No abstract

Background-Neutrophils are likely to play a major role in the inflammatory response seen in chronic obstructive pulmonary disease (COPD). This study sought to address the hypothesis that an enhanced neutrophil response to proinflammatory agents in COPD may contribute to their recruitment and activation in the lungs. Methods-Circulating neutrophils were obtained from 10 patients with COPD, eight long term smokers with normal lung function, and eight healthy never smoking controls. The in vitro production of reactive oxygen species (ROS) was measured by the NADPH oxidase method (respiratory burst) and the surface expression of several adhesion molecules (Mac-1, LFA-1 and L-selectin) was measured by flow cytometry. Measurements were obtained under basal conditions and after stimulation with phorbol myristate acetate (PMA) and tumour necrosis factor alpha (TNF ). mRNA levels of p22-phox (a subunit of NADPH oxidase) and Mac-1 (CD11b) were also determined by reverse transcriptase polymerase chain reaction (RT-PCR). 15) v 263 (11); mean diVerence -77 (95% CI of the diVerence -119 to -34), p=0.001). These diVerences were also apparent when patients with COPD were compared with non-smokers (p<0.05). The mRNA levels of p22-phox and Mac-1 (CD11b) were similar in patients with COPD and smokers with normal lung function, suggesting that the observed differences were due to post-transcriptional regulation. Results-PatientsConclusions-These results demonstrate an enhanced neutrophil response to proinflammatory agents in patients with COPD which may contribute to their enhanced recruitment and activation in the lungs of these patients. These findings support those of other studies which have indicated that the neutrophil is likely to play a major role in the pathogenesis of this disease. (Thorax 2001;56:432-437)

We investigated the expression of adhesion molecules in circulating neutrophils (lymphocyte function-associated antigen-1 [LFA-1], Mac-1, and L-selectin) and endothelial cells (soluble intercellular adhesion molecule-1[sICAM-1]) in 23 patients with stable chronic obstructive pulmonary disease (COPD), 18 subjects with exacerbated COPD, and 23 healthy volunteers. Also, in these circulating neutrophils, we assessed the expression of two G protein subunits (Galphas and Galphai1/2). Compared with control subjects, patients with stable COPD showed increased expression of Mac-1 (p < 0.001) and lower levels of sICAM-1 (p = 0.002); LFA-1 and L-selectin expression was similar in patients and control subjects. During exacerbations, compared with stable patients, the expression of Mac-1 and LFA-1 was reduced (p < 0.001). Finally, the expression of Galphas (but not Galphai1/2) was also reduced (p < 0.001) in circulating neutrophils of patients with COPD, irrespective of the clinical condition of the patient. These results indicate that in patients with COPD: (1) the expression of some neutrophil adhesion molecules (Mac-1) is abnormal, and that this pattern changes during exacerbations; (2) there may be a form of endothelial dysfunction, as suggested by the low sICAM-1 levels; (3) the expression of G protein subunit (Galphas) in circulating neutrophils is downregulated, irrespective of their clinical conditions. Overall, these results indicate the presence of significant systemic abnormalities in COPD.

This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to identify patients with FTLD-related syndromes.

Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.