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1.  Anti-Inflammatory Effect of Caffeine is Associated with Improved Lung Function after LPS-induced Amnionitis 
Neonatology  2014;106(3):235-240.
Background:
Although caffeine enhances respiratory control and decreases the need for mechanical ventilation and resultant bronchopulmonary dysplasia, it may also have anti-inflammatory properties in protecting lung function.
Objective:
We hypothesized that caffeine improves respiratory function via an anti-inflammatory effect in lungs of a lipopolysaccharide (LPS)-induced pro-inflammatory amnionitis rat pup model.
Methods:
Caffeine was given orally (10 mg/kg/d) from postnatal days (p) 1-14 to pups exposed to intra-amniotic LPS or normal saline (NS). Expression of IL-1β was assessed in lung homogenates at p8 and p14, and respiratory system resistance (Rrs) and compliance (Crs) as well as CD68 cell counts and radial alveolar counts (RACs) were assessed at p8.
Results:
In LPS-exposed rats IL-1β and CD68 cell counts both increased at p8 compared to NS controls. These increases in proinflammatory markers were no longer present in caffeinetreated LPS-exposed pups. Rrs was higher in LPS-exposed pups (4.7±0.9 cmH2O/ml.s) at p8 vs controls (1.6±0.3 cmH2O/ml.s, p<0.01). LPS-exposed pups no longer exhibited a significant increase in Rrs (2.8±0.5 cmH2O/ml.s) after caffeine. Crs did not differ significantly between groups, although radial alveolar counts were lower in both groups of LPS-exposed pups.
Conclusions:
Caffeine promotes anti-inflammatory effects in the immature lung of prenatal LPS-exposed rat pups associated with improvement of Rrs and suggesting a protective effect of caffeine on respiratory function via an anti-inflammatory mechanism.
doi:10.1159/000363217
PMCID: PMC4123217  PMID: 25011471
caffeine; inflammation; amnionitis; lung function; newborn
2.  Lung inflammation induces IL-1β expression in hypoglossal neurons in rat brainstem 
Perinatal inflammation is associated with respiratory morbidity. Immune modulation of brainstem respiratory control centers may provide a link for this pathobiology. We exposed 11-day old rats to intratracheal lipopolysaccharide (LPS, 0.5 µg/g) to test the hypothesis that intrapulmonary inflammation increases expression of the proinflammatory cytokine IL-1β within respiratory-related brainstem regions. Intratracheal LPS resulted in a 32% increase in IL-1β protein expression in the medulla oblongata. In situ hybridization showed increased intensity of IL-1β mRNA but no change in neuronal numbers. Co-localization experiments showed that hypoglossal neurons express IL-1β mRNA and immunostaining showed a 43% increase in IL-1β protein-expressing cells after LPS exposure. LPS treatment also significantly increased microglial cell numbers though they did not express IL-1β mRNA. LPS-induced brainstem expression of neuronal IL-1β mRNA and protein may have implications for our understanding of the vulnerability of neonatal respiratory control in response to a peripheral pro-inflammatory stimulus.
doi:10.1016/j.resp.2013.04.022
PMCID: PMC3700631  PMID: 23648475
Brainstem; neuro-inflammation; in situ hybridization; lipopolysaccharide; respiratory control
3.  Brain-Derived Neurotrophic Factor in the Airways 
Pharmacology & therapeutics  2014;143(1):74-86.
In addition to their well-known roles in the nervous system, there is increasing recognition that neurotrophins such as brain derived neurotrophic factor (BDNF) as well as their receptors are expressed in peripheral tissues including the lung, and can thus potentially contribute to both normal physiology and pathophysiology of several diseases. The relevance of this family of growth factors lies in emerging clinical data indicating altered neurotrophin levels and function in a range of diseases including neonatal and adult asthma, sinusitis, influenza, and lung cancer. The current review focuses on 1) the importance of BDNF expression and signaling mechanisms in early airway and lung development, critical to both normal neonatal lung function and also its disruption in prematurity and insults such as inflammation and infection; 2) how BDNF, potentially derived from airway nerves modulate neurogenic control of airway tone, a key aspect of airway reflexes as well as dysfunctional responses to allergic inflammation; 3) the emerging idea that local BDNF production by resident airway cells such as epithelium and airway smooth muscle can contribute to normal airway structure and function, and to airway hyperreactivity and remodeling in diseases such as asthma. Furthermore, given its pleiotropic effects in the airway, BDNF may be a novel and appealing therapeutic target.
doi:10.1016/j.pharmthera.2014.02.006
PMCID: PMC3990251  PMID: 24560686
Neurotrophin; Lung; Tropomyosin related kinase; p75; Asthma; Rhinitis; Inflammation; Fibrosis; Bronchopulmonary Dysplasia; Development
4.  The Effect of Red Blood Cell Transfusion on Intermittent Hypoxemia in ELBW Infants 
Objective
To test the hypothesis that the effect of red blood cell (RBC) transfusion on intermittent hypoxemia (IH) in extremely low birth weight (ELBW) infants is dependent on postnatal age.
Study Design
Oxygen saturation of 130 ELBW infants, who required transfusion, was monitored continuously for the first 8wks of life. We compared the characteristics of IH (SpO2 ≤ 80% for ≥4s and ≤3min), 24h before and both 24h and 24-48h after each RBC transfusion at three distinct time periods: Epoch 1, 1-7d; Epoch 2, 8-28d; and Epoch 3, >28d.
Results
In Epoch 1, the frequency and severity of IH events were not significantly different before and after transfusion. In both Epochs 2 and 3 there was a decrease in IH frequency and severity 24h after RBC transfusion that persisted for 48h. In addition, there was a decrease in the overall time spent with SpO2 ≤ 80% which persisted for 24h after transfusion in Epochs 1 and 3, and for 48h in Epoch 3.
Conclusion
The benefit of RBC transfusion on IH is age dependent as improvement in the frequency and severity of IH after transfusion only occurs beyond the first week of life. These observations will aid clinician’s decision making by clarifying the benefit of RBC transfusions on patterns of oxygenation in preterm infants.
doi:10.1038/jp.2014.115
PMCID: PMC4245392  PMID: 24921411
Red Blood Cell Transfusion; Intermittent Hypoxemia; Apnea of Prematurity; Oxygen Saturation
5.  Relationship Between Patterns of Intermittent Hypoxia and Retinopathy of Prematurity in Preterm Infants 
Pediatric research  2012;72(6):606-612.
Background
We have previously shown an increased incidence of intermittent hypoxemic events (IH) in preterm infants with severe retinopathy of prematurity (ROP). Animal models suggest that patterns of IH events may play a role in ROP severity as well. We hypothesize that specific IH patterns are associated with ROP in preterm infants.
Methods
Variability in IH duration, severity and the time interval between IH (≤80%, ≥10 seconds and ≤3min) along with the frequency spectrum of the oxygen saturation (SpO2) waveform were assessed.
Results
Severe ROP was associated with 1) an increased mean and standard deviation of the duration of IH (p<0.005), 2) more variability (Histogram Entropy) of the time interval between IH (p<0.005), 3) a higher IH nadir (p<0.05), 4) a time interval between IH of 1–20min (p<0.05) and 5) increased spectral power in the range of 0.002–0.008Hz (p<.05), corresponding to SpO2 waveform oscillations of 2–8 minutes in duration. Spectral differences were detected as early as 14 days of life.
Conclusions
Severe ROP was associated with more variable, longer, and less severe IH events. Identification of specific spectral components in the SpO2 waveform may assist in early identification of infants at risk for severe ROP.
doi:10.1038/pr.2012.132
PMCID: PMC4433009  PMID: 23037873
6.  A Higher Incidence of Intermittent Hypoxemic Episodes is Associated with Severe Retinopathy of Prematurity 
The Journal of pediatrics  2010;157(1):69-73.
Objective
Retinopathy of prematurity (ROP), a vasoproliferative disorder of the retina in preterm infants, has been associated with multiple factors including levels of oxygenation. As intermittent hypoxemic events are common in preterm infants, this study investigates their association with the development of ROP.
Study Design
Oxygen desaturation events were quantified in 79 preterm infants (gestational age 24–27 6/7wks) during the first 8 weeks of life. Infants were classified as requiring laser treatment for ROP (LaserROP) versus less severe or no ROP. A linear mixed model was used to study the association between the incidence of intermittent hypoxia and LaserROP, controlling for gestational age, gender, race, multiple births and initial severity of illness.
Results
For all infants, there was an increase in hypoxemic events with increasing postnatal age (p<0.001). Controlling for all covariates, a higher incidence of oxygen desaturation events was found in the LaserROP infants (p<0.001), males (p<0.02) and infants of younger gestational age (p<0.003).
Conclusion
This study demonstrated a higher incidence of hypoxemic events in infants with ROP requiring laser therapy. Therapeutic strategies to optimize baseline oxygenation in preterm infants should include minimization of desaturation episodes, which may in turn decrease serious morbidity in this high risk population.
doi:10.1016/j.jpeds.2010.01.046
PMCID: PMC4428609  PMID: 20304417
Intermittent hypoxia; oxygen saturation; retinopathy of prematurity; infant
7.  Delivering Perinatal Psychiatric Services in the Neonatal Intensive Care Unit 
Acta paediatrica (Oslo, Norway : 1992)  2013;102(9):e392-e397.
Aim
To describe characteristics of mothers who would likely benefit from on-site short-term psychiatric services while their infant is in the Neonatal Intensive Care Unit (NICU).
Methods
For 150 consecutive mothers who were referred for psychiatric evaluation and psychotherapeutic intervention in an innovative NICU mental health program, baseline information was collected. Data regarding their referrals, diagnosis, treatments, and their infants was analyzed.
Results
Most mothers were referred because of depression (43%), anxiety (44%), and/ or difficulty coping with their infant's medical problems and hospitalization (60%). Mothers of VLBW infants were disproportionately more likely to be referred. A majority of mothers accepted the referral and were treated; most only required short-term psychotherapy. A minority resisted or refused psychiatric assessment; a quarter of these had more difficult interactions with staff or inappropriate behaviors. In these cases the role of the psychiatrist was to work with staff to promote healthy interactions and to foster maternal-infant bonding.
Conclusion
Overall, on-site psychiatric services have been accepted by a majority of referred NICU mothers, and most did not require long-term treatment. A considerable need exists for psychiatric services in the NICU to promote optimal parenting and interactions.
doi:10.1111/apa.12323
PMCID: PMC4420733  PMID: 23772977
depression; neonatal morbidity; anxiety; coping skills
8.  Why Do Former Preterm Infants Wheeze? 
The Journal of pediatrics  2012;162(3):10.1016/j.jpeds.2012.11.028.
doi:10.1016/j.jpeds.2012.11.028
PMCID: PMC3870137  PMID: 23260100
10.  Tribendimidine: Mode of Action and nAChR Subtype Selectivity in Ascaris and Oesophagostomum 
PLoS Neglected Tropical Diseases  2015;9(2):e0003495.
The cholinergic class of anthelmintic drugs is used for the control of parasitic nematodes. One of this class of drugs, tribendimidine (a symmetrical diamidine derivative, of amidantel), was developed in China for use in humans in the mid-1980s. It has a broader-spectrum anthelmintic action against soil-transmitted helminthiasis than other cholinergic anthelmintics, and is effective against hookworm, pinworms, roundworms, and Strongyloides and flatworm of humans. Although molecular studies on C. elegans suggest that tribendimidine is a cholinergic agonist that is selective for the same nematode muscle nAChR as levamisole, no direct electrophysiological observations in nematode parasites have been made to test this hypothesis. Also the hypothesis that levamisole and tribendimine act on the same receptor, does not explain why tribendimidine is effective against some nematode parasites when levamisole is not. Here we examine the effects of tribendimidine on the electrophysiology and contraction of Ascaris suum body muscle and show that tribendimidine produces depolarization antagonized by the nicotinic antagonist mecamylamine, and that tribendimidine is an agonist of muscle nAChRs of parasitic nematodes. Further pharmacological characterization of the nAChRs activated by tribendimidine in our Ascaris muscle contraction assay shows that tribendimidine is not selective for the same receptor subtypes as levamisole, and that tribendimidine is more selective for the B-subtype than the L-subtype of nAChR. In addition, larval migration inhibition assays with levamisole-resistant Oesophagostomum dentatum isolates show that tribendimidine is as active on a levamisole-resistant isolate as on a levamisole-sensitive isolate, suggesting that the selectivity for levamisole and tribendimidine is not the same. It is concluded that tribendimidine can activate a different population of nematode parasite nAChRs than levamisole, and is more like bephenium. The different nAChR subtype selectivity of tribendimidine may explain why the spectrum of action of tribendimidine is different to that of other cholinergic anthelmintics like levamisole.
Author Summary
Nematode parasites are a plague on the human condition in many developing countries with limited health care and sanitation. The morbidity produced by these parasites limits human health, development and prosperity. Nematode parasites also adversely affect animal welfare and production. Vaccines are not effective, so anthelmintic drugs are necessary for prophylaxis and treatment. Most anthelmintics belong to one of three classes: the macrocyclic lactones (ivermectin, moxidectin); the nicotinic anthelmintics (levamisole, pyrantel, derquantel) or; the benzimidazoles (albendazole, mebendazole). With the limited number of drugs available, there is real concern about the development of resistance. Tribendimidine was developed in China in the mid-1980s as a broad spectrum anthelmintic against soil-transmitted nematodes. Its mode of action has been investigated molecularly in C. elegans and on expressed nAChRs but, its mode of action has not been investigated directly in parasitic nematodes. Here we describe its effects on muscle contraction and electrophysiology in the pig nematode parasite, A. suum, which is very similar or the same as the human parasite, A. lumbricoides. Here we show that tribendimidine is a B-subtype selective nicotinic anthelmintic agonist that activates muscle nAChRs that are pharmacologically different from other cholinergic anthelmintics. It is concluded that tribendimidine could be effective against nematode parasites resistant to another cholinergic anthelmintic.
doi:10.1371/journal.pntd.0003495
PMCID: PMC4334517  PMID: 25679515
11.  Transcriptomic Evaluation of the Nicotinic Acetylcholine Receptor Pathway in Levamisole-resistant and -sensitive Oesophagostomum dentatum 
Nematode anthelminthic resistance is widespread for the 3 major drug classes commonly used in agriculture: benzamidazoles, macrocyclic lactones, and nicotinic agonists e.g. levamisole. In parasitic nematodes the genetics of resistance are unknown other than to the benzimidazoles which primarily involve a single gene. In previous work with a levamisole resistant Oesophagostomum dentatum isolate, the nicotinic acetylcholine receptor (nAChR) exhibited decreased levamisole sensitivity. Here, using a transcriptomic approach on the same isolate, we investigate whether that decreased nAChR sensitivity is achieved via a 1-gene mechanism involving 1 of 27 nAChR pathway genes. 3 nAChR receptor subunit genes exhibited ≥ 2-fold change in transcript abundance: acr-21 and acr-25 increased, and unc-63 decreased. 4 SNPs having a ≥ 2-fold change in frequency were also identified. These data suggest that resistance is likely polygenic, involving modulated abundance of multiple subunits comprising the heteropentameric nAChR, and is not due to a simple 1-gene mechanism.
doi:10.1016/j.molbiopara.2014.02.002
PMCID: PMC3992831  PMID: 24530453
resistance; levamisole; nAChR; nodular worm
12.  Perinatal Oxygen in the Developing Lung 
Lung diseases, such as bronchopulmonary dysplasia (BPD), wheezing, and asthma, remain significant causes of morbidity and mortality in the pediatric population, particularly in the setting of premature birth. Pulmonary outcomes in these infants are highly influenced by perinatal exposures including prenatal inflammation, postnatal intensive care unit interventions, and environmental agents. Here, there is strong evidence that perinatal supplemental oxygen administration has significant effects on pulmonary development and health. This is of particular importance in the preterm lung, where premature exposure to room air represents a hyperoxic insult that may cause harm to a lung primed to develop in a hypoxic environment. Preterm infants are also subject to increased episodes of hypoxia, which may also result in pulmonary damage and disease. Here, we summarize current understanding of the effects of oxygen on the developing lung and how low vs. high oxygen may predispose to pulmonary disease that may extend even into adulthood. Better understanding of the underlying mechanisms will help lead to improved care and outcomes in this vulnerable population.
doi:10.1139/cjpp-2014-0387
PMCID: PMC4313769  PMID: 25594569
Neonatal; Bronchopulmonary Dysplasia; Asthma; Hypoxia; Hyperoxia
13.  Mechanisms of Injury to the Preterm Lung and Airway: Implications for Long Term Pulmonary Outcome 
Neonatology  2012;101(4):345-352.
Despite changes in the epidemiology of bronchopulmonary dysplasia [BPD], longer term morbidity, particularly in the form of airway dysfunction, remains a substantial problem in former preterm infants. The stage for this respiratory morbidity may begin as early as the transition from fetal to neonatal life. Newer therapeutic approaches for BPD should be directed toward minimizing this longer term respiratory morbidity. Neonatal animal models focused primarily on hyperoxic exposure may provide important insights into the pathogenesis of longer term airway hyperreactivity in this population.
doi:10.1159/000337355
PMCID: PMC3567481  PMID: 22940624
bronchopulmonary dysplasia; neonatal airway function; pediatric asthma
14.  Anthelmintics – From Discovery to Resistance 
Graphical abstract
Highlights
•Special Issue from the “Anthelmintics: From Discovery to Resistance” meeting, San Francisco, February 2014.•Meeting themes: drug discovery, modes of action and resistance.•Human and veterinary parasites covered.•Academic and industrial attendees.
The scientific meeting entitled ‘Anthelmintics: From Discovery to Resistance’ was held in San Francisco in February 2014. The themes of the meeting were drug discovery, modes of action and resistance. Both human and veterinary parasites were covered in the oral and poster presentations. The attendees were from both academic and industrial backgrounds. In the present article we introduce a number of the papers that emerged from the meeting. Several of the papers covered current drug discovery efforts underway worldwide, with some specific examples focusing on ion channels, protein kinases and cysteine proteases. These efforts included the repurposing of known drugs as well as the discovery of novel actives. Two papers described recently-developed whole-organism screening techniques. Finally, we introduce several papers looking at mechanisms and management of drug resistance in human and veterinary parasites.
doi:10.1016/j.ijpddr.2014.10.001
PMCID: PMC4266783  PMID: 25516831
Anthelmintics; Resistance; Drug discovery; Scientific meeting
15.  Diethylcarbamazine Increases Activation of Voltage-Activated Potassium (SLO-1) Currents in Ascaris suum and Potentiates Effects of Emodepside 
Diethylcarbamazine is a drug that is used for the treatment of filariasis in humans and animals; it also has effects on intestinal nematodes, but its mechanism of action remains unclear. Emodepside is a resistance-busting anthelmintic approved for treating intestinal parasitic nematodes in animals. The novel mode of action and resistance-breaking properties of emodepside has led to its use against intestinal nematodes of animals, and as a candidate drug for treating filarial parasites. We have previously demonstrated effects of emodepside on SLO-1 K+-like currents in Ascaris suum. Here, we demonstrate that diethylcarbamazine, which has been proposed to work through host mediated effects, has direct effects on a nematode parasite, Ascaris suum. It increases activation of SLO-1 K+ currents and potentiates effects of emodepside. Our results suggest consideration of the combination of emodepside and diethylcarbamazine for therapy, which is predicted to be synergistic. The mode of action of diethylcarbamazine may involve effects on parasite signaling pathways (including nitric oxide) as well as effects mediated by host inflammatory mediators.
Author Summary
Filarial parasites and soil-transmitted nematodes (STNs) are Neglected Tropical Diseases (NTDs) that affect millions of people in the developing world. There is an urgent need for novel drugs and improved use of existing drugs, because of concerns about the development of resistance. The mode of action of one of these drugs, diethylcarbamazine, remains unclear, despite the fact that it has been used for a long time for treatment and prevention of filariae and STNs. The resistance-busting anthelmintic emodepside also has effects against filariae and STNs, with a mode of action that involves activation of nematode SLO-1 K+ channels. The effects of both diethylcarbamazine and emodepside may be increased by inflammatory mediators, which suggests that the effects of diethylcarbamazine and emodepside will be additive. We used our Ascaris suum preparation to test the activation of SLO-1 K+ channels by diethylcarbamazine and its potentiating effect on emodepside. Our results suggest potential for diethylcarbamazine and emodepside in combination therapy for parasitic nematodes.
doi:10.1371/journal.pntd.0003276
PMCID: PMC4238981  PMID: 25411836
16.  The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma 
Rationale: The role of airway microbiome in corticosteroid response in asthma is unknown.
Objectives: To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids.
Methods: 16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation.
Measurements and Main Results: Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-β–associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids.
Conclusions: A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.
doi:10.1164/rccm.201304-0775OC
PMCID: PMC3863730  PMID: 24024497
microbiome; asthma; corticosteroids
17.  Effect of Vitamin D3 on Asthma Treatment Failures in Adults With Symptomatic Asthma and Lower Vitamin D Levels 
JAMA  2014;311(20):2083-2091.
IMPORTANCE
In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency.
OBJECTIVE
To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels.
DESIGN, SETTING, AND PARTICIPANTS
The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized.
INTERVENTIONS
Oral vitamin D3 (100 000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained.
MAIN OUTCOMES AND MEASURES
The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care).
RESULTS
Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28%[95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%–35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6–1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2–120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2–135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1–27.7 µg/d]).
CONCLUSIONS AND RELEVANCE
Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01248065
doi:10.1001/jama.2014.5052
PMCID: PMC4217655  PMID: 24838406
18.  Predictors of Response to Tiotropium Versus Salmeterol in Adults with Asthma1 
The Journal of allergy and clinical immunology  2013;132(5):10.1016/j.jaci.2013.08.003.
Background
Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described.
Objective
To describe individual and differential response of patients with asthma to salmeterol and tiotropium, when added to an ICS, as well as predictors of a positive clinical response.
Methods
Data from the double-blind, three-way crossover NHLBI Asthma Clinical Research Network’s TALC trial (ClinicalTrials.gov number, NCT00565266) were analyzed for individual and differential treatment responses to salmeterol and tiotropium, and predictors of a positive response to the endpoints FEV1, morning peak expiratory flow (AM PEF), and asthma control days (ACDs).
Results
While approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of AM PEF (90 and 78, respectively), and ACDs (49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (104) than salmeterol (62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (OR 4.08 [CI 2.00–8.31], P < 0.001) and AM PEF (OR 2.12 [CI 1.12–4.01], P = 0.021), as did a decreased FEV1/FVC ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in the FEV1/FVC ratio). Higher cholinergic tone was also a predictor, while ethnicity, gender, atopy, IgE Level, sputum eosinophils, FENO, asthma duration, and BMI were not.
Conclusion
While these results need confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors which could help identify appropriate patients for this therapy.
doi:10.1016/j.jaci.2013.08.003
PMCID: PMC3826080  PMID: 24084072
asthma; tiotropium; salmeterol; responder analysis; predictor of response
19.  Comparing the effectiveness of small-particle versus large-particle inhaled corticosteroid in COPD 
Purpose
Small airway changes and dysfunction contribute importantly to airway obstruction in chronic obstructive pulmonary disease (COPD), which is currently treated with inhaled corticosteroids (ICS) and long-acting bronchodilators at Global initiative for Obstructive Lung Disease (GOLD) grades 2–4. This retrospective matched cohort analysis compared effectiveness of a representative small-particle ICS (extrafine beclomethasone) and larger-particle ICS (fluticasone) in primary care patients with COPD.
Patients and methods
Smokers and ex-smokers with COPD ≥40 years old initiating or stepping-up their dose of extrafine beclomethasone or fluticasone were matched 1:1 for demographic characteristics, index prescription year, concomitant therapies, and disease severity during 1 baseline year. During 2 subsequent years, we evaluated treatment change and COPD exacerbations, defined as emergency care/hospitalization for COPD, acute oral corticosteroids, or antibiotics for lower respiratory tract infection.
Results
Mean patient age was 67 years, 57%–60% being male. For both initiation (n=334:334) and step-up (n=189:189) patients, exacerbation rates were comparable between extrafine beclomethasone and fluticasone cohorts during the 2 year outcome period. Odds of treatment stability (no exacerbation or treatment change) were significantly greater for patients initiating extrafine beclomethasone compared with fluticasone (adjusted odds ratio 2.50; 95% confidence interval, 1.32–4.73). Median ICS dose exposure during 2 outcome years was significantly lower (P<0.001) for extrafine beclomethasone than fluticasone cohorts (315 μg/day versus 436 μg/day for initiation, 438 μg/day versus 534 μg/day for step-up patients).
Conclusion
We observed that small-particle ICS at significantly lower doses had comparable effects on exacerbation rates as larger-particle ICS at higher doses, whereas initiation of small-particle ICS was associated with better odds of treatment stability during 2-years’ follow-up.
doi:10.2147/COPD.S68289
PMCID: PMC4207569  PMID: 25378918
COPD exacerbation; extrafine particle; matched cohort analysis; real life; small airways
20.  Vagal afferents modulate cytokine-mediated respiratory control at the neonatal medulla oblongata 
Perinatal sepsis and inflammation trigger lung and brain injury in preterm infants, and associated apnea of prematurity. We hypothesized that endotoxin exposure in the immature lung would upregulate proinflammatory cytokine mRNA expression in the medulla oblongata and be associated with impaired respiratory control. Lipopolysaccharide (LPS, 0.1 mg/kg) or saline was administered intratracheally to rat pups and medulla oblongatas were harvested for quantifying expression of mRNA for proinflammatory cytokines. LPS-exposure significantly increased medullary mRNA for IL-1β and IL-6, and vagotomy blunted this increase in IL-1β, but not IL-6. Whole-body flow plethysmography revealed that LPS-exposed pups had an attenuated ventilatory response to hypoxia both before and after carotid sinus nerve transection. Immunochemical expression of IL-1β within the nucleus of the solitary tract and area postrema was increased after LPS-exposure. In summary, intratracheal endotoxin-exposure in rat pups is associated with upregulation of proinflammatory cytokines in the medulla oblongata that is vagally-mediated for IL-1β and associated with an impaired hypoxic ventilatory response.
doi:10.1016/j.resp.2011.03.003
PMCID: PMC3150618  PMID: 21397055
21.  Perinatal Factors in Neonatal and Pediatric Lung Diseases 
Wheezing and asthma are significant clinical problems for infants and young children, particularly following premature birth. Recurrent wheezing in infants can progress to persistent asthma. As in adults, altered airway structure (remodeling) and function (increased bronchoconstriction) are also important in neonatal and pediatric airway diseases. Accumulating evidence suggests that airway disease in children is influenced by perinatal factors including perturbations in normal fetal lung development, postnatal interventions in the intensive care unit, and environmental and other insults in the neonatal period. Here, in addition to genetics, maternal health, environmental processes, innate immunity, and impaired lung development/function can all influence pathogenesis of airway disease in children. We summarize current understanding of how prenatal and postnatal factors can contribute to development of airway diseases in neonates and children. Understanding these mechanisms will help identify and develop novel therapies for childhood airway diseases.
doi:10.1586/17476348.2013.838020
PMCID: PMC4109979  PMID: 24090092
Infant; Child; Perinatal; Asthma; Wheezing; Remodeling; Bronchoconstriction
22.  Oxygen Desaturation Complicates Feeding in Infants With Bronchopulmonary Dysplasia After Discharge 
Pediatrics  1992;90(3):380-384.
Recurrent episodes of hypoxemia may affect the growth, cardiac function, neurologic outcome, and survival of infants with bronchopulmonary dysplasia (BPD). As oral feeding might stress these infants by compromising pulmonary function even after hospital discharge, we measured oxygen saturation (Sao2) via pulse oximetry before, during the initial 10 minutes of, and immediately after oral feeding in 11 patients with BPD, 12 very low birth weight infants, and 23 healthy full-term infants. All infants with BPD had been previously discharged from the hospital after weaning from supplemental oxygen. Studies were done at a mean postconceptional age of 43 weeks while the infants were fed at home by one of their parents. Levels of Sao2 for the three groups were comparable before and during feeds. After feeding, the infants with BPD had significantly lower mean levels of Sao2 (84 ± 8% [SD] vs 93 ± 4% and 93 ± 3%, respectively; P < .01). They also spent more time after feeding with an Sao2 <90% (64 ± 34% of time vs 27 ± 33% for the very low birth weight and 22 ± 20% for the term group; P < .01) and greater time with an Sao2 <80% (37 ± 28% vs 4 ± 10% and 4 ± 8%, respectively; P < .01). Desaturation in infants with BPD was related to larger volume and faster oral intake during feeding. Thus, the data indicate that desaturation after feeding remains a recurrent problem for survivors of BPD after discharge. Individual approaches which incorporate parental education and behavioral interventions might decrease the risk of significant hypoxemia during oral feeding in infants with BPD.
PMCID: PMC4182863  PMID: 1518692
23.  Intermittent Hypoxic Episodes in Preterm Infants: Do They Matter? 
Neonatology  2011;100(3):303-310.
Intermittent hypoxic episodes are typically a consequence of immature respiratory control and remain a troublesome challenge for the neonatologist. Furthermore, their frequency and magnitude are underestimated by clinically employed pulse oximeter settings. In extremely low birth weight infants the incidence of intermittent hypoxia progressively increases over the first 4 weeks of postnatal life, with a subsequent plateau followed by a slow decline beginning at weeks 6–8. Such episodic hypoxia/reoxygenation has the potential to sustain a proinflammatory cascade with resultant multisystem morbidity. This morbidity includes retinopathy of prematurity and impaired growth, as well as possible longer-term cardiorespiratory instability and poor neurodevelopmental outcome. Therapeutic approaches for intermittent hypoxic episodes comprise determination of optimal baseline saturation and careful titration of supplemental inspired oxygen, as well as xanthine therapy to prevent apnea of prematurity. In conclusion, characterization of the pathophysiologic basis for such intermittent hypoxic episodes and their consequences during early life is necessary to provide an evidence-based approach to their management.
doi:10.1159/000329922
PMCID: PMC3252018  PMID: 21986336
Intermittent hypoxic episodes; Pulse oximetry; Extremely low birth weight infants
24.  Intrapulmonary lipopolysaccharide exposure upregulates cytokine expression in the neonatal brainstem 
Perinatal inflammation and neonatal sepsis trigger lung and brain injury. We hypothesized that endotoxin exposure in the immature lung upregulates proinflammatory cytokine expression in the brainstem and impairs respiratory control. Lipopolysaccharide (LPS) or saline was administered intratracheally to vagal intact or denervated rat pups. LPS increased brainstem IL-1β and vagotomy blunted this response. There was an attenuated ventilatory response to hypoxia and increased brainstem IL-1β expression after LPS.
Conclusion
Intratracheal endotoxin exposure in rat pups is associated with upregulation of IL-1β in the brainstem that is vagally mediated and associated with an impaired hypoxic ventilatory response.
doi:10.1111/j.1651-2227.2011.02564.x
PMCID: PMC4132655  PMID: 22176020
Brainstem cytokines; Hypoxic ventilatory response; Neonatal respiratory control
25.  Recent advances in candidate-gene and whole-genome approaches to the discovery of anthelmintic resistance markers and the description of drug/receptor interactions 
Graphical abstract
Highlights
•We report on the Consortium for Anthelmintic Resistance and Susceptibility 2013 meeting.•Recent advances in the identification of markers for anthelmintic resistance are described.•The use of markers for benzimidazole resistance in field studies with veterinary and human nematodes.•The application of the newest high-throughput sequencing technologies to the study of anthelmintic resistance.
Anthelmintic resistance has a great impact on livestock production systems worldwide, is an emerging concern in companion animal medicine, and represents a threat to our ongoing ability to control human soil-transmitted helminths. The Consortium for Anthelmintic Resistance and Susceptibility (CARS) provides a forum for scientists to meet and discuss the latest developments in the search for molecular markers of anthelmintic resistance. Such markers are important for detecting drug resistant worm populations, and indicating the likely impact of the resistance on drug efficacy. The molecular basis of resistance is also important for understanding how anthelmintics work, and how drug resistant populations arise. Changes to target receptors, drug efflux and other biological processes can be involved. This paper reports on the CARS group meeting held in August 2013 in Perth, Australia. The latest knowledge on the development of molecular markers for resistance to each of the principal classes of anthelmintics is reviewed. The molecular basis of resistance is best understood for the benzimidazole group of compounds, and we examine recent work to translate this knowledge into useful diagnostics for field use. We examine recent candidate-gene and whole-genome approaches to understanding anthelmintic resistance and identify markers. We also look at drug transporters in terms of providing both useful markers for resistance, as well as opportunities to overcome resistance through the targeting of the transporters themselves with inhibitors. Finally, we describe the tools available for the application of the newest high-throughput sequencing technologies to the study of anthelmintic resistance.
doi:10.1016/j.ijpddr.2014.07.007
PMCID: PMC4266812  PMID: 25516826
Anthelmintic resistance; Anthelmintic drugs; Molecular markers; Anthelmintic targets; Receptors

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