Mannose-binding lectin gene polymorphism predicts hospital admissions for COPD infections

Infection frequently causes exacerbations of chronic obstructive pulmonary disease (COPD). Mannose-binding lectin (MBL) is a pattern-recognition receptor that assists in clearing microorganisms. Polymorphisms in the MBL2 gene reduce serum MBL levels and are associated with risk of infection. We studied whether the MBL2 codon 54 B allele affected serum MBL levels, admissions for infective exacerbation in COPD and disease susceptibility. Polymorphism frequency was determined by PCR-RFLP in 200 COPD patients and 104 smokers with normal lung function. Serum MBL was measured as mannan-binding activity in a subgroup of 82 stable COPD patients. Frequency of COPD admissions for infective exacerbation was ascertained for a 2-year period. The MBL2 codon 54 B allele reduced serum MBL in COPD patients. In keeping, patients carrying the low MBL-producing B allele had increased risk of admission for infective exacerbation (OR 4.9, P-corrected = 0.011). No association of MBL2 genotype with susceptibility to COPD was detected. In COPD, serum MBL is regulated by polymorphism at codon 54 in its encoding gene. Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD. MBL2 genotype should be explored prospectively as a prognostic marker for infection risk in COPD.

Regional, disease specific patterns of smoking-attributable mortality in 2000

Background: Smoking has been causally associated with increased mortality from several diseases, and has increased considerably in many developing countries in the past few decades. Mortality attributable to smoking in the year 2000 was estimated for adult males and females, including estimates by age and for specific diseases in 14 epidemiological subregions of the world. Methods: Lung cancer mortality was used as an indirect marker of the accumulated hazard of smoking. Never-smoker lung cancer mortality was estimated based on the household use of coal with poor ventilation. Estimates of mortality caused by smoking were made for lung cancer, upper aerodigestive cancer, all other cancers, chronic obstructive pulmonary disease ( COPD), other respiratory diseases, cardiovascular diseases, and selected other medical causes. Estimates were limited to ages 30 years and above. Results: In 2000, an estimated 4.83 million premature deaths in the world were attributable to smoking, 2.41 million in developing countries and 2.43 million in industrialised countries. There were 3.84 million male deaths and 1.00 million female deaths attributable to smoking. 2.69 million smoking attributable deaths were between the ages of 30 - 69 years, and 2.14 million were 70 years of age and above. The leading causes of death from smoking in industrialised regions were cardiovascular diseases ( 1.02 million deaths), lung cancer (0.52 million deaths), and COPD (0.31 million deaths), and in the developing world cardiovascular diseases (0.67 million deaths), COPD (0.65 million deaths), and lung cancer (0.33 million deaths). The share of male and female deaths and younger and older adult deaths, and of various diseases in total smoking attributable deaths exhibited large inter-regional heterogeneity, especially in the developing world. Conclusions: Smoking was an important cause of global mortality in 2000, affecting a large number of diseases. Age, sex, and disease patterns of smoking-caused mortality varied greatly across regions, due to both historical and current smoking patterns, and the presence of other risk factors that affect background mortality from specific diseases.

The short-term effects of air pollution on hospital admissions in four Australian cities

Background. This paper examines the short-term health effects of air pollution on daily hospital admissions in Australian cities (those considered comprise more than 50% of the Australian population) for the period 1996-99. Methods: The study used a similar protocol to overseas studies and derived single city and pooled estimates using different statistical approaches to assess the accuracy of the results. Results: There was little difference between the results derived from the different statistical approaches for cardiovascular admissions, while in those for respiratory admissions there were differences. For three of the four cities (for the other the results were positive but not significant), fine particles (measured by nephelometry - bsp) and nitrogen dioxide (NO2) have a significant impact on cardiovascular admissions (for total cardiac admissions, RR=1.0856 for a one-unit increase in bsp (10(-4). m(-1)), RR=1.0023 for a 1 ppb increase in NO2). For three of the four cities (for the other, the results were negative and significant), fine particles, NO2 and ozone have a significant impact on respiratory admissions (for total elderly respiratory admissions, RR=1.0552 per 1 unit (10(-4).m(-1)) increase in bsp, RR=1.0027 per 1ppb increase in NO2, RR=10014 per 1 ppb increase in ozone for elderly asthma and COPD admissions). In all analyses the particle and NO2 impacts appear to be related. Conclusions: Similar to overseas studies, air pollution has an impact on hospital admissions in Australian cities, but there can be significant differences between cities.

S100A8 chemotactic protein is abundantly increased, but only a minor contributor to LPS-induced, steroid resistant neutrophilic lung inflammation in vivo

Neutrophilic lung inflammation is an essential component of host defense against diverse eukaryotic and prokaryotic pathogens, but in chronic inflammatory lung diseases, such as chronic obstructive lung disease (COPD), severe asthma, cystic fibrosis, and bronchiolitis, it may damage the host. Glucocorticosteroids are widely used in these conditions and in their infectious exacerbations; however, the clinical efficacy of steroids is disputed. In this study, we used a proteomic approach to identify molecules contributing to neutrophilic inflammation induced by transnasal administration of lipopolysaccharide (LPS) that were also resistant to the potent glucocorticosteroid dexamethasone (Dex). We confirmed that Dex was biologically active at both the transcript (suppression of GM-CSF and TNFalpha transcripts) and protein levels (induction of lipocortin) and used 2D-PAGE/MALDI-TOF to generate global expression profiles, identifying six LPS-induced proteins that were Dex resistant. Of these, S100A8, a candidate neutrophil chemotactic factor, was profiled in detail. Steroid refractory S100A8 expression was highly abundant, transcriptionally regulated, secreted into lung lavage fluid and immunohistochemically localized to tissue infiltrating neutrophils. However, in marked contrast to other vascular beds, neutralizing antibodies to S100A8 had only a weak anti-neutrophil recruitment effect and antibodies against the related S100A9 were ineffective. These data highlight the need for extensive in vivo profiling of proteomically identified candidate molecules and demonstrates that S100A8, despite its abundance, resistance to steroids and known chemotactic activity, is unlikely to be an important determinant of LPS-induced neutrophilic lung inflammation in vivo.

Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects

Background: Inflammatory markers are increased in chronic obstructive pulmonary disease ( COPD) and are hypothesised to play an important part in muscle dysfunction and exercise intolerance. Methods: The Health Aging and Body Composition ( Health ABC) study is a prospective observational cohort of well functioning individuals aged 70 - 79 years. A cross sectional analysis of the baseline data was conducted to examine the association between inflammatory markers and ventilatory limitation, muscle strength, and exercise capacity. These associations were compared in participants with and without obstructive lung disease ( OLD). Results: Of the 3075 participants enrolled in the Health ABC cohort, OLD was identified by spirometric testing in 268 participants and 2005 participants had normal spirometric results. Of the participants with OLD, 35%, 38%, and 27% participants had mild, moderate, and severe OLD, respectively. Participants with OLD had lower quadriceps strength (102.5 Nm v 108.9 Nm, p = 0.02), lower maximum inspiratory pressure (64.7 cm H2O v 74.2 cm H2O, p< 0.0001), higher systemic interleukin (IL)-6 levels (2.6 pg/ml v 2.2 pg/ml, p< 0.0001), and higher C-reactive protein (CRP) levels (3.5 mg/l v 2.5 mg/l, p< 0.0001) than those with normal spirometry. In participants with OLD and those with normal spirometry, forced expiratory volume in 1 second (FEV1) was associated with IL-6 ( adjusted regression coefficients (beta) = -5.3 (95% CI -9.1 to -1.5) and -3.1 (95% CI -4.3 to -1.9), respectively). IL-6 and TNF were also associated with quadriceps strength among participants with OLD and those with normal spirometry (beta = -6.4 (95% CI -12.8 to -0.03) and -3.4 (95% CI -5.4 to -1.3), respectively, for IL-6 and beta = -10.1 (95% CI -18.7 to -1.5) and -3.8 (95% CI -7 to -0.6), respectively, for TNF). IL-6, quadriceps strength, and maximum inspiratory pressures were independent predictors of reduced exercise capacity in both groups. Conclusions: In well functioning elderly subjects with or without OLD, IL-6 is associated with reduced FEV1, quadriceps strength, and exercise capacity.

Measuring the global burden of disease and epidemiological transitions: 2002-2030

Any planning process for health development ought to be based on a thorough understanding of the health needs of the population. This should be sufficiently comprehensive to include the causes of premature death and of disability, as well as the major risk factors that underlie disease and injury. To be truly useful to inform health-policy debates, such an assessment is needed across a large number of diseases, injuries and risk factors, in order to guide prioritization. The results of the original Global Burden of Disease Study and, particularly, those of its 2000-2002 update provide a conceptual and methodological framework to quantify and compare the health of populations using a summary measure of both mortality and disability: the disability-adjusted life-year (DALY). Globally, it appears that about 5 6 million deaths occur each year, 10. 5 million (almost all in poor countries) in children. Of the child deaths, about one-fifth result from perinatal causes such as birth asphyxia and birth trauma, and only slightly less from lower respiratory infections. Annually, diarrhoeal diseases kill over 1.5 million children, and malaria, measles and HIV/AIDS each claim between 500,000 and 800,000 children. HIV/AIDS is the fourth leading cause of death world-wide (2.9 million deaths) and the leading cause in Africa. The top three causes of death globally are ischaemic heart disease (7.2 million deaths), stroke (5.5 million) and lower respiratory diseases (3.9 million). Chronic obstructive lung diseases (COPD) cause almost as many deaths as HIV/AIDS (2.7 million). The leading causes of DALY, on the other hand, include causes that are common at young ages [perinatal conditions (7. 1 % of global DALY), lower respiratory infections (6.7%), and diarrhoeal diseases (4.7%)] as well as depression (4.1%). Ischaemic heart disease and stroke rank sixth and seventh, retrospectively, as causes of global disease burden, followed by road traffic accidents, malaria and tuberculosis. Projections to 2030 indicate that, although these major vascular diseases will remain leading causes of global disease burden, with HIV/AIDS the leading cause, diarrhoeal diseases and lower respiratory infections will be outranked by COPD, in part reflecting the projected increases in death and disability from tobacco use.