Repeated Nitrogen Dioxide Exposures and Eosinophilic Airway Inflammation in Asthmatics: A Randomized Crossover Study

Background: Nitrogen dioxide (NO₂), a ubiquitous atmospheric pollutant, may enhance the asthmatic response to allergens through eosinophilic activation in the airways. However, the effect of NO₂ on inflammation without allergen exposure is poorly studied.Objectives: We investigated whether repeated peaks of NO₂, at various realistic concentrations, induce changes in airway inflammation in asthmatics.Methods: Nineteen nonsmokers with asthma were exposed at rest in a double-blind, crossover study, in randomized order, to 200 ppb NO₂, 600 ppb NO₂, or clean air once for 30 min on day 1 and twice for 30 min on day 2. The three series of exposures were separated by 2 weeks. The inflammatory response in sputum was measured 6 hr (day 1), 32 hr (day 2), and 48 hr (day 3) after the first exposure, and compared with baseline values measured twice 10–30 days before the first exposure.Results: Compared with baseline measurements, the percentage of eosinophils in sputum increased by 57% after exposure to 600 ppb NO₂ (p = 0.003) but did not change significantly after exposure to 200 ppb. The slope of the association between the percentage of eosinophils and NO₂ exposure level was significant (p = 0.04). Eosinophil cationic protein in sputum was highly correlated with eosinophil count and increased significantly after exposure to 600 ppb NO₂ (p = 0.001). Lung function, which was assessed daily, was not affected by NO₂ exposure.Conclusions: We observed that repeated peak exposures of NO₂ performed without allergen exposure were associated with airway eosinophilic inflammation in asthmatics in a dose-related manner.Citation: Ezratty V, Guillossou G, Neukirch C, Dehoux M, Koscielny S, Bonay M, Cabanes PA, Samet JM, Mure P, Ropert L, Tokarek S, Lambrozo J, Aubier M. 2014. Repeated nitrogen dioxide exposures and eosinophilic airway inflammation in asthmatics: a randomized crossover study. Environ Health Perspect 122:850–855; http://dx.doi.org/10.1289/ehp.1307240     

Beyond “One Size Fits All”: Physician Nonverbal Adaptability to Patients’ Need for Paternalism and Its Positive Consultation Outcomes

In this study, we tested whether physicians’ ability to adapt their nonverbal behavior to their patients’ preferences for a paternalistic interaction style is related to positive consultation outcomes. We hypothesized that the more physicians adapt their nonverbal dominance behavior to match their patients’ preferences for physician paternalism, the more positively the patients perceive the medical interaction. We assessed the actual nonverbal dominance behavior of 32 general practitioners when interacting with two of their patients and compared it with each of their patients’ preferences for paternalism to obtain a measure of adaptability. Additionally, we measured patient outcomes with a questionnaire assessing patient satisfaction, trust in the physician, and evaluation of physician competence. Results show that the more nonverbal dominance the physician shows toward the patient who prefers a more paternalistic physician, as compared to toward the patient who prefers a less paternalistic physician (i.e., the more the physician shows nonverbal behavioral adaptability), the more positive the consultation outcomes are. This means that physicians’ ability to adapt aspects of their nonverbal dominance behavior to their individual patients’ preferences is related to better outcomes for patients. As this study shows, it is advantageous for patients when a physician behaves flexibly instead of showing the same behavior towards all patients. Physician training might want to focus more on teaching a diversity of different behavior repertoires instead of a given set of behaviors.     

Gut microbiota limits heavy metals burden caused by chronic oral exposure

Environmental exposure to pollutants such as heavy metal(s) is responsible for various altered physiological functions which are detrimental for health. The gut microbiota is critical for intestinal homeostasis but its role on xenobiotic handling is not fully understood, especially when continuous sub-chronic exposure is addressed. We first confirmed the essential role of the intestinal microbiome to limit heavy metal body burden by using germ-free mice following 6-weeks oral exposure. Significant increases of cadmium and lead absorption and dissemination in blood and target organs were measured in germ-free mice when compared with conventional specific pathogen free (SPF) mice. Besides the “barrier” function of the luminal microbiota, this may involve specific host-genes such as metallothioneins, which are differentially expressed in the gastrointestinal tract of each group of mice. Considering genes relevant for divalent metal transporters and oxidative pathways, significant differences in basal gene expression were measured between control and germ-free mice. Moreover, the magnitude of induction of these genes upon stimulation by heavy metals varied greatly depending on the dose and type of metal as well as the microbial status of the animal. Collectively, these data illustrate the complex host-microbes interplay occurring with environmental pollutants inside the gut.     

Note Free Flavonoid Aglycones from Inula montana

Inula montana L. (Asteraceae) is sometimes used in folk medicine in France in place of Arnica montana L. (and improperly called “Arnica”). A preliminary study on the flavonoid chemistry of Inula montana showed the occurrence of four major flavonoid aglycones: luteolin (5,7,3',4'-hydroxyflavone), hispidulin (5,7,4'-hydroxy-6-methoxyflavone), nepetin (5,7,3'-hydroxy-6-methoxyflavone) and cirsimaritin (5,4'-hydroxy-6,7-dimethoxyflavone). This species contains less free flavonoid aglycones (only 5 compounds detected) than Arnica montana (nearly 20 free aglycones isolated and identified).     

Fluoxetine induces glucose uptake and modifies glucose transporter palmitoylation in human peripheral blood mononuclear cells

ABSTRACT

Introduction: In line with the monoamine hypothesis of major depressive disorder (MDD), the clinical efficacy of the selective serotonin reuptake inhibitor fluoxetine has classically been ascribed to central serotonin enhancing properties. Current research described disturbances in brain energy metabolism in MDD. Additionally, fluoxetine showed beneficial effects in neuropsychiatric disorders associated with central energy imbalance.

Areas covered: The effect of in vitro fluoxetine exposure on cellular glucose uptake and cerebral glucose transporter function was assessed in human peripheral blood mononuclear cells (PBMC) and murine neuroblastoma N2a cells. Fluoxetine augmented glucose uptake, measured by utilizing the radionuclide-labled glucose analog [18]F-fluorodeoxyglucose, in PBMC without affecting glucose transporter protein content. Analysis of protein palmitoylation using the acyl-biotinyl exchange method revealed GLUT3 to be palmitoylated in PBMC and N2a cells, while palmitoylation of GLUT1 was detected only in N2a cells. Treatment with fluoxetine significantly increased palmitoylation of GLUT3 in PBMC and strongly induced palmitoylation of GLUT1 in PBMC and N2a cells.

Expert opinion: Our findings suggest a novel mechanism exerted by fluoxetine targeting glucose metabolism by regulating glucose transporter palmitoylation. Thus, fluoxetine might evoke its therapeutic effects in neuropsychiatric diseases characterized by disturbances in central energy metabolism at least partly by improving cerebral glucose uptake.     

The painDETECT project – far more than a screening tool on neuropathic pain

Background and objectives The painDETECT questionnaire (PD-Q), a simple and reliable screening questionnaire of neuropathic pain, was developed in 2004 in cooperation with the German Research Network on Neuropathic Pain. The initial aim was to implement quality management and to improve the situation of neuropathic pain (NeP) patients in Germany. The PD-Q proved immediately successful and was translated into and validated in multiple languages. Subsequently a comprehensive electronic system (PD) comprising various validated questionnaires with regard to pain typical comorbidities, such as function, sleep, mood or anxiety, was implemented Germany wide. We aimed to provide a comprehensive overview about the development and validation as well as the application of the PD-Q in various clinical conditions.

Methods This overview is based on a literature search on English full-text papers using the term ‘painDETECT’ in Medline and PubMed covering the time period from 2006 to September 2015, amended with further publications cited in the retrieved publications or provided by the questionnaire developers.

Results PD-Q as screening tool for NeP described in patients with lower back pain (8 studies), rheumatoid arthritis and osteoarthritis (10), thoracotomy (2 studies), tumor diseases (4 studies), fibromyalgia (4 studies), diverse musculoskeletal conditions (12 studies) and diverse other conditions (10 studies). In addition, the PD-Q was used in 9 studies that investigated the effect of drugs for the treatment of patients with a NeP component.

Conclusion To date more than 300,000 patients were assessed, providing the basis for one of the world’s largest datasets for chronic pain. Among others the extensive pool of PD-Q data triggered the idea of subgrouping patients on the basis of their individual sensory profiles which might in the future lead to a stratified treatment approach and ultimately to personalized therapy. Started as a healthcare utilization project in Germany, the PD-Q is nowadays used for clinical and research purposes around the world.     

Impact of interleukin-13 and -18 promoter polymorphisms in health care workers with natural rubber latex allergy

It is a matter of debate whether single nucleotide polymorphisms (SNP) in the promoter region of interleukin (IL)-13, an IgE regulator, and IL-18, an inducer of immune responses, modulating the respective protein expression, are accompanied by an increased risk of atopy, allergic asthma, and total IgE levels. The suspected associations were noted in health care workers (HCW) with and without latex allergy. IL-13 (-1055C>T) and three IL-18 (-656T>G,?-607C>A,?-137G>C) SNP were studied in 523 HCW with natural rubber latex (NRL) exposure and diagnosis in the late 1990s. Three hundred and thirty-four HCW displayed NRL sensitization and allergic symptoms, 93 with latex-allergic asthma, and 189 HCW with neither symptoms nor NRL sensitization. SNP analyses were performed by real-time polymerase chain reaction (PCR) using newly developed LightCycler assays. Analysis of IL-13?-1055C>T by analysis of variance (ANOVA) revealed significantly elevated total IgE levels in HCW carrying the CT or TT variant compared with the CC variant. None of the studied SNP showed an association with NRL-specific IgE. The IL-18 variants -656GG and -607CC displayed 99.5% linkage disequilibrium. Frequencies of alleles -656GG and -607CC were elevated in HCW with NRL asthma (48.4%) compared with HCW without symptoms (37.6%). In contrast, IL-18?-137G>C variants displayed an overall homogenous distribution. The association between the IL-13 -1055T allele and elevated total IgE levels confirms the role of a genetic background for total IgE regulation. The studied IL-18 SNP demonstrated no significant association with the clinical outcome, total IgE, or specific IgE in HCW with natural rubber latex allergy.     

Agomelatine suppresses locomotor hyperactivity in olfactory bulbectomised rats: a comparison to melatonin and to the 5-HT(2c) antagonist, S32006

The novel melatonergic agonist/5-HT(2C) antagonist agomelatine displays robust antidepressant properties in humans and is active in pre-clinical models predictive of antidepressant effects. In this study, we investigated its potential influence on the locomotor hyperactivity displayed by olfactory bulbectomised rats, a putative measure of potential antidepressant activity. In addition, we compared the actions of agomelatine to those of melatonin and S32006, a selective antagonist at 5-HT(2C) receptors. Vehicle, agomelatine (10 and 50mg/kg), melatonin (10 and 50mg/kg), S32006 (0.16mg/kg to 10mg/kg) and the prototypical tricyclic antidepressant, imipramine (10mg/kg), were administered by intraperitoneal injection for 14days to male, Sprague-Dawley sham-operated and bulbectomised rats. In agreement with previous studies, imipramine was active in the model and both the lower and higher doses of agomelatine also significantly and markedly reversed the bulbectomy-induced hyperactivity to a level comparable to that seen in sham operated animals, in which agomelatine exerted no effect. Similarly the 5-HT(2C) antagonist, S32006, dose-dependently and significantly attenuated hyperactivity of bulbectomised animals, albeit with a maximal effect somewhat less marked than that of agomelatine. On the other hand, melatonin did not affect the locomotor behaviour of bulbectomised rats. The activity of agomelatine in the model is consistent with its known antidepressant properties in the clinic.