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- Inhibition of Protein Kinase C Delta Attenuates Allergic Airway Inflammation through Suppression of PI3K/Akt/mTOR/HIF-1 Alpha/VEGF Pathway. [Journal Article]
- PLoS One 2013; 8(11):e81773.
Vascular endothelial growth factor (VEGF) is supposed to contribute to the pathogenesis of allergic airway disease. VEGF expression is regulated by a variety of stimuli such as nitric oxide, growth factors, and hypoxia-inducible factor-1 alpha (HIF-1α). Recently, inhibition of the mammalian target of rapamycin (mTOR) has been shown to alleviate cardinal asthmatic features, including airway hyperresponsiveness, eosinophilic inflammation, and increased vascular permeability in asthma models. Based on these observations, we have investigated whether mTOR is associated with HIF-1α-mediated VEGF expression in allergic asthma. In studies with the mTOR inhibitor rapamycin, we have elucidated the stimulatory role of a mTOR-HIF-1α-VEGF axis in allergic response. Next, the mechanisms by which mTOR is activated to modulate this response have been evaluated. mTOR is known to be regulated by phosphoinositide 3-kinase (PI3K)/Akt or protein kinase C-delta (PKC δ) in various cell types. Consistent with these, our results have revealed that suppression of PKC δ by rottlerin leads to the inhibition of PI3K/Akt activity and the subsequent blockade of a mTOR-HIF-1α-VEGF module, thereby attenuating typical asthmatic attack in a murine model. Thus, the present data indicate that PKC δ is necessary for the modulation of the PI3K/Akt/mTOR signaling cascade, resulting in a tight regulation of HIF-1α activity and VEGF expression. In conclusion, PKC δ may represent a valuable target for innovative therapeutic treatment of allergic airway disease.
- Asthma and Pneumonia among Children Less Than Five Years with Acute Respiratory Symptoms in Mulago Hospital, Uganda: Evidence of Under-Diagnosis of Asthma. [Journal Article]
- PLoS One 2013; 8(11):e81562.
Pneumonia is considered the major cause of mortality among children with acute respiratory disease in low-income countries but may be over-diagnosed at the cost of under-diagnosing asthma. We report the magnitude of asthma and pneumonia among "under-fives" with cough and difficulty breathing, based on stringent clinical criteria. We also describe the treatment for children with acute respiratory symptoms in Mulago Hospital.We enrolled 614 children aged 2-59 months with cough and difficulty breathing. Interviews, physical examination, blood and radiological investigations were done. We defined asthma according to Global Initiative for Asthma guidelines. Pneumonia was defined according to World Health Organization guidelines, which were modified by including fever and white cell count, C-reactive protein, blood culture and chest x-ray. Children with asthma or bronchiolitis were collectively referred to as "asthma syndrome" due to challenges of differentiating the two conditions in young children. Three pediatricians reviewed each participant's case report post hoc and made a diagnosis according to the study criteria.Of the 614 children, 41.2% (95% CI: 37.3-45.2) had asthma syndrome, 27.2% (95% CI: 23.7-30.9) had bacterial pneumonia, 26.5% (95% CI: 23.1-30.2) had viral pneumonia, while 5.1% (95% CI: 3.5-7.1) had other diagnoses including tuberculosis. Only 9.5% of the children with asthma syndrome had been previously diagnosed as asthma. Of the 253 children with asthma syndrome, 95.3% (95% CI: 91.9-97.5) had a prescription for antibiotics, 87.7% (95% CI: 83.1-91.5) for bronchodilators and 43.1% (95% CI: 36.9-49.4) for steroids.Although reports indicate that acute respiratory symptoms in children are predominantly due to pneumonia, asthma syndrome contributes a significant proportion. Antibiotics are used irrationally due to misdiagnosis of asthma as pneumonia. There is need for better diagnostic tools for childhood asthma and pneumonia in Uganda.
- NOD-Like Receptors in Lung Diseases. [REVIEW]
- Front Immunol 2013.:393.
The lung is a particularly vulnerable organ at the interface of the body and the exterior environment. It is constantly exposed to microbes and particles by inhalation. The innate immune system needs to react promptly and adequately to potential dangers posed by these microbes and particles, while at the same time avoiding extensive tissue damage. Nucleotide-binding oligomerization domain-like receptors (NLRs) represent a group of key sensors for microbes and damage in the lung. As such they are important players in various infectious as well as acute and chronic sterile inflammatory diseases, such as pneumonia, chronic obstructive pulmonary disease (COPD), acute lung injury/acute respiratory distress syndrome, pneumoconiosis, and asthma. Activation of most known NLRs leads to the production and release of pro-inflammatory cytokines, and/or to the induction of cell death. We will review NLR functions in the lung during infection and sterile inflammation.
- Attitudes of Hungarian asthmatic and COPD patients affecting disease control: empirical research based on Health Belief Model. [JOURNAL ARTICLE]
- Front Pharmacol 2013.:135.
Introduction: Patient non-adherence to treatment is a major problem across most chronic diseases. In COPD and asthma treatments it is a complex issue because people need to make behavioral and lifestyle changes while taking medications. Poor adherence results in increased rates of morbidity and mortality, more frequent hospitalizations, and ultimately higher healthcare expenditures. Materials and methods: The objective of the study was to assess asthmatic and COPD patient's attitudes toward adherence in Hungary. Health Belief Model was used to help explain reasons of non-adherence. The results of the study should provide additional support to understanding health-related behaviors and to developing health related programs enhancing adherence of asthmatic and COPD patients. 145 diagnosed COPD patients and 161 diagnosed asthmatic patients were involved in 6 pulmonary centers. The questions were designed to measure Health Belief Model dimensions A 1-5 point verbal Likert scale was used. As a second stage, the answers were compared with the registered patient's personal health data available in pulmonary center's documentation. The data was analyzed using SPSS software. Results: More than 32% of patients are very interested in new asthma or COPD research results, but their main information source is physician. The trust toward the physician is very high. Patients accept treatments and rarely ask questions. Respondents are cooperative but sometimes fail to follow therapeutic recommendations. There is no willingness to join self-help groups or associations. Discussion: The paternalistic approach was generally accepted, moreover expected by the patients from the physicians. It is important to train patients, increase their self-efficacy, responsibility and involve them into self-management programs. Both physicians and patients should be trained how to communicate-this approach can lead to increased understanding and better adherence.
- Genetic heterogeneity of asthma phenotypes identified by a clustering approach. [JOURNAL ARTICLE]
- Eur Respir J 2013 Dec 5.
The aim was to identify genetic variants associated with refined asthma phenotypes enabling to take into account multiple features of the disease.Latent class analysis (LCA) was applied in 3001 adults ever having asthma recruited in the frame of three epidemiological surveys (ECRHS, SAPALDIA, EGEA). Fourteen personal and phenotypic characteristics from questionnaires and clinical examination were used. A genome wide association study (GWAS) was conducted for each LCA-derived asthma phenotype, compared to subjects without asthma (n=3474).The LCA identified four adult asthma phenotypes, mainly characterized by the activity of the disease, the age of asthma onset and the atopic status. Associations of genome wide significance (<1.25×10-7) were observed between "active adult-onset non-allergic asthma" and rs9851461 flanking CD200 (3q13.2) and between "Inactive/mild non-allergic asthma" and rs2579931 flanking GRIK2 (6q16.3). Borderline significant results (2.5×10(-7)<p<8.2×10(-7)) were observed between three SNPs in ALCAM region (3q13.11) and "active adult-onset non-allergic asthma". These results were consistent across studies. Fifteen SNPs identified in previous GWAS for asthma have been replicated with at least one asthma phenotype, most of them with the "active allergic asthma" phenotype.Our results provide evidence that a better understanding of the asthma phenotypic heterogeneity helps to disentangle the genetic heterogeneity of asthma.
- Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis. [JOURNAL ARTICLE]
- Eur Respir J 2013 Dec 5.
Severe asthma with fungal sensitization (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) encompass two closely related subgroups of patients with severe allergic asthma. Pulmonary disease is due to pronounced host inflammatory responses to non-invasive subclinical endobronchial infection with filamentous fungi, usually Aspergillus fumigatus. These patients usually do not achieve satisfactory disease control with conventional treatment of severe asthma, i.e., high-dose inhaled corticosteroids and long-acting bronchodilators. Although prolonged systemic corticosteroids are effective, they carry a substantial toxicity profile. Supplementary or alternative therapies have primarily focused on use of antifungal agents including oral triazoles and inhaled amphotericin B. Immunomodulation with omalizumab, a humanized anti-IgE monoclonal antibody, or "pulse" monthly high-dose intravenous corticosteroid, has also been employed. This review considers the experience with these approaches with emphasis on recent clinical trials.
- Telomere length in circulating leukocytes is associated with lung function and disease. [JOURNAL ARTICLE]
- Eur Respir J 2013 Dec 5.
Several clinical studies suggest the involvement of premature aging processes in COPD. Using an epidemiological approach we studied whether accelerated aging indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the inter-individual variability of lung function.Our meta-analysis of 14 studies included 934 COPD cases with 15,846 controls defined according to GLI criteria (or 1,189 COPD cases according to GOLD), 2,834 asthma cases with 28,195 controls, and spirometric parameters (FEV1, FVC and FEV1/FVC) of 12,595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex, and smoking status.We observed negative associations between telomere length and asthma (β= -0.0452, p=0.024) as well as COPD (β= -0.0982, p=0.001), with associations being stronger and more significant when using GLI in comparison to GOLD. In both diseases, effects were stronger in females compared to males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10(-7)), FVC (p=2.07×10(-5)), and their ratio FEV1/FVC (p=5.27×10(-3)). The effect was somewhat weaker in apparently healthy subjects compared to COPD or asthma patients.Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma and that lung function may reflect biological aging primarily due to intrinsic processes which are likely to be aggravated in lung diseases.
- Ambient temperature and lung function in children with asthma in Australia. [JOURNAL ARTICLE]
- Eur Respir J 2013 Dec 5.
Background: The association between ambient temperature and lung function in children with asthma is still uncertain.Methods: A panel of 270 children (7-12 years) with asthma was recruited from six Australian cities. They performed three successive forced expiratory maneuvers twice daily for four weeks. The highest peak expiratory flow rate (PEF) and forced expiratory volume in one second (FEV1) were stored for each session. Daily data were obtained on ambient temperature, relative humidity and air pollution, during the same period. Mixed models were used to examine the effects of temperature on lung function, controlling for individual characteristics and environmental factors.Results: Ambient temperature was negatively related to both morning and evening PEF and FEV1 for lag 0-3 days. In general, the effects of temperature were stronger in boys than in girls for evening PEF, while the effects were stronger in girls for evening FEV1. Children with asthma living in southern cities were more sensitive to high temperature than those in the northern most city.Conclusions: Higher ambient temperature is associated with lower lung function in children with asthma. Preventive health policies will be required for protecting children with asthma from the increasing frequency of high temperatures.
- Treatment of life-threatening hypercapnia with isoflurane in an infant with status asthmaticus. [JOURNAL ARTICLE]
- J Anesth 2013 Dec 6.
We encountered a 2-year-old child with life-threatening hypercapnia, with a PaCO2 of 238 mm Hg and severe respiratory and metabolic acidosis, due to status asthmaticus that was refractory to steroid and bronchodilator therapy. Suspecting ventilatory failure and excessive ventilation-induced obstructive shock, we started respiratory physiotherapy in synchrony with her respiration, to facilitate exhalation from her over-inflated lungs. Isoflurane inhalation was commenced in preparation for extracorporeal circulation, to reduce the hypercapnia. The combination of respiratory physiotherapy and isoflurane inhalation resulted in a rapid decrease in ventilatory resistance and PaCO2 levels within a few minutes, with recovery of consciousness within 60 min. Isoflurane inhalation was gradually discontinued and steroid and aminophylline therapy were commenced. The patient recovered completely without any recurrence of her bronchospasm and without any residual neurological deficits. In our patient with a severe asthmatic attack, decreased exhalation secondary to asthma and overventilation during artificial ventilation resulted in overinflation of the lungs, which in turn led to cerebral edema and obstructive cardiac failure. The favorable outcome in this case was due to the short duration of hypercapnia. Hence, we conclude that the duration of hypercapnia is an important determinant of the morbidity and mortality of status asthmaticus-induced severe hypercapnia.
- Prevalence of allergen sensitization, most important allergens and factors associated with atopy in children. [Journal Article]
- Sao Paulo Med J 2013; 131(5):301-8.
Knowledge of the profile of allergen sensitization among children is important for planning preventive measures. The objective of this study was to assess the prevalence and profile of sensitization to inhaled allergens and food among children and adolescents in an outpatient population in the city of Palmas.Cross-sectional study at outpatient clinics in Palmas, Tocantins, Brazil.Ninety-four patients aged 1-15 years who were attending two pediatric outpatient clinics were selected between September and November 2008. All of the subjects underwent clinical interviews and skin prick tests.A positive skin prick test was observed in 76.6% of the participants (72.3% for inhalants and 28.9% for food allergens). The most frequent allergens were Dermatophagoides pteronyssinus (34%), cat epithelium (28.7%), dog epithelium (21.3%), Dermatophagoides farinae (19.1%), Blomia tropicalis (18.1%), cow's milk (9.6%) and grasses (9.6%). A positive skin prick test correlated with a history of atopic disease (odds ratio, OR = 5.833; P = 0.002), a family history of atopic disease (OR = 8.400; P < 0.001), maternal asthma (OR = 8.077; P = 0.048), pet exposure (OR = 3.600; P = 0.012) and cesarean delivery (OR = 3.367; P = 0.019).Dermatophagoides pteronyssinus was the most frequent aeroallergen and cow's milk was the most prevalent food allergen. There was a positive correlation between a positive skin prick test and several factors, such as a family history of atopic disease, maternal asthma, pet exposure and cesarean delivery.