Obesity alters the topographical distribution of ventilation and the regional response to bronchoconstriction.

Obesity is associated with reduced operating lung volumes that may contribute to increased airway closure during tidal breathing and abnormalities in ventilation distribution. We investigated the effect of obesity on the topographical distribution of ventilation before and after methacholine-induced bronchoconstriction using single-photon emission computed tomography (SPECT)-computed tomography (CT) in healthy subjects. Subjects with obesity (n = 9) and subjects without obesity (n = 10) underwent baseline and postbronchoprovocation SPECT-CT imaging, in which Technegas was inhaled upright and followed by supine scanning. Lung regions that were nonventilated (Ventnon), low ventilated (Ventlow), or well ventilated (Ventwell) were calculated using an adaptive threshold method and were expressed as a percentage of total lung volume. To determine regional ventilation, lungs were divided into upper, middle, and lower thirds of axial length, derived from CT. At baseline, Ventnon and Ventlow for the entire lung were similar in subjects with and without obesity. However, in the upper lung zone, Ventnon (17.5 ± 10.6% vs. 34.7 ± 7.8%, P < 0.001) and Ventlow (25.7 ± 6.3% vs. 33.6 ± 5.1%, P < 0.05) were decreased in subjects with obesity, with a consequent increase in Ventwell (56.8 ± 9.2% vs. 31.7 ± 10.1%, P < 0.001). The greater diversion of ventilation to the upper zone was correlated with body mass index (rs = 0.74, P < 0.001), respiratory system resistance (rs = 0.72, P < 0.001), and respiratory system reactance (rs = -0.64, P = 0.003) but not with lung volumes or basal airway closure. Following bronchoprovocation, overall Ventnon increased similarly in both groups; however, in subjects without obesity, Ventnon only increased in the lower zone, whereas in subjects with obesity, Ventnon increased more evenly across all lung zones. In conclusion, obesity is associated with altered ventilation distribution during baseline and following bronchoprovocation, independent of reduced lung volumes.NEW & NOTEWORTHY Using ventilation SPECT-computed tomography imaging in healthy subjects, we demonstrate that ventilation in obesity is diverted to the upper lung zone and that this is strongly correlated with body mass index but is independent of operating lung volumes and of airway closure. Furthermore, methacholine-induced bronchoconstriction only occurred in the lower lung zone in individuals who were not obese, whereas in subjects who were obese, it occurred more evenly across all lung zones. These findings show that obesity-associated factors alter the topographical distribution of ventilation.

Steroid insensitive fixed airflow obstruction is not related to airway inflammation in older non-smokers with asthma.

There is limited evidence linking airway inflammation and lung function impairment in older non-smoking asthmatics with fixed airflow obstruction (FAO), which can develop despite treatment with inhaled corticosteroids (ICS). We assessed lung function (spirometry, forced oscillation technique (FOT)), lung elastic recoil and airway inflammation using bronchoalveolar lavage (BAL) in non-smoking adult asthmatics with FAO, following 2 months treatment with high-dose ICS/long-acting beta-agonist. Subjects demonstrated moderate FAO, abnormal FOT indices and loss of lung elastic recoil. This cross-sectional study showed a lack of a relationship between BAL neutrophils, eosinophils, inflammatory cytokines and lung function impairment. Other inflammatory pathways or the effect of inflammation on lung function over time may explain FAO development.

The Duffy antigen receptor for chemokines regulates asthma pathophysiology.

BACKGROUND: The Duffy antigen receptor for chemokines (DARC) is an atypical receptor that regulates pro-inflammatory cytokines. However, the role of DARC in asthma pathophysiology is unknown. OBJECTIVE: To determine the role of DARC in allergic airways disease in mice, and the association between DARC single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with asthma. METHODS: Mice with targeted disruption of the Darc gene (Darc∆E2 ) or WT mice were challenged over 3 weeks with house dust mite (HDM) antigen. Allergic airways disease was assessed 24 hours and 7 days following the final challenge. Additionally, associations between DARC SNPs and clinical outcomes were analysed in a cohort of poorly controlled asthmatics. RESULTS: Total airway inflammation following HDM did not differ between Darc∆E2 and WT mice. At 24 hours, Darc∆E2 mice had increased airway hyperresponsiveness; however, at 7 days airway hyperresponsiveness had completely resolved in Darc∆E2 but persisted in WT mice. In poorly controlled asthmatics, DARC SNPs were associated with worse asthma control at randomization and subsequent increased risk of healthcare utilization (odds ratio 3.13(1.37-7.27), P=.0062). CONCLUSIONS AND CLINICAL RELEVANCE: Our animal model and human patient data suggest a novel role for DARC in the temporal regulation in asthma pathophysiology and symptoms.

Mechanisms of airway hyper-responsiveness in asthma: the past, present and yet to come.

Airway hyper-responsiveness (AHR) has long been considered a cardinal feature of asthma. The development of the measurement of AHR 40 years ago initiated many important contributions to our understanding of asthma and other airway diseases. However, our understanding of AHR in asthma remains complicated by the multitude of potential underlying mechanisms which in reality are likely to have different contributions amongst individual patients. Therefore, the present review will discuss the current state of understanding of the major mechanisms proposed to contribute to AHR and highlight the way in which AHR testing is beginning to highlight distinct abnormalities associated with clinically relevant patient populations. In doing so we aim to provide a foundation by which future research can begin to ascribe certain mechanisms to specific patterns of bronchoconstriction and subsequently match phenotypes of bronchoconstriction with clinical phenotypes. We believe that this approach is not only within our grasp but will lead to improved mechanistic understanding of asthma phenotypes and we hoped to better inform the development of phenotype-targeted therapy.

Increased airway closure is a determinant of airway hyperresponsiveness.

In order to investigate whether increased airway closure is a component of airway hyperresponsiveness (AHR), airway closure was compared during induced bronchoconstriction in 62 asthmatic, 41 nonasthmatic nonobese (control) and 20 nonasthmatic obese (obese) subjects. Airway closure and airway narrowing were measured by spirometry as percentage change in forced vital capacity (%DeltaFVC) and change in forced expiratory ratio (DeltaFER), respectively. Multiple regression analyses were used to assess the determinants of AHR, assessed by the dose response slope (DRS). The DRS was significantly increased in asthmatics compared with controls but did not differ between obese and controls. The spirometric predictors of logDRS were baseline FER, DeltaFER, body mass index (BMI) and %DeltaFVC. There was a negative relationship between BMI and logDRS in the regression, suggesting a protective effect. The present findings suggest that the extent of airway closure during induced bronchoconstriction is a determinant of airway hyperresponsiveness, independent of the level of airway narrowing. However, after adjusting for airway closure, obesity appears to protect against airway hyperresponsiveness.

Aggregation of Staphylococcus aureus following treatment with the antibacterial flavonol galangin.

AIM: The flavonol galangin, an antimicrobial constituent of the traditional medicines propolis and Helichrysum aureonitens, is being assessed as part of an ongoing investigation into the antibacterial activity of flavonoids. The present study sought to establish whether galangin has any aggregatory effect on bacterial cells. METHODS AND RESULTS: In preparatory time-kill assays, 50 microg ml(-1) of galangin was found to reduce colony counts of c. 5 x 10(7) CFU ml(-1)Staphylococcus aureus NCTC 6571 by approximately 15 000-fold during 60 min of incubation. Subsequent light microscopy studies demonstrated significant increases in the number of large clusters of bacterial cells in populations treated with the flavonol. CONCLUSION: Data presented here show that galangin causes aggregation of bacterial cells. SIGNIFICANCE AND IMPACT OF THE STUDY: The finding that galangin causes bacterial cells to clump together may implicate the cytoplasmic membrane as a target site for this compound's activity. More importantly, this observation indicates that decreases in CFU numbers detected in time-kill and minimum bactericidal concentration (MBC) assays in previous investigations were at least partially attributable to this aggregatory effect. This raises the possibility that galangin is not genuinely bactericidal in action, and calls into question the suitability of time-kill and MBC assays for determining the nature of activity of naturally occurring flavonoids.

Postantibiotic effect of meropenem on members of the family Enterobacteriaceae determined by five methods.

The postantibiotic effect (PAE) of meropenem was determined for 11 strains, both clinical isolates and reference strains of members of the family Enterobacteriaceae. The study compares PAE results obtained by five methods used to monitor bacterial regrowth, including viable counting, alone and in combination with impedance; bioluminescence, alone and in combination with impedance; and a morphological technique. After exposure of the test organisms to meropenem (0.1 x to 100 x MIC) for 2 h, concentration-dependent differences in counts by bioluminescence and viable counts were observed, the latter always being lower. The differences varied with the test organism. For example, after exposure of Providentia stuartii NCTC 10318 to 0.1 x MIC, the counts were 5.5 x 10(5) and 2.0 x 10(5) whereas after exposure of Citrobacter freundii MR76 to 0.1 x MIC of meropenem the counts were 2.3 x 10(6) and 6.8 x 10(3) by bioluminescence and viable counting, respectively. The discrepancies were probably due to the relative inability of the viable counting procedure to detect fragile aberrant morphologies and resulted in differences in the calculated PAE values. With methods which do not detect fragile morphologies, the PAE may be underestimated. A general trend was observed for the order of magnitude of the PAEs by the following methods (in order of decreasing magnitude of PAE): (i) morphological technique, (ii) bioluminescence technique alone, (iii) bioluminescence in combination with impedance, (iv) viable counting in combination with impedance, and (v) viable counting alone. It is our opinion that of the methods examined in this study, bioluminescence in combination with impedance best reflects the true values for PAEs, and these results were examined more closely.

Comparison of methodologies used in assessing the postantibiotic effect.

The postantibiotic effect (PAE) of the carbapenem antibiotic meropenem was determined for the reference strains of Escherichia coli NCTC 4174 and E. coli NCTC 12210. Regrowth of bacteria after antibiotic exposure was determined by viable counting and bioluminescence alone and in combination with an impedance technique and a morphological technique was also employed. Different methods of calculating the PAE were also used. After exposure of E. coli to 0.1-100 x MIC of meropenem for 2 h, concentration dependent differences in counts by bioluminescence, and viable counting were observed, the latter always being lower. The unexposed control of E. coli NCTC 4174 yielded counts of 1.1 x 10(6) +/- 1.1 x 10(5) and 1.3 x 10(6) +/- 4.7 x 10(5) by viable counting and bioluminescence respectively and E. coli NCTC 12210 gave counts of 4.2 x 10(6) +/- 1.8 x 10(6) and 1.1 x 10(7) +/- 4.3 x 10(6) by the same methods. After exposure to 100 x MIC of meropenem, NCTC 4174 yielded counts of 1.28 x 10(3) +/- 5.35 x 10(2) and 2.59 x 10(5) +/- 8.61 x 10(4) and NCTC 12210 gave counts of 5.22 x 10(3) +/- 9.74 x 10(2) and 5.21 x 10(6) +/- 1.45 x 10(6) by viable counting and bioluminescence, respectively. The discrepancies were due to the inability of the viable counting procedure to detect spheroplasts. Falsely low post exposure counts led to falsely low determinations of PAE by viable counting alone and in combination with the impedance technique.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of posterior cortical lesions on responses to visual threats in the Mongolian gerbil (Meriones unguiculatus).

Mongolian gerbils received aspiration lesions of either primary visual cortex (PVC), medial extrastriate visual cortex, retrosplenial cortex (RSC), or sham operations. The responses of gerbils to the presentation of an overhead visual stimulus were recorded in an open field. In all groups, presentation of the stimulus produced an increase in rearing. This suggests that the stimulus was detected by all animals. Gerbils with RSC or PVC lesions showed reduced levels of response to the stimulus. We suggest that some of the observed deficits can be explained as failures to produce responses to threat that are appropriate to the context in which the the threat was presented.

Calibration of retinal image size with distance in the Mongolian gerbil: rapid adjustment of calibrations in different contexts.

Mongolian gerbils were trained to jump from one platform to another across a gap whose size varied randomly from trial to trial. In test sessions, probe landing platforms differing in width from those used in training were used, and the distance that the animals jumped was measured. The first experiment demonstrated that the gerbils learned to calibrate the retinal image size of the landing platform with its distance and that they could learn more than one calibration at a time. The second experiment provided evidence that such calibrations are rapidly adjusted to environmental contingencies. These findings suggest that retinal image size might be a useful distance cue for gerbils in a variety of ecological contexts.

Tris- and deoxycholate-induced lysis in colistin-treated Proteus strains.

Strains of Proteus spp. were pretreated with colistin (polymyxin E) and resuspended in either Tris buffer or sodium deoxycholate. Leakage of potassium and materials with an absorption maxima at 260 nm increased on resuspension of two pretreated Proteus mirabilis strains in Tris buffer or sodium deoxycholate. The activity of Tris increased up to pH 9 and of sodium deoxycholate up to 1,000 micrograms/ml. Greater leakage occurred with resuspension in Tris buffer than in sodium deoxycholate. Other Proteus strains tested did not produce leakage following similar treatment.

Pretreatment with colistin and Proteus sensitivity to other agents.

The effects of pretreatment with colistin (polymyxin E) on the sensitivity of Proteus mirabilis, P. vulgaris and P. morganii strains to tris and sodium deoxycholate (DOC) have been studied. Pretreatment of two P. mirabilis strains (NCTC 60 and 4199) with low concentrations (0.25 approximately 1 microgram/ml) of colistin rendered them sensitive to lysis by tris (0.05M) or DOC (250 approximately 1,000 microgram/ml) although DOC induced lysis of control (non-colistin-treated) suspensions also. In contrast, the other P. mirabilis strains, as well as the P. vulgaris and P. morganii strains were little affected by tris (0.2M) or DOC (10,000 microgram/ml) even after exposure of the cells to high colistin concentrations (up to 500 microgram/ml). Colistin-pretreated or control cells of P. mirabilis NCTC 60 rapidly lost viability when suspended in water but not when held in 0.16M sodium chloride solution. Ethylenediamine tetraacetate-pretreated cells of strains 60 and 4199 were fairly sensitive to tris, although the extent of the lysis was less than when colistin was used as pretreating agent. One strain of P. vulgaris (NCTC 4175) became sensitive to tris and to DOC following exposure of the cells to ampicillin.