T. Bernard Kinane

The Effect of Chronic or Intermittent Hypoxia on Cognition in Childhood: A Review of the Evidence

Objective. A review of the evidence concerning the effect of chronic or intermittent hypoxia on cognition in childhood was performed by using both a systematic review of the literature and critical appraisal criteria of causality. Because of the significant impact of behavioral disorders such as attention-deficit/hyperactivity disorder on certain cognitive functions as well as academic achievement, the review also included articles that addressed behavioral outcomes. Methods. Both direct and indirect evidence were collected. A structured Medline search was conducted from the years 1966-2000 by using the OVID interface. Both English- and non–English-language citations were included. Significant articles identified by the reviewers up to 2003 were also included. To be included as direct evidence, an article needed to be an original report in a peer-reviewed journal with data on cognitive, behavioral, or academic outcomes in children up to 14 years old, with clinical conditions likely to be associated with exposure to chronic or intermittent hypoxia. Indirect evidence from other reviews and publications in closely related fields, including experimental studies in adults, was used to help formulate conclusions. Two reviewers screened abstracts and titles. Each article included as direct evidence received a structured evaluation by 2 reviewers. Adjudication of differences was performed by a group of 2 reviewers and a research consultant. After this review, tables of evidence were constructed that were used as the basis for group discussion and consensus development. Indirect evidence assigned by topic to specific reviewers was also presented as part of this process. A formal procedure was used to rank the studies by design strength. The critical appraisal criteria for causation described in Evidence Based Pediatrics and Child Health (Moyer V, Elliott E, Davis R, et al, eds. London, United Kingdom: BMJ Books; 2000:46–55) were used to develop consensus on causality. Results. A total of 788 literature citations were screened. For the final analysis, 55 articles met the criteria for inclusion in the direct evidence. Of these, 43 (78.2%) reported an adverse effect. Of the 37 controlled studies, 31 (83.8%) reported an adverse effect. Adverse effects were noted at every level of arterial oxygen saturation and for exposure at every age level except for premature newborns. The studies were classified into 5 clinical categories: congenital heart disease (CHD), sleep-disordered breathing (SDB), asthma, chronic ventilatory impairment, and respiratory instability in infants. Two of these categories, CHD and SDB, which accounted for 42 (76.4%) of the included articles, fulfilled the Evidence Based Pediatrics and Child Health criteria for causation. The indirect evidence included 8 reviews, 1 meta-analysis, and 10 original reports covering the fields of adult anoxia, animal research, SDB in adults, natural and experimental high-altitude studies, perinatal hypoxic-ischemic encephalopathy, anemia, and carbon-monoxide poisoning. The studies of high-altitude and carbon-monoxide poisoning provided evidence for causality. Conclusions. Adverse impacts of chronic or intermittent hypoxia on development, behavior, and academic achievement have been reported in many well-designed and controlled studies in children with CHD and SDB as well as in a variety of experimental studies in adults. This should be taken into account in any situation that may expose children to hypoxia. Because adverse effects have been noted at even mild levels of oxygen desaturation, future research should include precisely defined data on exposure to all levels of desaturation.

RET proto-oncogene is important for the development of respiratory CO2 sensitivity

Brain stem muscarinic cholinergic pathways are important in respiratory carbon dioxide (CO2) chemosensitivity. Defects in the muscarinic system have been reported in children with congenital/developmental disorders of respiratory control such as sudden infant death syndrome (SIDS) and congenital central hypoventilation syndrome (CCHS). This early onset of disease suggests a possible genetic basis. The muscarinic system is part of the autonomic nervous system which develops from the neural crest. Ret proto-oncogene is important for this development. Thus, a potential role for ret in the development of respiratory CO2 chemosensitivity was considered. Using plethysmography, we assessed the ventilatory response to inhaled CO2 in the unanesthetized offsprings of ret +/- mice. Fractional increases in minute ventilation during hypercapnia relative to isocapnia were 5.1 +/- 3.2, 3.0 +/- 1.6 and 1.4 +/- 0.8 for the ret +/+, ret +/- and ret +/- mice, respectively. The ret knockout mice have a depressed ventilatory response to inhaled CO2. Therefore, the ret gene is an important factor in the pathway of neuronal development which allow respiratory CO2 chemosensitivity.

Pneumocystis activates human alveolar macrophage NF-kappaB signaling through mannose receptors.

ABSTRACT Alveolar macrophages (AM) represent important effector cells in the innate immune response to the AIDS-related pathogen Pneumocystis, but the early AM host defense signaling events are poorly defined. Using AM from healthy individuals, we showed in the present study that Pneumocystis organisms stimulate AM NF-κB p50 and p65 nuclear translocation in a time-dependent and multiplicity-of-infection-dependent manner as determined by electrophoretic mobility shift assay and immunofluorescence microscopy and that NF-κB nuclear translocation is associated with I-κB phosphorylation. Importantly, competitive inhibition of mannose receptor and targeted short interfering RNA-mediated gene suppression of mannose receptor mRNA and protein is associated with complete elimination of NF-κB nuclear translocation in response to Pneumocystis. Furthermore, human immunodeficiency virus (HIV) infection of AM (as a model human disease state of reduced AM mannose receptor expression and function) inhibits Pneumocystis-mediated NF-κB nuclear translocation and is associated with reduced I-κB phosphorylation and reduced interleukin-8 (IL-8) release. In contrast, NF-κB nuclear translocation and IL-8 release in response to lipopolysaccharide are intact in AM from both healthy and HIV-infected individuals, indicating that the observed impairment is not a global disturbance of the NF-κB pathway. Thus, in addition to phagocytic and endocytic effector functions, the present study identifies mannose receptors as pattern recognition receptors capable of NF-κB activation in response to infectious non-self challenge. AM mannose receptor-mediated NF-κB activation may represent an important mechanism of the host cell response to Pneumocystis, and altered NF-κB activation in the context of HIV infection may impair a critical innate immune signaling response and may contribute to pathogenesis of opportunistic lung infections.

Negative regulatory role of mannose receptors on human alveolar macrophage proinflammatory cytokine release in vitro.

Alveolar macrophages (AM) are critical components of lung innate immunity and contribute to an effective host response to Pneumocystis pneumonia. Recognition of unopsonized Pneumocystis organisms by human AM is mediated predominantly via mannose receptors and results in phagocytosis, release of reactive oxygen species, and activation of the nuclear transcription factor (NF)‐κB. However, the AM host defense genes activated by Pneumocystis have not been defined. In the present study, incubation of AM with unopsonized Pneumocystis organisms was not associated with release of interleukin (IL)‐1β, IL‐6, or tumor necrosis factor (TNF)‐α (important cytokines in the host response to Pneumocystis) and did not induce IL‐1β, IL‐6, or TNF‐α mRNA transcripts. These findings were not attributed to Pneumocystis‐induced cytopathic changes, as these same AM released IL‐8 and matrix metalloproteinase‐9 in response to Pneumocystis. NF‐κB‐mediated IL‐8 release was independent of Pneumocystis phagocytosis. The observed response was specific, as IL‐1β, IL‐6, and TNF‐α release and mRNA induction were preserved in response to lipopolysaccharide or serum‐opsonized Pneumocystis. The absence of IL‐1β, IL‐6, and TNF‐α release in response to Pneumocystis was predominately influenced by AM mannose receptors, as blocking mannose receptors or targeted mannose receptor small interfering RNA functional gene silencing resulted in TNF‐α release in response to unopsonized Pneumocystis organisms. Furthermore, ligation of AM mannose receptors by unopsonized Pneumocystis organisms reduced Toll‐like receptor 4‐mediated TNF‐α release. Taken together, these data suggest that mannose receptors on human AM may suppress select proinflammatory cytokine release and may serve to regulate the innate inflammatory responses to infectious challenge in the lungs.

“Friending” Teens: Systematic Review of Social Media in Adolescent and Young Adult Health Care

Background Social media has emerged as a potentially powerful medium for communication with adolescents and young adults around their health choices. Objective The goal of this systematic review is to identify research on the use of social media for interacting with adolescents and young adults in order to achieve positive health outcomes. Methods A MEDLINE/PubMed electronic database search was performed between January 1, 2002 and October 1, 2013, using terms to identify peer-reviewed research in which social media and other Web 2.0 technologies were an important feature. We used a systematic approach to retrieve papers and extract relevant data. Results We identified 288 studies involving social media, of which 87 met criteria for inclusion; 75 studies were purely observational and 12 were interventional. The ways in which social media was leveraged by these studies included (1) observing adolescent and young adult behavior (n=77), (2) providing health information (n=13), (3) engaging the adolescent and young adult community (n=17), and (4) recruiting research participants (n=23). Common health topics addressed included high-risk sexual behaviors (n=23), alcohol, tobacco, and other drug use (n=19), Internet safety (n=8), mental health issues (n=18), medical conditions (n=11), or other specified issues (n=12). Several studies used more than one social media platform and addressed more than one health-related topic. Conclusions Social media technologies offer an exciting new means for engaging and communicating with adolescents and young adults; it has been successfully used to engage this age group, identify behaviors, and provide appropriate intervention and education. Nevertheless, the majority of studies to date have been preliminary and limited in their methodologies, and mostly center around evaluating how adolescents and young adults use social media and the resulting implications on their health. Although these explorations are essential, further exploration and development of these strategies into building effective interventions is necessary.

Relationship between sleep apnea, fat distribution, and insulin resistance in obese children.

BACKGROUND Obstructive sleep apnea (OSA) is associated with obesity, inflammation, and insulin resistance. The role of fat distribution in OSA pathogenesis has not been established in children. The objective of the study is to examine the relationship between fat distribution, OSA, and insulin resistance in an unselected population of obese children. METHODS All obese (BMI > 95th percentile) children (ages 5-18 y) seen at a pediatric obesity clinic were invited to participate. Subjects underwent polysomnography, and were tested for dyslipidemia, inflammation, and insulin resistance measured by the homeostasis model assessment (HOMA). In a subset of subjects, magnetic resonance (MRI) imaging was used to determine the abdominal visceral and subcutaneous adipose tissue areas and magnetic resonance spectroscopy (MRS) spectroscopy was used to intramyocellular lipids in leg muscles. MEASUREMENTS AND MAIN RESULTS 31 obese subjects enrolled and completed polysomnography and serum testing, and 19 subjects underwent MRI/MRS. The mean age was 12.6 ± 3.0 y and the mean body mass index (BMI) was 39.5 ± 11.2 kg/m(2). Forty-eight percent had OSA (mean apnea hypopnea index [AHI] 6.26 ± 6.77 events/h) Subjects with OSA had significantly increased BMI, log HOMA, triglycerides, and leptin compared to those without OSA. In regression analysis, only BMI z-score was associated with log HOMA. In the subset of patients with imaging data, visceral fat area was strongly predictive of AHI (p = 0.003, r(2) = 0.556). BMI z-score, gender, and age were not predictive. CONCLUSIONS Visceral fat distribution is independently predictive of OSA severity in obese children.

A Novel L-ficolin/Mannose-binding Lectin Chimeric Molecule with Enhanced Activity against Ebola Virus

Ebola viruses constitute a newly emerging public threat because they cause rapidly fatal hemorrhagic fevers for which no treatment exists, and they can be manipulated as bioweapons. We targeted conserved N-glycosylated carbohydrate ligands on viral envelope surfaces using novel immune therapies. Mannose-binding lectin (MBL) and L-ficolin (L-FCN) were selected because they function as opsonins and activate complement. Given that MBL has a complex quaternary structure unsuitable for large scale cost-effective production, we sought to develop a less complex chimeric fusion protein with similar ligand recognition and enhanced effector functions. We tested recombinant human MBL and three L-FCN/MBL variants that contained the MBL carbohydrate recognition domain and varying lengths of the L-FCN collagenous domain. Non-reduced chimeric proteins formed predominantly nona- and dodecameric oligomers, whereas recombinant human MBL formed octadecameric and larger oligomers. Surface plasmon resonance revealed that L-FCN/MBL76 had the highest binding affinities for N-acetylglucosamine-bovine serum albumin and mannan. The same chimeric protein displayed superior complement C4 cleavage and binding to calreticulin (cC1qR), a putative receptor for MBL. L-FCN/MBL76 reduced infection by wild type Ebola virus Zaire significantly greater than the other molecules. Tapping mode atomic force microscopy revealed that L-FCN/MBL76 was significantly less tall than the other molecules despite similar polypeptide lengths. We propose that alterations in the quaternary structure of L-FCN/MBL76 resulted in greater flexibility in the collagenous or neck region. Similarly, a more pliable molecule might enhance cooperativity between the carbohydrate recognition domains and their cognate ligands, complement activation, and calreticulin binding dynamics. L-FCN/MBL chimeric proteins should be considered as potential novel therapeutics.

Endothelial Expression of Guidance Cues in Vessel Wall Homeostasis Dysregulation Under Proatherosclerotic Conditions

Objective—Emerging evidence suggests that neuronal guidance cues, typically expressed during development, are involved in both physiological and pathological immune responses. We hypothesized that endothelial expression of such guidance cues may regulate leukocyte trafficking into the vascular wall during atherogenesis. Approach and Results—We demonstrate that members of the netrin, semaphorin, and ephrin family of guidance molecules are differentially regulated under conditions that promote or protect from atherosclerosis. Netrin-1 and semaphorin3A are expressed by coronary artery endothelial cells and potently inhibit chemokine-directed migration of human monocytes. Endothelial expression of these negative guidance cues is downregulated by proatherogenic factors, including oscillatory shear stress and proinflammatory cytokines associated with monocyte entry into the vessel wall. Furthermore, we show using intravital microscopy that inhibition of netrin-1 or semaphorin3A using blocking peptides increases leukocyte adhesion to the endothelium. Unlike netrin-1 and semaphorin3A, the guidance cue ephrinB2 is upregulated under proatherosclerotic flow conditions and functions as a chemoattractant, increasing leukocyte migration in the absence of additional chemokines. Conclusions—The concurrent regulation of negative and positive guidance cues may facilitate leukocyte infiltration of the endothelium through a balance between chemoattraction and chemorepulsion. These data indicate a previously unappreciated role for axonal guidance cues in maintaining the endothelial barrier and regulating leukocyte trafficking during atherogenesis.

Slit and robo: expression patterns in lung development

First described as an axonal guidance cue through its repulsive effect on neurons expressing its receptor Roundabout (Robo), the Slit ligand has effects on cell migration, axon branching and elongation. Indirect evidence implicates Slit and Robo in lung development. We now demonstrate that Slit-2 and Slit-3 are developmentally regulated in embryonic murine lung. Immunohistochemistry demonstrates Slit-2 and Slit-3 expression by the pulmonary mesenchyme and airway epithelium. Robo-1 and Robo-2 are also expressed by the developing mesenchyme and airway epithelium. As lung development progresses, Robo-1 and Robo-2 expression localizes to only the airway epithelium. We conclude Slit/Robo are expressed in temporo-spatially adjacent domains suggesting interactive roles in pulmonary bronchiolar development.

Expression of Netrin-1 and its two receptors DCC and UNC5H2 in the developing mouse lung

The ligand Netrin-1 and its receptors DCC and UNC5H2 are critical for the regulation of neuronal migration in nervous system development. Here we demonstrate expression of these molecules in lung development. The mRNA expression profiles of Netrin-1, DCC and UNC5H2 are developmentally regulated during embryonic mouse lung formation. Netrin-1 shows a bimodal expression pattern with elevated mRNA levels early followed by a second peak in late gestation. Peak expression of DCC occurs early in development whereas expression of UNC5H2 peaks late in development. We also demonstrate localization of Netrin-1, DCC and UNC5H2 during the stages of lung development. We present evidence that these proteins are modulated spatially in the mesenchyme and epithelium during lung organogenesis.