Airway inflammation and mannitol challenge test in COPD

Background

Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD.

Methods

Twenty-eight patients (age 58 ± 7.8 yr, packyears 40 ± 15.5, post-bronchodilator FEV₁ 77 ± 14.0%predicted, no inhaled steroids ≥4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum.

Results

There was a positive correlation between RDR to mannitol and eosinophil numbers (r = 0.47, p = 0.03) and level of IL-8 (r = 0.46, p = 0.04) in hypertonic saline-induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r = 0.71, p = 0.001), level of ECP (r = 0.72, p = 0.001), IL-8 (r = 0.57, p = 0.015) and MPO (r = 0.64, p = 0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum.

Conclusions

In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD.

Trial registration

Netherlands Trial Register (NTR): NTR1283     

The role of oxytocin and oxytocin receptor gene variants in childhood-onset aggression

Aggressive antisocial behaviours are the most common reasons why adolescents are referred to mental health clinics. Antisocial behaviours are costly in social and financial terms. The aetiology of aggressive behaviours is unknown but growing evidence suggests it is heritable, and certain genetic variants have been implicated as contributing factors. The purpose of this study was to determine whether genes regulating the hormone oxytocin (OXT) were associated with aggressive antisocial behaviour. The case-control study sample consisted of 160 cases of children displaying extreme, persistent and pervasive aggressive behaviour. This case sample was compared with 160 adult controls. We used polymerase chain reaction (PCR) to determine the genotype for three oxytocin gene (OXT) single nucleotide polymorphisms (SNPs): rs3761248, rs4813625 and rs877172; and five oxytocin receptor gene (OXTR) SNPs: rs6770632, rs11476, rs1042778, rs237902 and rs53576. Genotypic analyses were performed using stata, while differences in haplotypic and allelic frequencies were analysed using Unphased. We also performed within-case analyses (n = 236 aggressive cases) examining genotypic and allelic associations with callous-unemotional (CU) scores (as measured by the psychopathic screening device). OXTR SNPs rs6770632 and rs1042778 may be associated with extreme, persistent and pervasive aggressive behaviours in females and males, respectively. These and haplotype results suggest gender-specific effects of SNPs. No significant differences were detected with respect to CU behaviours. These results may help to elucidate the biochemical pathways associated with aggressive behaviours, which may aid in the development of novel medications.     

The maintenance of challenge strains used in the potency test for canine leptospira vaccines.

The challenge test for leptospira vaccines required by most licensing authorities is difficult to standardise and unreliable. One of the main contributory factors to this, is the difficulty in maintaining the virulence of the challenge strain. This paper describes work carried out to assess the practicality of storing challenge strains of Leptospira canicola and Leptospira icterohaemorrhagiae in liquid nitrogen. The effects of different concentrations of glycerol and dimethyl sulphoxide on the recovery of virulent and avirulent strains of Leptospira canicola and Leptospira icterohaemorrhagiae were investigated. Concentrations of cryopreservant above 5% increased the time taken for the leptospires to grow after recovery from vials stored in liquid nitrogen. In addition, the virulence of five challenge strains were shown to be little affected after 18 passages in vitro.     

The pineal and oxytocin synthesis.

The aim of this study was to investigate the effect of pineal removal on oxytocin synthesis in the hypothalamus using the colchicine method. To this end, rats were injected intracerebroventricularly (i.c.v.) with colchicine solution (5 microg/5 microl) or normal saline and decapitated 20 h later. The animals were either pinealectomized or sham-operated two or eight weeks before i.c.v. injection. The oxytocin content in the hypothalamus was significantly higher in colchicine-treated rats whereas no significant differences were seen in the neurohypophysial hormone level between saline- or colchicine-injected animals. Thus, colchicine inhibited the hormonal transport but probably did not affect the function of the neurohypophysis. Two weeks after pinealectomy neither the oxytocin synthesis rate nor its neurohypophysial content were significantly different from control values. The oxytocin synthesis rate was increased markedly eight weeks after pineal removal. At that time, the neurohypophysial oxytocin content was reduced suggesting the increased secretion of the hormone. It is concluded that the pineal has an inhibitory impact on both oxytocin synthesis and release.     

Molecular docking-based test for affinities of two ligands toward vasopressin and oxytocin receptors.

Molecular docking simulations are now fast developing area of research. In this work we describe an effective procedure of preparation of the receptor-ligand complexes. The amino-acid residues involved in ligand binding were identified and described.     

Influence of outdoor temperature and humidity on the methacholine challenge test

Objective of this study was to evaluate whether outdoor temperature and humidity can influence methacholine test results in outpatients living in temperate areas. 4,723 subjects (2,391 males; age: 35.1 ± 16.15; FEV₁ = 100.36 % [relative interquartile range (IQR):92.34–108.8]) that performed methacholine tests for suspected asthma between 2000 and 2010 were considered. Outdoor minimum, mean, and maximum temperature values (°C), relative humidity (%), and dew point (T _dp), registered when performing the tests, were examined. Airways hyperresponsive patients, with PD₂₀ (provocative dose to obtain a 20 % fall in FEV1) <3,200 μg were 2,889 (61.2 %) and median PD₂₀ was 359 μg [IQR:160-967]. On receiving operating curve (ROC) analysis, temperature, humidity, and T _dp did not significantly predict airways hyperresponsiveness (AHR), even using a 200, 800, and 3,200 μg cutoffs to identify AHR. When subjects were subdivided into subgroups, according to different levels of temperature, humidity, and dew point, no differences in PD₂₀ and prevalence were found. Only a higher number of hyperresponsive subjects was detected in smokers when they were tested in hot and humid conditions. A weak but significantly positive relationship between PD₂₀ and mean, maximum, and minimum temperatures was detected in severe hyperresponsive subjects (PD₂₀ < 200 μg) (r = 0.100, 0.112, 0.110, respectively; p = 0.001). The regression logistic model showed that maximum temperature was a significantly protective factor for AHR (OR:0.995, 95 % CI: 0.982–0.998; p = 0.012) especially in severe hyperresponsive subjects (OR:0.988, 95 % CI: 0.977–0.999; p = 0.035). In conclusion, weather conditions do not seem to influence PD₂₀ values obtained with methacholine tests in real life. Hot and humid environments may increase the prevalence of AHR in smokers while a temperature increase may reduce the AHR risk especially in severe hyperresponsive subjects.     

The cross-generation transmission of oxytocin in humans

Animal studies demonstrated that the neuropeptide oxytocin (OT), implicated in bond formation across mammalian species, is transmitted from mother to young through mechanisms of early social experiences; however, no research has addressed the cross-generation transmission of OT in humans. Fifty-five parents (36 mothers and 19 fathers) engaged in a 15-min interaction with their infants. Baseline plasma OT was sampled from parents and salivary OT was sampled from parents and infants before and after play and analyzed with ELISA methods. Interactions were micro-coded for parent and child's socio-affective behavior. Parent and infant's salivary OT was individually stable across assessments and showed an increase from pre- to post-interaction. Significant correlations emerged between parental and infant OT at both assessments and higher OT levels in parent and child were related to greater affect synchrony and infant social engagement. Parent-infant affect synchrony moderated the relations between parental and infant OT and the associations between OT in parent and child were stronger under conditions of high affect synchrony. Results demonstrate consistency in the neuroendocrine system supporting bond formation in humans and other mammals and underscore the role of early experience in shaping the cross-generation transmission of social affiliation in humans.