Update on Gastroesophageal Reflux and Respiratory Disease in Children

Pediatric respiratory diseases have been linked to gastroesophageal reflux disease (GERD), but evidence regarding the association and its potential mechanisms continues to accumulate, and important aspects remain to be determined. Evidence for the association in two common pediatric respiratory disorders - infantile apnea and asthma in older children - and difficult clinical issues associated with the diagnosis and treatment of these two disorders are reviewed. The provocative embryological and physiological connections between the upper gastrointestinal tract and the respiratory tract, and recent understanding of the compensatory anatomy and physiology that protect the normal individual from respiratory manifestations of GERD are also explored. Dysfunctions of these protections likely underlie the pathophysiology of these disorders

Prenatal Organochlorine and Methylmercury Exposure and Memory and Learning in School-Age Children in Communities Near the New Bedford Harbor Superfund Site, Massachusetts

Background: Polychlorinated biphenyls (PCBs), organochlorine pesticides, and methylmercury (MeHg) are environmentally persistent with adverse effects on neurodevelopment. However, especially among populations with commonly experienced low levels of exposure, research on neurodevelopmental effects of these toxicants has produced conflicting results. Objectives: We assessed the association of low-level prenatal exposure to these contaminants with memory and learning. Methods: We studied 393 children, born between 1993 and 1998 to mothers residing near a PCB-contaminated harbor in New Bedford, Massachusetts. Cord serum PCB, DDE (dichlorodiphenyldichloroethylene), and maternal peripartum hair mercury (Hg) levels were measured to estimate prenatal exposure. Memory and learning were assessed at 8 years of age (range, 7–11 years) using the Wide Range Assessment of Memory and Learning (WRAML), age-standardized to a mean ± SD of 100 ± 15. Associations with each WRAML index—Visual Memory, Verbal Memory, and Learning—were examined with multivariable linear regression, controlling for potential confounders. Results: Although cord serum PCB levels were low (sum of four PCBs: mean, 0.3 ng/g serum; range, 0.01–4.4), hair Hg levels were typical of the U.S. fish-eating population (mean, 0.6 μg/g; range, 0.3–5.1). In multivariable models, each microgram per gram increase in hair Hg was associated with, on average, decrements of –2.8 on Visual Memory (95% CI: –5.0, –0.6, p = 0.01), –2.2 on Learning (95% CI: –4.6, 0.2, p = 0.08), and –1.7 on Verbal Memory (95% CI: –3.9, 0.6, p = 0.14). There were no significant adverse associations of PCBs or DDE with WRAML indices. Conclusions: These results support an adverse relationship between low-level prenatal MeHg exposure and childhood memory and learning, particularly visual memory. Citation: Orenstein ST, Thurston SW, Bellinger DC, Schwartz JD, Amarasiriwardena CJ, Altshul LM, Korrick SA. 2014. Prenatal organochlorine and methylmercury exposure and memory and learning in school-age children in communities near the New Bedford Harbor Superfund Site, Massachusetts. Environ Health Perspect 122:1253–1259; http://dx.doi.org/10.1289/ehp.130780

The transcriptional profile of coronary arteritis in Kawasaki disease

BackgroundKawasaki Disease (KD) can cause potentially life-threatening coronary arteritis in young children, and has a likely infectious etiology. Transcriptome profiling is a powerful approach to investigate gene expression in diseased tissues. RNA sequencing of KD coronary arteries could elucidate the etiology and the host response, with the potential to improve KD diagnosis and/or treatment.MethodsDeep RNA sequencing was performed on KD (n = 8) and childhood control (n = 7) coronary artery tissues, revealing 1074 differentially expressed mRNAs. Non-human RNA sequences were subjected to a microbial discovery bioinformatics platform, and microbial sequences were analyzed by Metastats for association with KD.ResultsT lymphocyte activation, antigen presentation, immunoglobulin production, and type I interferon response were significantly upregulated in KD arteritis, while the tumor necrosis factor α pathway was not differentially expressed. Transcripts from known infectious agents were not specifically associated with KD coronary arteritis.ConclusionsThe immune transcriptional profile in KD coronary artery tissues has features of an antiviral immune response such as activated cytotoxic T lymphocyte and type I interferon-induced gene upregulation. These results provide new insights into the pathogenesis of KD arteritis that can guide selection of new immunomodulatory therapies for high-risk KD patients, and provide direction for future etiologic studies

The effect of time since measles vaccination and age at first dose on measles vaccine effectiveness - A systematic review.

BACKGROUND: In settings where measles has been eliminated, vaccine-derived immunity may in theory wane more rapidly due to a lack of immune boosting by circulating measles virus. We aimed to assess whether measles vaccine effectiveness (VE) waned over time, and if so, whether differentially in measles-eliminated and measles-endemic settings. METHODS: We performed a systematic literature review of studies that reported VE and time since vaccination with measles-containing vaccine (MCV). We extracted information on case definition (clinical symptoms and/or laboratory diagnosis), method of vaccination status ascertainment (medical record or vaccine registry), as well as any biases which may have arisen from cold chain issues and a lack of an age at first dose of MCV. We then used linear regression to evaluate VE as a function of age at first dose of MCV and time since MCV. RESULTS: After screening 14,782 citations, we identified three full-text articles from measles-eliminated settings and 33 articles from measles-endemic settings. In elimination settings, two-dose VE estimates increased as age at first dose of MCV increased and decreased as time since MCV increased; however, the small number of studies available limited interpretation. In measles-endemic settings, one-dose VE increased by 1.5% (95% CI 0.5, 2.5) for every month increase in age at first dose of MCV. We found no evidence of waning VE in endemic settings. CONCLUSIONS: The paucity of data from measles-eliminated settings indicates that additional studies and approaches (such as studies using proxies including laboratory correlates of protection) are needed to answer the question of whether VE in measles-eliminated settings wanes. Age at first dose of MCV was the most important factor in determining VE. More VE studies need to be conducted in elimination settings, and standards should be developed for information collected and reported in such studies

RNA-Containing Cytoplasmic Inclusion Bodies in Ciliated Bronchial Epithelium Months to Years after Acute Kawasaki Disease

Kawasaki Disease (KD) is the most common cause of acquired heart disease in children in developed nations. The KD etiologic agent is unknown but likely to be a ubiquitous microbe that usually causes asymptomatic childhood infection, resulting in KD only in genetically susceptible individuals. KD synthetic antibodies made from prevalent IgA gene sequences in KD arterial tissue detect intracytoplasmic inclusion bodies (ICI) resembling viral ICI in acute KD but not control infant ciliated bronchial epithelium. The prevalence of ICI in late-stage KD fatalities and in older individuals with non-KD illness should be low, unless persistent infection is common.Lung tissue from late-stage KD fatalities and non-infant controls was examined by light microscopy for the presence of ICI. Nucleic acid stains and transmission electron microscopy (TEM) were performed on tissues that were strongly positive for ICI. ICI were present in ciliated bronchial epithelium in 6/7 (86%) late-stage KD fatalities and 7/27 (26%) controls ages 9-84 years (p = 0.01). Nucleic acid stains revealed RNA but not DNA within the ICI. ICI were also identified in lung macrophages in some KD cases. TEM of bronchial epithelium and macrophages from KD cases revealed finely granular homogeneous ICI.These findings are consistent with a previously unidentified, ubiquitous RNA virus that forms ICI and can result in persistent infection in bronchial epithelium and macrophages as the etiologic agent of KD

Challenges and perspectives on tackling illegal or unsustainable wildlife trade

Illegal or unsustainable wildlife trade (IUWT) currently presents one of the most high-profile conservation challenges. There is no “one-size-fits-all” strategy, and a variety of disciplines and actors are needed for any counteractive approach to work effectively. Here, we detail common challenges faced when tackling IUWT, and we describe some available tools and technologies to curb and track IUWT (e.g. bans, quotas, protected areas, certification, captive-breeding and propagation, education and awareness). We discuss gaps to be filled in regulation, enforcement, engagement and knowledge about wildlife trade, and propose practical solutions to regulate and curb IUWT, paving the road for immediate action

Three Linked Vasculopathic Processes Characterize Kawasaki Disease: A Light and Transmission Electron Microscopic Study

Kawasaki disease is recognized as the most common cause of acquired heart disease in children in the developed world. Clinical, epidemiologic, and pathologic evidence supports an infectious agent, likely entering through the lung. Pathologic studies proposing an acute coronary arteritis followed by healing fail to account for the complex vasculopathy and clinical course.Specimens from 32 autopsies, 8 cardiac transplants, and an excised coronary aneurysm were studied by light (n=41) and transmission electron microscopy (n=7). Three characteristic vasculopathic processes were identified in coronary (CA) and non-coronary arteries: acute self-limited necrotizing arteritis (NA), subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). NA is a synchronous neutrophilic process of the endothelium, beginning and ending within the first two weeks of fever onset, and progressively destroying the wall into the adventitia causing saccular aneurysms, which can thrombose or rupture. SA/C vasculitis is an asynchronous process that can commence within the first two weeks onward, starting in the adventitia/perivascular tissue and variably inflaming/damaging the wall during progression to the lumen. Besides fusiform and saccular aneurysms that can thrombose, SA/C vasculitis likely causes the transition of medial and adventitial smooth muscle cells (SMC) into classic myofibroblasts, which combined with their matrix products and inflammation create progressive stenosing luminal lesions (SA/C-LMP). Remote LMP apparently results from circulating factors. Veins, pulmonary arteries, and aorta can develop subclinical SA/C vasculitis and SA/C-LMP, but not NA. The earliest death (day 10) had both CA SA/C vasculitis and SA/C-LMP, and an "eosinophilic-type" myocarditis.NA is the only self-limiting process of the three, is responsible for the earliest morbidity/mortality, and is consistent with acute viral infection. SA/C vasculitis can begin as early as NA, but can occur/persist for months to years; LMP causes progressive arterial stenosis and thrombosis and is composed of unique SMC-derived pathologic myofibroblasts

Adoption of an “Open” Envelope Conformation Facilitating CD4 Binding and Structural Remodeling Precedes Coreceptor Switch in R5 SHIV-Infected Macaques

A change in coreceptor preference from CCR5 to CXCR4 towards the end stage disease in some HIV-1 infected individuals has been well documented, but the reasons and mechanisms for this tropism switch remain elusive. It has been suggested that envelope structural constraints in accommodating amino acid changes required for CXCR4 usage is an obstacle to tropism switch, limiting the rate and pathways available for HIV-1 coreceptor switching. The present study was initiated in two R5 SHIVSF162P3N-infected rapid progressor macaques with coreceptor switch to test the hypothesis that an early step in the evolution of tropism switch is the adoption of a less constrained and more “open” envelope conformation for better CD4 usage, allowing greater structural flexibility to accommodate further mutational changes that confer CXCR4 utilization. We show that, prior to the time of coreceptor switch, R5 viruses in both macaques evolved to become increasingly sCD4-sensitive, suggestive of enhanced exposure of the CD4 binding site and an “open” envelope conformation, and this correlated with better gp120 binding to CD4 and with more efficient infection of CD4low cells such as primary macrophages. Moreover, significant changes in neutralization sensitivity to agents and antibodies directed against functional domains of gp120 and gp41 were seen for R5 viruses close to the time of X4 emergence, consistent with global changes in envelope configuration and structural plasticity. These observations in a simian model of R5-to-X4 evolution provide a mechanistic basis for the HIV-1 coreceptor switch

Lipoprotein Particle Concentrations in Children and Adults following Kawasaki Disease

OBJECTIVE: To test the hypothesis that children and adults with history of Kawasaki disease (KD) are more likely to have abnormal lipoprotein particle profiles that could place them at increased risk of atherosclerosis later in life. STUDY DESIGN: Fasting serum samples were obtained from 192 children and 63 adults with history of KD and 90 age-similar healthy controls. Lipoprotein particle (P) concentrations and sizes were measured by Nuclear Magnetic Resonance (NMR) spectroscopy (Liposcience Inc., Raleigh, NC) and serum was assayed for total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL)-C. Low-density lipoprotein cholesterol (LDL)-C was estimated using the Friedewald formula. Data were analyzed in a least-square means model adjusting for age and sex and using Holm correction for multiple comparisons. RESULTS: Compared with respective control groups, both adult and pediatric subjects with KD had significantly lower mean very-low-density lipoprotein-chylomicron particle concentrations (VLDLC-P), intermediate-density lipoproteins (IDL), TG, and TC concentrations. Pediatric subjects with KD had significantly lower LDL-P and LDL-C concentrations and lower mean TC/HDL-C ratio (p<0.001). In contrast, the adult subjects with KD had significantly lower HDL-P, small HDL-P, and HDL-C concentrations (p<0.001), but HDL-C was within normal range. CONCLUSIONS: NMR lipoprotein particle analysis suggests that pediatric and adult subjects with KD regardless of their aneurysm status are no more likely than age-similar, healthy controls to have lipid patterns associated with increased risk of atherosclerosis