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.
This study reveals novel insights into how Escherichia coli ribosomal protein S1 functions as an RNA chaperone on the ribosome, unfolding and positioning mRNAs for translation initiation.
Regulation of translation initiation is well appropriate to adapt cell growth in response to stress and environmental changes. Many bacterial mRNAs adopt structures in their 5′ untranslated regions that modulate the accessibility of the 30S ribosomal subunit. Structured mRNAs interact with the 30S in a two-step process where the docking of a folded mRNA precedes an accommodation step. Here, we used a combination of experimental approaches in vitro (kinetic of mRNA unfolding and binding experiments to analyze mRNA–protein or mRNA–ribosome complexes, toeprinting assays to follow the formation of ribosomal initiation complexes) and in vivo (genetic) to monitor the action of ribosomal protein S1 on the initiation of structured and regulated mRNAs. We demonstrate that r-protein S1 endows the 30S with an RNA chaperone activity that is essential for the docking and the unfolding of structured mRNAs, and for the correct positioning of the initiation codon inside the decoding channel. The first three OB-fold domains of S1 retain all its activities (mRNA and 30S binding, RNA melting activity) on the 30S subunit. S1 is not required for all mRNAs and acts differently on mRNAs according to the signals present at their 5′ ends. This work shows that S1 confers to the ribosome dynamic properties to initiate translation of a large set of mRNAs with diverse structural features.
Gene expression is regulated at multiple levels, including the decision of whether or not to translate a mRNA. This phenomenon, known as translational regulation, allows rapid changes in cellular concentrations of proteins and is well suited to the adjustment of cellular growth in response to stress and environmental changes. Many bacterial mRNAs adopt structures in their 5′ untranslated regions that modulate the accessibility of the mRNA to the small ribosomal 30S subunit and so are directly involved in this regulatory process. Structured mRNAs must interact with the 30S subunit in a two-step pathway whereby the docking of a folded mRNA is followed by an accommodation step that involves unfolding of these structures. However, it is not known how the ribosome unfolds mRNA structures to promote translation initiation, nor which ribosomal factors are responsible for this activity. We demonstrate that the first three domains of ribosomal protein S1 endow the 30S subunit with an RNA chaperone activity that is essential for the binding and unfolding of structured mRNAs, allowing the correct positioning of the initiation codon for translation. However, ribosomal protein S1 is not required for all mRNAs and acts differently depending on the type of regulatory elements present in a given mRNA. In all, we have shown that ribosomal protein S1 provides an RNA-melting activity to the exit site of the 30S decoding channel and confers some plasticity on the ribosome to initiate translation of mRNAs.
The central nervous system mechanisms of defenses against falling plasma glucose concentrations, and how they go awry and result in iatrogenic hypoglycemia in diabetes, are not known. Hypoglycemic plasma glucose concentrations of 55 mg/dL (3.0 mmol/L) cause symptoms, activate glucose counterregulatory systems, and increase synaptic activity in a network of brain regions including the dorsal midline thalamus in humans. We tested the hypothesis that slightly subphysiological plasma glucose concentrations of 65 mg/dL (3.6 mmol/L), which do not cause symptoms but do activate glucose counterregulatory systems, also activate brain synaptic activities.
RESEARCH DESIGN AND METHODS
We measured relative regional cerebral blood flow (rCBF), an index of synaptic activity, in predefined brain regions with [15O]water positron emission tomography, symptoms, and plasma epinephrine and glucagon concentrations during a 2-h euglycemic (90 mg/dL) to hypoglycemic (55 mg/dL) clamp (n = 20) or a 2-h euglycemic to slight subphysiological (65 mg/dL) clamp (n = 9) in healthy humans.
Clamped plasma glucose concentrations of 65 mg/dL did not cause hypoglycemic symptoms, but raised plasma epinephrine and glucagon concentrations and increased rCBF (P = 0.007) only in the dorsal midline thalamus.
Slightly subphysiological plasma glucose concentrations increase synaptic activity in the dorsal midline thalamus in humans.
There is considerable evidence supporting a role for mold exposure in the pathogenesis and expression of childhood asthma. Aspergillus versicolor and Cladosporium cladosporioides are common molds that have been implicated in asthma. In a model of mold-induced asthma, mice were repeatedly exposed to either A. versicolor or C. cladosporioides spores. The two molds induced distinct phenotypes and this effect was observed in both Balb/c and C57BL/6 strains. C. cladosporioides induced robust airway hyperresponsiveness (AHR), eosinophilia, and a predominately Th2 response, while A. versicolor induced a strong Th17 response and neutrophilic inflammation, but very mild AHR. Neutralization of IL-17A resulted in strong AHR and eosinophilic inflammation following A. versicolor exposure. In Dectin-1 deficient mice, A. versicolor exposure resulted in markedly attenuated IL-17A and robust AHR compared to wild type mice. In contrast, C. cladosporioides induced AHR and eosinophilic inflammation independent of IL-17A and Dectin-1. A. versicolor, but not C. cladosporioides, spores had increased exposure of beta-glucans on their surface and were able to bind Dectin-1. Thus, the host response to C. cladosporioides was IL-17A- and Dectin1-independent, while Dectin-1 and IL-17A-dependent pathways were protective against the development of asthma after exposure to A. versicolor.
IL-13 receptor α2 (IL-13Rα2) is a high-affinity receptor for IL-13, a central mediator of allergic asthma. It acts predominantly as a decoy receptor but can also contribute to IL-13 responses under certain conditions. IL-13Rα2 exists in soluble and membrane forms, which can both bind IL-13 and modulate its activity. Yet the proteolytic processes that contribute to the generation of soluble IL-13Rα2 are largely unknown.
We sought to investigate the role of matrix metalloproteinases (MMPs) in the generation of soluble IL-13Rα2.
Acellular cleavage assays by MMPs were performed by using glutathione-S-transferase fusion proteins of murine or human IL-13Rα2. IL-13Rα2 stable-transfected cells were used for analysis of surface expression and release of soluble IL-13Rα2. Wild-type and MMP-8–deficient mice were used for analysis of allergen-induced airway hyperresponsiveness and solubilization of IL-13Rα2.
Among several MMPs tested, only MMP-8 cleaved IL-13Rα2. Treatment of transfected human or murine cells expressing high levels of surface IL-13Rα2 with MMP-8 resulted in release of soluble IL-13Rα2 into the supernatants, with a concomitant decrease in surface IL-13Rα2 levels. The IL-13Rα2 solubilized by MMP-8 retained IL-13 binding activity. In an asthma model MMP-8–deficient mice displayed increased airway hyperresponsiveness and decreased soluble IL-13Rα2 protein levels in bronchoalveolar lavage fluid compared with those seen in wild-type mice after house dust mite challenge.
MMP-8 cleaves IL-13Rα2 in vitro and contributes to the solubilization of IL-13Rα2 in vivo.
Matrix metalloproteinase 8; IL-13; IL-13 receptor α2
Small proline rich protein 2B (SPRR2B) is a skin and lung epithelial protein associated with allergic inflammation in mice that has not been evaluated in human atopic diseases.
To determine whether single-nucleotide polymorphisms (SNPs) in SPRR2B are associated with childhood eczema and with the phenotype of childhood eczema combined with asthma.
Genotyping for SPRR2B and filaggrin (FLG) was performed in 2 independent populations: the Cincinnati Childhood Allergy & Air Pollution Study (CCAAPS; N = 762; birth-age, 4 years) and the Greater Cincinnati Pediatric Clinical Repository (GCPCR;N = 1152; ages 5–10 years). Eczema and eczema plus asthma were clinical outcomes based on parental report and clinician’s diagnosis. Genetic analyses were restricted to whites and adjusted for sex in both cohorts and adjusted for environmental covariates in CCAAPS.
Variants in SPRR2B were not significantly associated with eczema in either cohort after Bonferroni adjustment. Children from both cohorts with the CC genotype of the SPRR2B rs6693927 SNP were at 4 times the risk for eczema plus asthma (adjusted odds ratio, 4.1; 95% confidence interval, 1.5– 10.9; P = .005 in CCAAPS; and adjusted odds ratio, 4.0; 95% confidence interval, 1.8 –9.1; P <.001 in the GCPCR), however. SNPs in SPRR2B were not in strong linkage disequilibrium with the R501X and del2282 FLG mutations, and these findings were independent of FLG.
An SNP in SPRR2B was predictive of asthma among white children with eczema from 2 independent populations. SPRR2B polymorphisms may serve as important predictive markers for the combined eczema plus asthma phenotype.
The specific cause(s) of asthma development must be identified in order to prevent this disease.
Our hypothesis was that specific mold exposures are associated with childhood asthma development.
Infants were identified from birth certificates. Dust samples were collected from 289 homes when the infants were age eight months. Samples were analyzed for concentrations of 36 molds that comprise the Environmental Relative Moldiness Index (ERMI) and endotoxin, house dust mite, cat, dog, and cockroach allergens. Children were evaluated at age seven for asthma based on reported symptoms and objective measures of lung function. Host, environmental exposures and home characteristics evaluated included history of parental asthma, race, gender, upper and lower respiratory symptoms, season of birth, family income, cigarette smoke exposure, air conditioning, dehumidifier, carpeting, age of home, and visible mold at age one and child positive skin prick test (SPT) to aeroallergens and molds at age seven.
Asthma was diagnosed in 24% of the children at age seven. A statistically significant increase in asthma risk at age seven was associated with high ERMI levels in the child’s home in infancy (adjusted risk ratio (aRR) for a 10-unit increase in ERMI = 1.8, 95% CI=1.5, 2.2). The summation of levels of three mold species, Aspergillus ochraceus, Aspergillus unguis, and Penicillium variabile was significantly associated with asthma (aRR = 2.2, 95% CI=1.8, 2.7).
In this birth cohort study, exposure during infancy to three mold species common to water-damaged buildings was associated with childhood asthma at age seven.
Asthma; molds; speciation; infants; Environmental Relative Moldiness Index
The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia®) in select solid tumors in dogs. Cases in which toceranib was used to treat dogs with anal sac anal gland adenocarcinoma, metastatic osteosarcoma, thyroid carcinoma, head and neck carcinoma, and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 anal sac tumors (8PR, 20SD), 11/23 osteosarcomas (1PR, 10SD), 12/15 thyroid carcinomas (4PR, 8SD), 7/8 head and neck carcinomas (1CR, 5PR, 1SD) and 5/7 (1CR, 4SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg/kg, 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis, and 47/63 (74.6%) were treated 4 months or longer. While these data povide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumors, future prospective studies are necessary to define its true activity.
toceranib; dog; tumor; carcinoma; sarcoma
Pretreatment brain activity in major depressive disorder correlates with response to antidepressant therapies, including pharmacotherapies and transcranial magnetic stimulation. The purpose of this trial was to examine whether pretreatment regional metabolic activity in selected regions of interest (ROIs) predicts antidepressant response following 12 months of vagus nerve stimulation (VNS) in 15 patients with treatment-resistant major depression (TRMD).
Fluorodeoxyglucose positron emission tomography (FDG PET) was used to assess regional mean relative cerebral metabolic rate for glucose (CMRGlu) in four ROIs (anterior insular, orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices) at baseline (prior to VNS activation). Depression severity was assessed at baseline and after 12 months of VNS using the Hamilton Depression Rating Scale (HDRS), with response defined as ≥50% reduction in HDRS from baseline.
Baseline CMRGlu in the anterior insular cortex differentiated VNS responders (n = 11) from nonresponders (n = 4) and correlated with HDRS change (r = .64, p = .01). In a regression analysis, lower anterior insular cortex CMRGlu (p = .004) and higher orbitofrontal cortex CMRGlu (p = .047) together predicted HDRS change (R2 = .58, p = .005). In a whole brain, voxel-wise analysis, baseline CMRGlu in the right anterior insular cortex correlated with HDRS change (r = .78, p = .001).
Sample size was small, limiting statistical power; patients remained on their psychiatric medications; study was open-label and uncontrolled.
This preliminary study suggests that pretreatment regional CMRGlu may be useful in predicting response to VNS in TRMD patients.
Vagus nerve stimulation; Depression; Positron emission tomography; Treatment-resistant depression; Fluorodeoxyglucose PET; Treatment response
IL-17A is produced from Th17 cells, and is involved in many autoimmune and inflammatory diseases. The IL-13 receptor (IL-13R) has not previously been reported to be functionally expressed on T cells; however, we found that purified BALB/c CD4+ cells polarized to Th17 with TGF-β, IL-6, and IL-23 have increased mRNA and protein expression of IL-13Rα1 and mRNA expression of IL-4Rα compared to Th0, Th1, or Th2 polarized cells. The addition of IL-13 at Th17 polarization negatively regulated IL-17A and IL-21 expression, and reduced the number of CD4+ T cells producing IL-17A. Further, adding IL-13 at the time of Th17 cell restimulation attenuated IL-17A expression. CD4+ Th17 polarized cells from IL-4 KO mice also had IL-13-induced inhibition of IL-17A production, but this was not observed in IL-4R KO and STAT6 KO mice. Addition of IL-13 at polarization increased IL-13R expression in WT Th17 cells. Further, IL-13 administration during Th17 polarization downregulated ROR-γT, the transcription required for Th17 development; increased STAT6 phosphorylation, and upregulated GATA3, the transcription factor activated during the development of Th2 cells. This IL-13-mediated effect was specific to Th17 cells as IL-13 neither decreased IFN-γ expression by Th1 cells nor affected Th2 cell production of IL-4. Collectively, we have shown that Th17 cells express a functional IL-13R and that IL-13 negatively regulates IL-17A and IL-21 production by decreasing ROR-γT expression and while increasing phosphorylation of STAT6 and GATA3 expression. Therefore, therapeutic intervention inhibiting IL-13 production could have adverse consequences by upregulating Th17 inflammation in certain disease states.
T cells; cytokines; cytokine receptors
Wolfram syndrome (WFS), a rare neurodegenerative disorder, is characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities. Although previously unreported, we hypothesized that neurological complications may be detectable in relatively early stages of the disease. As the cerebellum and brainstem seem particularly vulnerable in WFS, we focused on balance functions critically dependent on these regions. The primary goal of this investigation was to compare balance in young individuals with WFS, in relatively early stages of the disease, to an age-matched cohort using a clinically applicable test.
Balance was assessed via the mini-BESTest in 13 children, adolescents and young adults with WFS and 30 typically developing age-matched individuals.
A significant difference was observed between groups in balance as well as in three of four subcomponents of the mini-BESTest and in two timed tasks related to balance. Mini-BESTest scores were correlated with age (p < 0.001, rs = 0.59) among typically developing individuals. In the WFS group, mini-BESTest scores were related to overall motor dysfunction, but not age.
Impairments in balance in WFS may occur earlier in the disease process than previously recognized and appear to be related to overall neurological progression rather than chronological age. Recognizing balance impairments and understanding which balance systems contribute to balance deficits in those with WFS may allow for development of effective patient-centered treatment paradigms.
Wolfram syndrome; balance; neurodevelopment; pediatric rehabilitation; clinical scale
The standard approach to determine unique or shared genetic factors across populations is to identify risk alleles in one population and investigate replication in others. However, since populations differ in DNA sequence information, allele frequencies, effect sizes, and linkage disequilibrium patterns, SNP association using a uniform stringent threshold on p values may not be reproducible across populations. Here, we developed rank-based methods to investigate shared or population-specific loci and pathways for childhood asthma across individuals of diverse ancestry. We performed genome-wide association studies on 859,790 SNPs genotyped in 527 affected offspring trios of European, African, and Hispanic ancestry using publically available asthma database in the Genotypes and Phenotypes database.
Rank-based analyses showed that there are shared genetic factors for asthma across populations, more at the gene and pathway levels than at the SNP level. Although the top 1,000 SNPs were not shared, 11 genes (RYR2, PDE4D, CSMD1, CDH13, ROBO2, RBFOX1, PTPRD, NPAS3, PDE1C, SEMA5A, and CTNNA2) mapped by these SNPs were shared across populations. Ryanodine receptor 2 (RYR2, a statin response-related gene) showed the strongest association in European (p value = 2.55 × 10−7) and was replicated in African (2.57 × 10−4) and Hispanic (1.18 × 10−3) Americans. Imputation analyses based on the 1000 Genomes Project uncovered additional RYR2 variants associated with asthma. Network and functional ontology analyses revealed that RYR2 is an integral part of dermatological or allergic disorder biological networks, specifically in the functional classes involving inflammatory, eosinophilic, and respiratory diseases.
Our rank-based genome-wide analysis revealed for the first time an association of RYR2 variants with asthma and replicated previously discovered PDE4D asthma gene across human populations. The replication of top-ranked asthma genes across populations suggests that such loci are less likely to be false positives and could indicate true associations. Variants that are associated with asthma across populations could be used to identify individuals who are at high risk for asthma regardless of genetic ancestry.
Asthma; GWAS; Ancestry; Trans-ancestral analysis; Rank analysis; Imputation; dbGaP; 1000 Genomes project; Networks/pathways, RYR2
A wealth of genomic information is available in public and private databases. However, this information is underutilized for uncovering population specific and functionally relevant markers underlying complex human traits. Given the huge amount of SNP data available from the annotation of human genetic variation, data mining is a faster and cost effective approach for investigating the number of SNPs that are informative for ancestry. In this study, we present AncestrySNPminer, the first web-based bioinformatics tool specifically designed to retrieve Ancestry Informative Markers (AIMs) from genomic data sets and link these informative markers to genes and ontological annotation classes. The tool includes an automated and simple “scripting at the click of a button” functionality that enables researchers to perform various population genomics statistical analyses methods with user friendly querying and filtering of data sets across various populations through a single web interface. AncestrySNPminer can be freely accessed at https://research.cchmc.org/mershalab/AncestrySNPminer/login.php.
Ancestry; Ancestry informative markers; AIMs; Bioinformatics; AncestrySNPminer; Data mining; Admixture; Admixture mapping
The objectives of this study were to assess comorbid psychiatric diagnoses in youth with chronic daily headache (CDH) and to examine relationships between psychiatric status and CDH symptom severity, as well as headache-related disability.
Standardized psychiatric interviews (Kiddie Schedule for Affective Disorders and Schizophrenia, KSADS) were conducted with 169 youth ages 10–17 diagnosed with CDH. Participants provided prospective reports of headache frequency with a daily headache diary and completed measures of symptom severity, headache-related disability (PedMIDAS) and quality of life (PedsQL).
Results showed that 29.6% of CDH patients met criteria for at least one current psychiatric diagnosis, and 34.9% met criteria for at least one lifetime psychiatric diagnosis. No significant relationship between psychiatric status and headache frequency, duration, or severity was found. However, children with at least one lifetime psychiatric diagnosis had greater functional disability and poorer quality of life than those without a psychiatric diagnosis.
Contrary to research in adults with chronic headaches, most youth with CDH did not appear to be at an elevated risk for comorbid psychiatric diagnosis. However, patients with a comorbid psychiatric diagnosis were found to have higher levels of headache-related disability and poorer quality of life. Implications for treatment are discussed.
Chronic daily headache; pediatric; psychiatric comorbidity; emotional adjustment; headache-related disability; quality of life
Developing sensors for in vivo chemical monitoring is a daunting challenge. An alternative approach is to couple sampling methods with online analytical techniques; however, such approaches are generally hampered by lower temporal resolution and slow analysis. In this work, microdialysis sampling was coupled with segmented flow electrospray ionization mass spectrometry (ESI-MS) to perform in vivo chemical monitoring. Use of segmented flow to prevent Taylor dispersion of collected zones and rapid analysis with direct ESI-MS allowed 5 s temporal resolution to be achieved. The MS “sensor” was applied to monitoring acetylcholine in the brain of live rats. The detection limit of 5 nM was sufficient to monitor basal acetylcholine as well as dynamic changes elicited by microinjection of neostigmine, an inhibitor of acetycholinesterase that evoked rapid increases in acetycholine, and tetrodotoxin, a blocker of Na+ channels, that lowered the acetylcholine concentration. The versatility of the sensor was demonstrated by simultaneously monitoring metabolites and infused drugs.
Secondhand smoke is associated with a myriad of adverse health outcomes. Therefore, it is essential for clinicians to ask precise questions about exposures, particularly for children. We present 4 questions that incorporate several locations of exposure and provide a more comprehensive account of children’s smoke exposures than maternal smoking alone.
Background: There is increasing concern about the potential effects of traffic-related air pollution (TRAP) on the developing brain. The impact of TRAP exposure on childhood behavior is not fully understood because of limited epidemiologic studies.
Objective: We explored the association between early-life exposure to TRAP using a surrogate, elemental carbon attributed to traffic (ECAT), and attention deficit/hyperactivity disorder (ADHD) symptoms at 7 years of age.
Methods: From the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort we collected data on exposure to ECAT during infancy and behavioral scores at 7 years of age. Children enrolled in CCAAPS had at least one atopic parent and a birth residence either < 400 m or > 1,500 m from a major highway. Children were followed from infancy through 7 years of age. ECAT exposure during the first year of life was estimated based on measurements from 27 air sampling sites and land use regression modeling. Parents completed the Behavioral Assessment System for Children, 2nd Edition, when the child was 7 years of age. ADHD-related symptoms were assessed using the Hyperactivity, Attention Problems, Aggression, Conduct Problems, and Atypicality subscales.
Results: Exposure to the highest tertile of ECAT during the child’s first year of life was significantly associated with Hyperactivity T-scores in the “at risk” range at 7 years of age, after adjustment [adjusted odds ratio (aOR) = 1.7; 95% CI: 1.0, 2.7]. Stratification by maternal education revealed a stronger association in children whose mothers had higher education (aOR = 2.3; 95% CI: 1.3, 4.1).
Conclusions: ECAT exposure during infancy was associated with higher Hyperactivity scores in children; this association was limited to children whose mothers had more than a high school education.
attention deficit/hyperactivity disorder; child behavior; epidemiology; land use regression; traffic-related air pollution
Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions.
Eighteen subjects (ages 5.9–25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging.
Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 ± 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 ± 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume.
WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression.
Diabetes mellitus; DIDMOAD; Diabetes insipidus; Hearing loss; Optic atrophy; Color blindness; Neurodegenerative disorder
Diesel exhaust particle (DEP) exposure enhances allergic inflammation and has been linked to the incidence of asthma. Oxidative stress on the thiol molecules cysteine (Cys) and glutathione (GSH) can promote inflammatory host responses. The effect of DEP on the thiol oxidation/reduction (redox) state in the asthmatic lung is unknown.
To determine if DEP exposure alters the Cys or GSH redox state in the asthmatic airway.
Bronchoalveolar lavage fluid was obtained from a house dust mite (HDM) induced murine asthma model exposed to DEP. GSH, glutathione disulfide (GSSG), Cys, cystine (CySS), and s-glutathionylated cysteine (CySSG) were determined by high pressure liquid chromatography.
DEP co-administered with HDM, but not DEP or HDM alone, decreased total Cys, increased CySS, and increased CySSG without significantly altering GSH or GSSG.
DEP exposure promotes oxidation and S-glutathionylation of cysteine amino acids in the asthmatic airway, suggesting a novel mechanism by which DEP may enhance allergic inflammatory responses.
Different brain regions sense and modulate the counterregulatory responses that can occur in response to declining plasma glucose levels. The aim of this study was to determine if changes in regional cerebral blood flow (rCBF) during hypoglycemia relative to euglycemia are similar for two imaging modalities–pulsed arterial spin labeling magnetic resonance imaging (PASL-MRI) and positron emission tomography (PET). Nine healthy non-diabetic participants underwent a hyperinsulinemic euglycemic (92±3 mg/dL) – hypoglycemic (53±1 mg/dL) clamp. Counterregulatory hormone levels were collected at each of these glycemic levels and rCBF measurements within the previously described network of hypoglycemia-responsive regions (thalamus, medial prefrontal cortex and globus pallidum) were obtained using PASL-MRI and [15O] water PET. In response to hypoglycemia, rCBF was significantly increased in the thalamus, medial prefrontal cortex, and globus pallidum compared to euglycemia for both PASL-MRI and PET methodologies. Both imaging techniques found similar increases in rCBF in the thalamus, medial prefrontal cortex, and globus pallidum in response to hypoglycemia. These brain regions may be involved in the physiologic and symptom responses to hypoglycemia. Compared to PET, PASL-MRI may provide a less invasive, less expensive method for assessing changes in rCBF during hypoglycemia without radiation exposure.
Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.
We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.
An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.
Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology® 2012;78:690–695
The mammalian target of rapamycin (mTOR) plays an important role in cell growth/differentiation, integrating environmental cues, and regulating immune responses. Our lab previously demonstrated that inhibition of mTOR with rapamycin prevented house dust mite (HDM)-induced allergic asthma in mice. Here, we utilized two treatment protocols to investigate whether rapamycin, compared to the steroid, dexamethasone, could inhibit allergic responses during the later stages of the disease process, namely allergen re-exposure and/or during progression of chronic allergic disease. In protocol 1, BALB/c mice were sensitized to HDM (three i.p. injections) and administered two intranasal HDM exposures. After 6 weeks of rest/recovery, mice were re-exposed to HDM while being treated with rapamycin or dexamethasone. In protocol 2, mice were exposed to HDM for 3 or 6 weeks and treated with rapamycin or dexamethasone during weeks 4–6. Characteristic features of allergic asthma, including IgE, goblet cells, airway hyperreactivity (AHR), inflammatory cells, cytokines/chemokines, and T cell responses were assessed. In protocol 1, both rapamycin and dexamethasone suppressed goblet cells and total CD4+ T cells including activated, effector, and regulatory T cells in the lung tissue, with no effect on AHR or total inflammatory cell numbers in the bronchoalveolar lavage fluid. Rapamycin also suppressed IgE, although IL-4 and eotaxin 1 levels were augmented. In protocol 2, both drugs suppressed total CD4+ T cells, including activated, effector, and regulatory T cells and IgE levels. IL-4, eotaxin, and inflammatory cell numbers were increased after rapamycin and no effect on AHR was observed. Dexamethasone suppressed inflammatory cell numbers, especially eosinophils, but had limited effects on AHR. We conclude that while mTOR signaling is critical during the early phases of allergic asthma, its role is much more limited once disease is established.
Exacerbation of migraine with menses is common in adolescent girls and women with migraine, occurring in up to 60% of females with migraine. These migraines are oftentimes longer and more disabling and may be related to estrogen levels and hormonal fluctuations.
This study identifies the unique genomic expression pattern of menstrually-related migraine (MRM) in comparison to migraine occurring outside the menstrual period and headache free controls.
Whole blood samples were obtained from female subjects having an acute migraine during their menstrual period (MRM) or outside of their menstrual period (nonMRM) and controls (C) – females having a menstrual period without any history of headache. The mRNA was isolated from these samples and genomic profile was assessed. Affymetrix Human Exon ST 1.0 arrays were used to examine the genomic expression pattern differences between these three groups.
Blood genomic expression patterns were obtained on 56 subjects (MRM = 18, nonMRM = 18 and C = 20). Unique genomic expression patterns were observed for both MRM and nonMRM. For MRM, 77 genes were identified that were unique to MRM, while 61 genes were commonly expressed for MRM and nonMRM and 127 genes appeared to have a unique expression pattern for nonMRM. In addition, there were 279 genes that differentially expressed for MRM compared to nonMRM that were not differentially expressed for nonMRM. Gene ontology of these samples indicated many of these groups of genes were functionally related and included categories of immunomodulation/inflammation, mitochondrial function and DNA homeostasis.
Blood genomic patterns can accurately differentiate MRM from nonMRM. These results indicate that MRM involves a unique molecular biology pathway that can be identified with a specific biomarker and suggest that individuals with MRM have a different underlying genetic etiology.
Migraine; Pediatric Headache; Adolescent Headaches; Menstrual Migraine; Gene Expression; Microarray; Personalized Medicine