Rationale: There is increasing evidence for the presence of autoantibodies in chronic obstructive pulmonary disease (COPD). Chronic oxidative stress is an essential component in COPD pathogenesis and can lead to increased levels of highly reactive carbonyls in the lung, which could result in the formation of highly immunogenic carbonyl adducts on "self" proteins. Objectives: To determine the presence of autoantibodies to carbonylmodified protein in patients with COPD and in a murine model of chronic ozone exposure. To assess the extent of activated immune responses toward carbonyl-modified proteins. Methods: Blood and peripheral lung were taken from patients with COPD, age-matched smokers, and nonsmokers with normal lung function, as well as patients with severe persistent asthma. Mice were exposed to ambient air or ozone for 6 weeks. Antibody titers were measured by ELISA, activated compliment deposition by immunohistochemistry, and cellular activation by ELISA and fluorescenceactivated cell sorter. Measurements and Main Results: Antibody titer against carbonylmodified self-protein was significantly increased in patients with Global Initiative for Chronic Obstructive Lung Disease stage III COPD compared with control subjects. Antibody levels inversely correlated with disease severity and showed a prevalence toward an IgG1 isotype. Deposition of activated complement in the vessels of COPD lung as well as autoantibodies against endothelial cells were also observed. Ozone-exposed mice similarly exhibited increased antibody titers to carbonyl-modified protein, as well as activated antigen-presenting cells in lung tissue and splenocytes sensitized to activation by carbonylmodified protein.Conclusions: Carbonyl-modified proteins, arising as a result of oxidative stress, promote antibody production, providing a link by which oxidative stress could drive an autoimmune response in COPD.Keywords: COPD; autoimmunity; oxidative stress; carbonyl Chronic obstructive pulmonary disease (COPD) is currently a leading cause of morbidity and mortality worldwide (1), with the main cause being long-term cigarette smoking in the western world (1, 2). Inflammation and remodeling of the small airways are major determinants for the progression and severity of COPD, as defined by the decline in FEV 1 (3). Accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells, such as CD4 1 cells, CD8 1 cells, B cells, macrophages, and neutrophils, and the formation of lymphoid follicles are all features of the observed inflammation that correlate with the severity of COPD (3, 4).Previous studies have suggested that autoimmune mechanisms may contribute to the pathogenesis of COPD. Serum autoantibodies against elastin (5) and bronchial epithelial cells along with corresponding IgG and complement (C3) deposition (6) have been observed in COPD lung. It has therefore been proposed that cigarette smoke-derived antigens may be responsible for driving this disease process in COPD (...

BackgroundChronic inflammation and oxidative stress are key features of chronic obstructive pulmonary disease (COPD). Oxidative stress enhances COPD inflammation under the control of the pro-inflammatory redox-sensitive transcription factor nuclear factor-kappaB (NF-κB). Histone acetylation plays a critical role in chronic inflammation and bromodomain and extra terminal (BET) proteins act as “readers” of acetylated histones. Therefore, we examined the role of BET proteins in particular Brd2 and Brd4 and their inhibitors (JQ1 and PFI-1) in oxidative stress- enhanced inflammation in human bronchial epithelial cells.MethodsHuman primary epithelial (NHBE) cells and BEAS-2B cell lines were stimulated with IL-1β (inflammatory stimulus) in the presence or absence of H2O2 (oxidative stress) and the effect of pre-treatment with bromodomain inhibitors (JQ1 and PFI-1) was investigated. Pro-inflammatory mediators (CXCL8 and IL-6) were measured by ELISA and transcripts by RT-PCR. H3 and H4 acetylation and recruitment of p65 and Brd4 to the native IL-8 and IL-6 promoters was investigated using chromatin immunoprecipitation (ChIP). The impact of Brd2 and Brd4 siRNA knockdown on inflammatory mediators was also investigated.ResultH2O2 enhanced IL1β-induced IL-6 and CXCL8 expression in NHBE and BEAS-2B cells whereas H2O2 alone did not have any affect. H3 acetylation at the IL-6 and IL-8 promoters was associated with recruitment of p65 and Brd4 proteins. Although p65 acetylation was increased this was not directly targeted by Brd4. The BET inhibitors JQ1 and PFI-1 significantly reduced IL-6 and CXCL8 expression whereas no effect was seen with the inactive enantiomer JQ1(-). Brd4, but not Brd2, knockdown markedly reduced IL-6 and CXCL8 release. JQ1 also inhibited p65 and Brd4 recruitment to the IL-6 and IL-8 promoters.ConclusionOxidative stress enhanced IL1β-induced IL-6 and CXCL8 expression was significantly reduced by Brd4 inhibition. Brd4 plays an important role in the regulation of inflammatory genes and provides a potential novel anti-inflammatory target.

BACKGROUND:The use of crossmatch-compatible platelets (PLTs) improves posttransfusion corrected count increments (CCIs) in patients with alloimmune PLT refractoriness. However, few reports address the efficacy of utilizing this strategy for patients requiring intensive PLT transfusion therapy lasting several weeks to months. STUDY DESIGN AND METHODS: Medical records of patients with two or more PLT crossmatch assays performed between 2002 and 2010 were reviewed. All patients were refractory to random single-donor apheresis PLT units, defined as two consecutive 1-hour posttransfusion CCIs of less than 7500. A commercial solid-phase adherence assay was used for crossmatching. RESULTS: Seventy-one patients were included. A median of four crossmatch assays were performed per patient (range, 2-17). Mean percent reactivity in initial (58.6%) versus last (55.3%) crossmatch assay for each patient demonstrated no trend toward progressive alloimmunization (p = NS). A total of 738 crossmatched PLT units were administered with a mean Ϯ standard deviation CCI of 7000 Ϯ 7900 (n = 443 units with adequate 1-hr posttransfusion counts), a significant improvement over random PLTs (p < 0.001). Patients with an initial crossmatch reactivity of greater than 66% were significantly more likely to demonstrate at least one panreactive crossmatch assay, impacting the availability of compatible PLTs for optimum transfusion support. One patient (1.4%) developed WHO Grade IV bleeding. CONCLUSIONS: Progressive alloimmunization to mismatched antigens does not impact medium-term transfusion support with crossmatched PLTs. Increased reactivity in the initial crossmatch assay can serve as a trigger to initiate workup for HLA-matched PLTs as a second-line approach. However, for most patients, medium-term transfusion support with crossmatched PLTs offers an effective and rapid first-line approach to management of PLT transfusion refractoriness.

Diabetic foot ulcers are a serious complication of diabetes mellitus which increases the patient morbidity and also have significant socioeconomic impact. The present review aims to summarize the causes and pathogenesis leading to diabetic foot ulcers, various classification systems and to focus on the current management of this significant and preventable health condition.

Neurological examination of preterm babies at term may be unreliable in the prediction of neurological outcome at 12 months corrected age. For early prediction of neurological outcome cranial ultrasound examination was found to be more reliable.