β, TNFα and CXCL2) and Th17 genes (IL17A and IL17F) were observed in TLR4 deficient mice compared to wild type mice. The absence of MyD88 alleviated disease (decreased TEWL, skin thickness, proinflammatory cytokines) whereas TRIF deficiency exacerbated disease. In conclusion, signaling through the TLR4 and TRIF pathways limits skin barrier dysfunction, cutaneous allergic sensitization, and proinflammatory cytokine production.
PMCID: PMC3788607  PMID: 23997219
atopic dermatitis; skin; TLR4; TRIF; MyD88; IL1; IL17; TSLP; S100A8; S100A9
20.  Microbial content of household dust associated with exhaled NO in asthmatic children 
Environment international  2013;0:141-147.
Exhaled nitric oxide (eNO) is increasingly used as a non-invasive measure of airway inflammation. Despite this, little information exists regarding the potential effects of indoor microbial components on eNO. We determined the influence of microbial contaminants in house dust and other indoor environmental characteristics on eNO levels in seven-year-olds with and without a physician- diagnosis of asthma. The study included 158 children recruited from a birth cohort study, and 32 were physician-diagnosed as asthmatic. The relationship between eNO levels and exposures to home dust streptomycetes, endotoxin, and molds was investigated. Streptomycetes and endotoxin were analyzed both as loads and concentrations in separate models. Dog, cat, and dust mite allergens also were evaluated. In the multivariate exposure models high streptomycetes loads and concentrations were significantly associated with a decrease in eNO levels in asthmatic (p <0.001) but not in healthy children. The presence of dog allergen, however, was associated with increased levels of eNO (p = 0.001). Dust endotoxin was not significant. The relationship between eNO and indoor exposure to common outdoor molds was u-shaped. In non-asthmatic children, none of the exposure variables were significantly associated with eNO levels. To our knowledge, this is the first study demonstrating a significant association between microbial components in the indoor environment and eNO levels in asthmatic children. This study demonstrates the importance of simultaneously assessing multiple home exposures of asthmatic children to better understand opposing effects. Common components of the indoor Streptomyces community may beneficially influence airway inflammation.
PMCID: PMC3759577  PMID: 23807177
streptomycetes; mold; allergens; asthma; exhaled nitric oxide; children
21.  Natural or engineered mutations in Surfactant Protein-D alter allergic asthmatic responses in mice and man 
Surfactant protein D (SP-D) has been proposed to be protective in allergic airway responses.
We aimed to determine the effect of SP-D deficiency on murine and human airway allergy.
Immunological responses of SP-D gene deficient mice (Sftpd−/−) at baseline and following four Aspergillus fumigatus exposures were assessed. In addition, the significance of a single nucleotide polymorphism (Met11Thr) in the human SP-D gene (known to decrease SP-D function) on asthma susceptibility was investigated.
Macrophage BALF levels and lung CD-4+ T-cells were increased in naive Sftpd−/− mice in association with increased lung CCL17 levels. Th2-associated antibody levels (IgG1 and IgE) were significantly lower in 4–6 week old Sftpd−/− mice (p<0.05). Accordingly, naive Sftpd−/− splenocytes released significantly less IL-4 and IL-13 upon anti-CD3/CD28 stimulation (p<0.01). Following intranasal allergen exposures, a modest decrease in BALF eosinophilia was observed in Sftpd−/− mice compared to wild type mice (p<0.01). Translational studies in a pediatric population of Caucasians with asthma revealed that a single nucleotide polymorphism in the SFTPD gene, affecting SP-D levels and pathogen binding, was associated with lower asthma susceptibility (p<0.05).
Sftpd−/− mice have an impaired systemic Th2 response at baseline and modestly reduced pulmonary eosinophilia following allergen exposure. Translational studies revealed that a mutation in the SFTPD gene was associated with lower asthma susceptibility in Caucasians. Taken together, these results support the hypothesis that SP-D-dependent innate immunity influences atopy and asthma.
Clinical implications
SP-D deficiency results in increased pulmonary inflammation and decreased susceptibility to asthma, perhaps related to impaired endotoxin and pathogen clearance.
PMCID: PMC4145593  PMID: 18355911
allergy; lung; surfactant protein D; polymorphism; eosinophil; IL-13; Aspergillus; endotoxin
22.  Pediatric Discharge Content: A Multisite Assessment of Physician Preferences and Experiences 
Hospital pediatrics  2014;4(1):9-15.
Professional medical societies endorse prompt, consistent discharge communication to primary care providers (PCPs) on discharge. However, evidence is limited about what clinical elements to communicate. Our main goal was to identify and compare the clinical elements considered by PCPs and pediatric hospitalists to be essential to communicate to PCPs within 2 days of pediatric hospital discharge. A secondary goal was to describe experiences of the PCPs and pediatric hospitalists regarding sending and receiving discharge information.
A survey of physician preferences and experiences regarding discharge communication was sent to 320 PCPs who refer patients to 16 hospitals, with an analogous survey sent to 147 hospitalists. Descriptive statistics were calculated, and χ2 analyses were performed.
A total of 201 PCPs (63%) and 71 hospitalists (48%) responded to the survey. Seven clinical elements were reported as essential by >75% of both PCPs and hospitalists: dates of admission and discharge; discharge diagnoses; brief hospital course; discharge medications; immunizations given during hospitalization; pending laboratory or test results; and follow-up appointments. PCPs reported reliably receiving discharge communication significantly less often than hospitalists reported sending it (71.8% vs 85.1%; P < .01), and PCPs considered this communication to be complete significantly less often than hospitalists did (64.9% vs 79.1%; P < .01).
We identified 7 core clinical elements that PCPs and hospitalists consider essential in discharge communication. Consistently and promptly communicating at least these core elements after discharge may enhance PCP satisfaction and patient-level outcomes. Reported rates of transmission and receipt of this information were suboptimal and should be targeted for improvement.
PMCID: PMC4128020  PMID: 24435595
care coordination; collaborative; discharge communication; discharge content; handoffs; pediatric hospitalist; primary care provider; transitions of care
23.  Importance of Cytokines in Murine Allergic Airway Disease and Human Asthma1 
Asthma is a common, disabling inflammatory respiratory disease that has increased in frequency and severity in developed nations. We review studies of murine allergic airway disease (MAAD2) and human asthma that evaluate the importance of Th2 cytokines, Th2 response-promoting cytokines, IL-17 and pro- and anti-inflammatory cytokines in MAAD and human asthma. We discuss murine studies that directly stimulate airways with specific cytokines or delete, inactivate, neutralize or block specific cytokines or their receptors, as well as controversial issues, including the roles of IL-5, IL-17 and IL-13Rα2 in MAAD and IL-4Rα expression by specific cell types. Studies of human asthmatic cytokine gene and protein expression, linkage of cytokine polymorphisms to asthma, cytokine responses to allergen stimulation and clinical responses to cytokine antagonists are discussed as well. Results of these analyses establish the importance of specific cytokines in MAAD and human asthma and have therapeutic implications.
PMCID: PMC4122090  PMID: 20130218
24.  Mapping distributed brain function and networks with diffuse optical tomography 
Nature photonics  2014;8(6):448-454.
Mapping of human brain function has revolutionized systems neuroscience. However, traditional functional neuroimaging by positron emission tomography or functional magnetic resonance imaging cannot be used when applications require portability, or are contraindicated because of ionizing radiation (positron emission tomography) or implanted metal (functional magnetic resonance imaging). Optical neuroimaging offers a non-invasive alternative that is radiation free and compatible with implanted metal and electronic devices (for example, pacemakers). However, optical imaging technology has heretofore lacked the combination of spatial resolution and wide field of view sufficient to map distributed brain functions. Here, we present a high-density diffuse optical tomography imaging array that can map higher-order, distributed brain function. The system was tested by imaging four hierarchical language tasks and multiple resting-state networks including the dorsal attention and default mode networks. Finally, we imaged brain function in patients with Parkinson’s disease and implanted deep brain stimulators that preclude functional magnetic resonance imaging.
PMCID: PMC4114252  PMID: 25083161
25.  Where are lifesaving automated external defibrillators located and how hard is it to find them in a large urban city? 
Resuscitation  2013;84(7):910-914.
Automated external defibrillators (AEDs) are lifesaving, but little is known about where they are located or how to find them. We sought to locate AEDs in high employment areas of Philadelphia and characterize the process of door-to-door surveying to identify these devices.
Block groups representing approximately the top 3rd of total primary jobs in Philadelphia were identified using the US Census Local Employment Dynamics database. All buildings within these block groups were surveyed during regular working hours over six weeks during July-August 2011. Buildings were characterized as publically accessible or inaccessible. For accessible buildings, address, location type, and AED presence were collected. Total devices, location description and prior use were gathered in locations with AEDs. Process information (total people contacted, survey duration) was collected for all buildings.
Of 1420 buildings in 17 block groups, 949 (67%) were accessible, but most 834 (88%) did not have an AED. 283 AEDs were reported in 115 buildings (12%). 81 (29%) were validated through visualization and 68 (24%) through photo because employees often refused access. In buildings with AEDs, several employees (median 2; range 1–8) were contacted to ascertain information, which required several minutes (mean 4; range 1–55).
Door-to-door surveying is a feasible, but time-consuming method for identifying AEDs in high employment areas. Few buildings reported having AEDs and few permitted visualization, which raises concerns about AED access. To improve cardiac arrest outcomes, efforts are needed to improve the availability of AEDs, awareness of their location and access to them.
PMCID: PMC3679218  PMID: 23357702
AED; cardiac arrest; CPR; sudden death; surveying

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