Comparison of FEV1 and specific airway conductance in assessing airway response to occupational agents

BACKGROUND: There is theoretical evidence that specific airway conductance (SGaw) could be more reliable than forced expiratory volume in 1 s (FEV1) for assessing changes in airway calibre. We investigated the changes in FEV1 and SGaw when assessing bronchial responses to occupational agents. METHODS: SGaw and FEV1 were measured during inhalation challenges with various occupational agents in 174 consecutive subjects investigated for possible occupational asthma. RESULTS: A decline in SGaw of 50% or greater was documented in 77 of 90 subjects (86%) who showed a >/=20% fall in FEV1 and in 11 of 84 subjects (13%) who failed to demonstrate such a fall in FEV1. Among subjects who developed a >/=20% fall in FEV1, those who failed to develop a >/=50% decline in SGaw had a lower baseline SGaw than those who did. Among the group without a >/=20% fall in FEV1, a >/=50% decrease in SGaw was associated with either an 'intermediate' fall in FEV1 (between 15 and 17% from baseline value) (n = 4), a significant postchallenge increase in nonspecific bronchial hyper-responsiveness to histamine (n = 2), or both features (n = 3). CONCLUSIONS: A decline in SGaw of 50% or greater may provide useful complementary evidence of a bronchial response during challenges that produce equivocal results in FEV1.     

Comparison of airway conductance and FEV(1) as measures of airway responsiveness to methacholine. Discrimination of small differences in bronchial responsiveness with Gaw and FEV(1).

When defining bronchial responsiveness in healthy, non-asthmatic, subjects exposed in different working situations, it is not clear whether different outcome measures yield similar results. Therefore, the concentration and dose of methacholine that caused a 20% decrease in forced expiratory volume in 1 s (FEV(1)) (PC20(FEV(1)) and PD20(FEV(1))), the corresponding change in Gaw and the relationship between the dose-response slope (DRS) for FEV(1) and Gaw was studied in different working populations and healthy control subjects (n=1038). The two outcome measures were compared in groups of subjects in whom differences in bronchial responsiveness could be anticipated [atopics (n=72) and non-atopics (n= 207) and subjects exposed (n=54) and not exposed (n=32) to saw dust]. A bronchial challenge was also made before and after exposure in a swine confinement building, an exposure known to increase bronchial responsiveness (n=37). PD20(FEV(1)) was 1.7 mg in atopics and 4.9 mg in non-atopics, 7.1 mg in saw dust exposed and >20 mg in non-exposed subjects and 5.3 mg before and 0.79 mg after exposure to organic dust. There was a correlation between DRS(FEV(1)) and DRS(Gaw), r=0.87 (P<0.001). In subjects who were highly sensitive to methacholine a 20% change in FEV(1) corresponded to <40% change in Gaw, while a 20% decrease in FEV1 corresponded to none or a minor decrease in Gaw in subjects with less methacholine-sensitive airways. The ability to detect differences in bronchial responsiveness between groups, or to detect changes in bronchial responsiveness following exposure was approximately the same for FEV(1) and Gaw. The reproducibility was similar for both variables and a second measurement was within one doubling of the methacholine concentration of the first provocation in approximately 95% of all measurements (n=41). In conclusion, with our methacholine provocation method, FEV(1) and Gaw had similar sensitivity in detecting small differences in bronchial responsiveness in healthy subjects.     

Longitudinal analysis of FEV1 changes related to antibiotic therapy in children with cystic fibrosis

The measurement of FEV1 in children with cystic fibrosis has been shown to be the most important objective measurement for survival. It has been observed that children receiving intravenous antibiotics usually show a significant improvement in FEV1 with therapy in the short term. We hypothesized that the FEV1 measured pre-antibiotic therapy and followed longitudinally would show a greater rate of decline and may be a better prognostic indicator than the FEV1 post antibiotic therapy. The study cohort consisted of 60 children with cystic fibrosis who attended the St. James' Hospital cystic fibrosis unit between 1993 and 1999. Mixed model regression analysis provided estimates of the average rate of change of the pre-FEV1, post-FEV1 and FEV1 difference in subgroups based on survival, sex and pseudomonas status. There was no significant difference seen in the rate of decline of the FEV1 difference when comparing those who died and those who survived (p = 0.93). This was also the case when males were compared to females (p = 0.09). Both pre-antibiotic FEV1 and post-antibiotic FEV1 measurements showed a significant difference in rate of decline when comparing those who died (FEV1 slope = -6.4, -6.3) to those who survived (FEV1 slope = -1.9, -1.7) [p = 0.001, p = 0.0005] and when males (FEV1 slope = -0.6, -0.03) were compared to females (FEV1 slope = -3.3, -3.5) [p = 0.03, p = 0.002]. Our study demonstrated that there was no additional value in measuring FEV1 pre-antibiotic therapy compared to the FEV1 post antibiotic therapy in improving the sensitivity of FEV1 as a marker of decline. This study confirms that the rate of decline in FEV1 is a strong predictor of mortality and that females in this age group decline faster than their male counterparts.     

FEV(1) is associated with risk of asthma attacks in a pediatric population

BACKGROUND: FEV(1) is endorsed by the National Asthma Education and Prevention Program as a means for grading asthma severity. However, few data exist on the relationship between FEV(1) and asthma outcomes during long-term follow-up. OBJECTIVE: We explored the relationship between the percent predicted FEV(1) (FEV(1)%) and subsequent asthma attacks in a longitudinal study of pediatric lung health. METHODS: A retrospective cohort of 13,842 children (100,292 observations) seen annually over a 15-year interval was analyzed for measurement of pulmonary function, and a respiratory questionnaire was completed. Up to grade 9, a standard questionnaire was completed by a parent or guardian; thereafter it was completed by the patient. For each observation, the report of an attack during the past year was paired with FEV(1) recorded at the field survey 1 year earlier. RESULTS: A progressive decrease in the proportion of individuals reporting an attack was associated with increasing decile of FEV(1)%. Two categorization schemes for FEV(1)% were examined: a scheme based on the National Asthma Education and Prevention Program recommendations (<60%, 60%-80%, and >80%), and an alternative scheme (<80%, 80%-100%, and >100%). In multivariate models, FEV(1)% was an independent predictor of attacks: among the parental report group, the odds ratios were 2.1 (95% CI, 1.3-3.4) and 1.4 (95% CI, 1.2-1.6) for FEV(1)% < 60% and FEV(1)% of 60% to 80% compared with FEV(1)% > 80%, respectively; and among the self-report group, odds ratios were 5.3 (95% CI, 2.2-12.9) and 1.4 (95% CI, 1.2-1.7) for FEV(1)% < 60% and FEV(1)% of 60% to 80% compared with FEV(1)% > 80%, respectively. With the alternative classification scheme, the relationship was similar, but the difference in risk between categories of FEV(1)% decreased. CONCLUSION: The strong association between FEV(1)% and risk of asthma attack over the subsequent year supports an emphasis on objective measures of lung function in assessment of risk for adverse asthma outcomes.     

Physiological and psychosocial age-related changes associated with reduced food intake in older persons

Dietary intake changes during the course of aging. Normally an increase in food intake is observed around 55 years of age, which is followed by a reduction in food intake in individuals over 65 years of age. This reduction in dietary intake results in lowered levels of body fat and body weight, a phenomenon known as anorexia of aging. Anorexia of aging has a variety of consequences, including a decline in functional status, impaired muscle function, decreased bone mass, micronutrient deficiencies, reduced cognitive functions, increased hospital admission and even premature death. Several changes during lifetime have been implicated to play a role in the reduction in food intake and the development of anorexia of aging. These changes are both physiological, involving peripheral hormones, senses and central brain regulation and non-physiological, with differences in psychological and social factors. In the present review, we will focus on age-related changes in physiological and especially non-physiological factors, that play a role in the age-related changes in food intake and in the etiology of anorexia of aging. At the end we conclude with suggestions for future nutritional research to gain greater understanding of the development of anorexia of aging which could lead to earlier detection and better prevention.     

Sustained sleep fragmentation results in delayed changes in hippocampal-dependent cognitive function associated with reduced dentate gyrus neurogenesis

Sleep fragmentation (SF) is prevalent in human sleep-related disorders. In rats, sustained SF has a potent suppressive effect on adult hippocampal dentate gyrus (DG) neurogenesis. Adult-generated DG neurons progressively mature over several weeks, and participate in certain hippocampal-dependent cognitive functions. We predicted that suppression of neurogenesis by sustained SF would affect hippocampal-dependent cognitive functions in the time window when new neurons would reach functional maturity. Sprague–Dawley rats were surgically-prepared with electroencephalogram (EEG) and electromyogram (EMG) electrodes for sleep state detection. We induced sleep-dependent SF for 12 days, and compared SF animals to yoked sleep fragmentation controls (SFC), treadmill controls (TC) and cage controls (CC). Rats were injected with bromodeoxyuridine on treatment days 4 and 5. Rats were returned to home cages for 14 days. Cognitive performance was assessed in a Barnes maze with 5 days at a constant escape position followed by 2 days at a rotated position. After Barnes maze testing rats were perfused and DG sections were immunolabeled for BrdU and neuronal nuclear antigen (NeuN), a marker of mature neurons.SF reduced BrdU-labeled cell counts by 32% compared to SFC and TC groups. SF reduced sleep epoch duration, but amounts of rapid eye movement (REM) sleep did not differ between SF and SFC rats, and non-rapid eye movement (NREM) was reduced only transiently. In the Barnes maze, SF rats exhibited a progressive decrease in escape time, but were slower than controls. SF animals used different search strategies. The use of a random, non-spatial search strategy was significantly elevated in SF compared to the SFC, TC and CC groups. The use of random search strategies was negatively correlated with NREM sleep bout length during SF. Sustained sleep fragmentation reduced DG neurogenesis and induced use of a non-spatial search strategy, which could be seen 2 weeks after terminating the SF treatment. The reduction in neurogenesis induced by sleep fragmentation is likely to underlie the delayed changes in cognitive function.     

Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs

DISC1 has been identified as a schizophrenia susceptibility gene based on linkage and SNP association studies and clinical data suggesting that risk SNPs impact on hippocampal structure and function. In cell and animal models, C-terminus-truncated DISC1 disrupts intracellular transport, neural architecture and migration, perhaps because it fails to interact with binding partners involved in neuronal differentiation such as fasciculation and elongation protein zeta-1 (FEZ1), platelet-activating factor acetylhydrolase, isoform Ib, PAFAH1B1 or lissencephaly 1 protein (LIS1) and nuclear distribution element-like (NUDEL). We hypothesized that altered expression of DISC1 and/or its molecular partners may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and these selected binding partners as well as reelin, a protein in a related signaling pathway, in the hippocampus and dorsolateral prefrontal cortex of postmortem human brain patients with schizophrenia and controls. We found no difference in the expression of DISC1 or reelin mRNA in schizophrenia and no association with previously identified risk DISC1 SNPs. However, the expression of NUDEL, FEZ1 and LIS1 was each significantly reduced in the brain tissue from patients with schizophrenia and expression of each showed association with high-risk DISC1 polymorphisms. Although, many other DISC1 binding partners still need to be investigated, these data implicate genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.     

小气道病变患者小气道黏膜层免疫病理的变化

探讨小气道病变患者小气道黏膜层的免疫病理学特点。86例因肺局限性病变需行肺叶切除患者,分为小气道病变组34例、COPD组22例及肺功能正常组30例。收集术后肺标本,应用免疫组化法检测小气道黏膜层内CD3^ 、CD8^ 、CD68^ 、CD45RA^ 、CD45RO^ 、CD20^ 细胞,并与FEV1．0、V50、V25做相关性分析。小气道病变组、COPD组CD3^ 、CD8^ 、CD68^ 细胞数明显高于正常组;而小气道病变组与COPD组相比无差异;小气道病变组CD8^ 细胞数与V50呈显著负相关;正常组内吸烟者CD45R0^ 细胞数明显高于非吸烟者;在小气道病变组或COPD组内,吸烟与非吸烟者之间CD3^ 、CD8^ 、CD45RO^ 细胞数均无差异;小气道病变组内非吸烟者CD68^ 细胞数高于吸烟者及正常非吸烟者。T淋巴细胞尤其CD8^ 细胞及CD68^ 细胞在小气道病变及COPD炎性过程中有重要意义,吸烟可导致CD45RO^ 细胞在小气道黏膜集聚,CD68^ 在非吸烟因素致小气道病变中意义更大。     

Altered protein expression profile associated with phenotypic changes in lung fibroblasts co-cultured with gold nanoparticle-treated small airway epithelial cells

Despite the availability of toxicity studies on cellular exposure to gold nanoparticles (AuNPs), there is scarcity of information with regard to the bystander effects induced by AuNPs on neighboring cells not exposed to the NPs. In this study, we showed that exposure of small airway epithelial cells (SAECs) to AuNPs induced changes in protein expression associated with functional effects in neighboring MRC5 lung fibroblasts in a co-culture system. Uptake of 20 nm size AuNPs by SAECs was first verified by focused ion beam scanning electron microscopy. Subsequently, pretreated SAECs were co-cultured with unexposed MRC5 lung fibroblasts, which then underwent proteome profiling using a quantitative proteomic approach. Stable-isotope labeling by amino acids in cell culture (SILAC)–based mass spectrometry identified 109 proteins (which included 47 up-regulated and 62 down-regulated proteins) that were differentially expressed in the lung fibroblasts co-cultured with AuNP pretreated SAECs. There was altered expression of proteins such as Paxillin, breast cancer anti-estrogen resistance 1 and Caveolin-1, which are known to be involved in the cell adhesion process. Morphological studies revealed that there was a concomitant increase in cell adhesion and altered F-actin stress fiber arrangement involving vinculin in the lung fibroblasts. It is likely that phenotypic changes observed in the underlying lung fibroblasts were mediated by AuNP-induced downstream signals in the pretreated SAECs and cell–cell cross talk.     

Capsule structure changes associated with Cryptococcus neoformans crossing of the blood-brain barrier

Cryptococcus neoformans is a yeast responsible for disseminated meningoencephalitis in patients with cellular immune defects. The major virulence factor is the polysaccharide capsule. We took advantage of a relevant murine model of disseminated meningoencephalitis to study the early events associated with blood-brain barrier (BBB) crossing. Mice were sacrificed at 1, 6, 24, and 48 hours post-intravenous inoculation, and classical histology, electron microscopy, and double immunofluorescence were used to study tissues and yeasts. Crossing of the BBB occurred early after inoculation, did not involve the choroid plexus but instead occurred at the level of the cortical capillaries, and caused early and severe damage to the structure of the microvessels. Seeding of the leptomeninges was not the primary event but occurred secondary to leakage of cortical pseudocysts. Organ invasion was associated with changes in cryptococcal capsule structure and cell size, which differed in terms of magnitude and kinetics, depending on both the organs involved, and potentially, on the bed structure of the local capillary. The rapid changes in capsule structure could contribute to inability of the host immune response to control cryptococcal infection in extrapulmonary spaces.     

Twelve year FEV1 changes and smoking habits among 556 workers in the Paris-area (author's transl)

The aim of the study was to analyse the effects of smoking, in particular to show its causal role in the development of airflow obstruction, and to look at changes in smoking habits. The study was conducted among 556 men, aged 30 to 54 in 1960, surveyed twice, in 1960 and 1972. The hypothesis of tobacco as a causal factor of airflow obstruction is strengthened, following this study, by three results: 1) FEV1 slope was related to tobacco consumption, even after adjustement for FEV1 level (42 ml/yrs for non-smokers, 51 ml/yrs for heavy smokers); 2) FEV1 loss with age increased with the amount of tobacco consumption: one pack a day smoked for 25 years was equivalent to an aging of 5 years; 3) FEV1 loss decelerated if the subject gave up smoking, thus preventing any further risk. What appeared to be a spontaneous regulation in smoking habits was observed. The men who stopped smoking were those with low respiratory status. In this population, men who were ex-smokers in 1960 and maintained this status until 1972 had a FEV1 slope similar to that of the non-smokers.     

High indoor microbial levels are associated with reduced Th1 cytokine secretion capacity in infancy

Background: Exposure to microbes and their components may affect the maturation of the immune system. We examined the association of house dust microbial content with cytokine-producing capacity at birth and at the age of 1 year. Methods: Production of TNF-α, IFN-γ, IL-5, IL-8 and IL-10 at birth (n = 228) and at the age of 1 year (n = 200) following 24- and 48-hour whole-blood stimulation with staphylococcal enterotoxin B (SEB), lipopolysaccharide and the combination of phorbol ester and ionomycin was measured. Concentrations of ergosterol (marker for fungal biomass), muramic acid (marker for Gram-positive bacteria) and 3-hydroxy fatty acids with a carbon chain length from 10 to 14 (marker for Gram-negative bacteria) in living room floor dust were analyzed using gas chromatography-tandem mass spectrometry. Five single microbial species or groups were determined using a quantitative polymerase chain reaction method. Results: A high total level of the studied Gram-positive bacteria in general or Mycobacterium spp. in house dust was associated with decreased SEB-stimulated IFN-γ production, especially at the age of 1 year. The total level of indoor fungi analyzed (Penicillium spp., Aspergillus spp. and Paecilomyces variotii group, Trichoderma viride/atroviride/koningii,Wallemia sebi) was also inversely associated with IFN-γ production at the age of 1 year, but this association did not remain significant after adjustment for potential confounders. A few associations were found between microbial exposures and other measured cytokines. Conclusions: High indoor microbial exposures may affect immune development in early life by reducing T helper type 1 cytokine secretion capacity. The observed hyporesponsiveness may reflect the adaptation of the immune system to environmental antigens. In future, more attention should be paid especially to the immunomodulatory role of exposures to Gram-positive bacteria.     

Ultrastructural changes in rat airway epithelium in asthmatic airway remodeling

ObjectivesTo explore asthmatic rat airway epithelial cells mitochondrial ultrastructure changes.MethodsSix female Wistar rats of the same weight (60–80 g) were randomly divided into two groups: the asthmatic group and the control group. According to the OVA inhaled method, the asthmatic airway remodeling rat model was established. Epithelial tissue of the rat trachea was taken from the two groups for transmission electron microscopy (TEM); we counted the number of mitochondria and observed the airway ciliated epithelium, intercellular collagen deposition in the two rat groups and mitochondrial ultrastructure change.ResultsAirway multilayer ciliated epithelium develops, with cilia fallen off; goblet cells increased and irregular, mitochondrial basement membrane density is decreased, mitochondrial crista is reduced, and the nucleus has more incisures and irregular shape in asthmatic rats; airway epithelial cell matrix collagen deposition increased; and lamellar body and mitochondrial cavity formation.ConclusionsIn the asthmatic rat airway, epithelial cells undergo apoptosis and the numbers of mitochondria increased compared with the ones in normal rat airway but lose normal structure.     

联合FEV1/FEV3与血清IL-6、TNF-α对轻中度慢性阻塞性肺疾病诊断和预后评估的研究

目的评估第1秒用力呼气容积(FEV1)/第3秒用力呼气容积(FEV3)联合血清白介素6(IL- 6)、肿瘤坏死因子α(TNF-α)对轻中度慢性阻塞性肺疾病(COPD)的诊断及预后评估价值。方法收集我院2011年1月至2013年10月140 例轻中度COPD患者为病例组,与同期在我院行体检的健康人群150 例为对照组,对两组研究对象进行肺功能检查与血清IL- 6、TNF-α检测。采用受试者工作特征曲线(ROC)分析FEV1/FEV3、IL- 6、TNF-α对COPD的诊断价值。依据患者纳入研究的时间依次进行40个月的随访,统计随访期间COPD急性加重(AECOPD)的发生次数与死亡人数,采用Kaplan- Meier法和对数秩检验(log- rank test)进行生存分析。结果 COPD患者的FEV1/FEV3显著低于健康人群,而血清IL- 6、TNF-α水平则显著高于对照组,差异具有统计学意义( P <0.05)。ROC分析结果表明,FEV1/FEV3、IL- 6、TNF-α诊断COPD的曲线下面积(AUC)分别为:0.786(95% CI :0.702~0.871, P <0.001)、0.518(95% CI :0.421~0.616, P =0.708)和0.684(95% CI :0.592~0.776, P <0.001);灵敏度/特异性分别为:86.1%/67.4%、58.1%/57.7%和58.4%/78.4%;联合三项指标的AUC为0.901(95% CI :0.840~0.963, P <0.001),在“并联”时,“PRE- 1值”约登指数为最大值时的灵敏度和特异性分别为90.6%和64.2%,对应的FEV1/FEV3、IL- 6和TNF-α的判断值分别为73.95%、10.13 ng/L和2.26μg/L;在“串联”时,“PRE- 1值”约登指数为最大值时的灵敏度为78.2%,特异性为98.1%,对应的FEV1/FEV3、IL- 6和TNF-α的判断值分别为72.32%、9.73 ng/L和2.21μg /L。随访及生存分析结果表明,低FEV1/FEV3组及高IL- 6、高TNF-α组的COPD患者AECOPD的平均发生次数及发生率均增高,而低FEV1/FEV3组及高TNF-α组生存时间均降低,差异具有统计学意义( P <0.05)。结论 FEV1/FEV3联合血清IL- 6、TNF-α检测对轻中度COPD具有较高的诊断和预后评估价值,可考虑在临床推广使用。     

GSTP1 hypermethylation is associated with reduced protein expression, aggressive disease and prognosis in neuroblastoma

Epigenetic modifications such as methylation of CpG islands in tumor-suppressor gene promoter regions have been associated with tumor development in many human cancers. Using methylation specific multiplex ligation-dependent probe amplification method, we analyzed the methylation status of 35 different genes in 16 neuroblastoma (NB) cell lines and 50 NB tumor samples (NBs), and investigated whether specific hypermethylation was associated with biological and/or clinical parameters. Among the genes found hypermethylated, the effect of GSTP1 hypermethylation on mRNA and protein expression was also explored. The median number of hypermethylated genes was higher in cell lines compared to NBs (5.5 vs. 2). For eight genes, aberrant methylation of CpG-islands in NB was not (ESR1, PAX5, WT1, CADM1, MSH6, and CDKN2B) or very rarely (CDH13 and GSTP1) reported in literature. GSTP1 was found hypermethylated in 44% of the NB cell lines and in 33% of the stage 4-11qLOH -non MYCN-amplified high risk NBs. Hypermethylation was correlated with reduced mRNA and protein expression. In the whole NBs cohort, GSTP1 hypermethylation was less frequently detected (8%), but found to be associated with lower event-free (EFS) and overall survival. Hypermethylation of GSTP1 showed also association with lower EFS in high risk subgroups as stage 4 and older patients (≥547 days). Our results suggest that, as in several adult cancers, aberrant methylation of GSTP1 may contribute to the carcinogenetic process in NB and could be potentially used as a new marker leading to define an ultra-high risk subgroup.