Vitamin C supplementation lowers advanced glycation end products (AGEs) and malondialdehyde (MDA) in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled clinical trial.

This study evaluated how daily vitamin C administration impacts systemic oxidative stress and inflammation and its safety in T2D patients. This randomized, double-blinded, placebo-controlled, parallel-arm clinical trial included 70 patients with T2D. They were allocated to receive either 500 mg/day of vitamin C or a matching placebo for 8 weeks. Of the 70 subjects assigned to the trial, 57 were included in the statistical analysis (vitamin C: n = 32, placebo: n = 25). Inflammatory and oxidative markers, including advanced glycation end products (AGEs), malondialdehyde (MDA), advanced oxidation protein products (AOPP), oxidized low-density lipoprotein (ox-LDL), highly sensitive C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and ferric reducing ability of plasma (FRAP) were measured at baseline and the end of the trial. In addition, vitamin C tolerance was evaluated. A nutritionist visited all participants for a standard diabetic regimen. Following vitamin C supplementation, the serum levels of MDA (p-value < .001) and AGEs (p-value = .002) demonstrated a significant decrease after controlling for multiple confounders, including age, blood pressure, waist circumference, HbA1C, TG, and LDL-C, while no significant changes were observed for AOPP (p-value = .234) and ox-LDL (p-value = .480). The FRAP showed an increasing trend as an antioxidant marker but was not statistically significant (p-value = .312). The hs-CRP and TNF-α had no significant changes (p-value: .899 and .454, respectively). Also, no major adverse events were observed. Vitamin C supplementation may be beneficial in reducing AGEs and MDA in patients with T2D.

Mucins 3A and 3B Are Expressed in the Epithelium of Human Large Airway.

Aberrant mucus secretion is a hallmark of chronic obstructive pulmonary disease (COPD). Expression of the membrane-tethered mucins 3A and 3B (MUC3A, MUC3B) in human lung is largely unknown. In this observational cross-sectional study, we recruited subjects 45-65 years old from the general population of Stockholm, Sweden, during the years 2007-2011. Bronchial mucosal biopsies, bronchial brushings, and bronchoalveolar lavage fluid (BALF) were retrieved from COPD patients (n = 38), healthy never-smokers (n = 40), and smokers with normal lung function (n = 40). Protein expression of MUC3A and MUC3B in bronchial mucosal biopsies was assessed by immunohistochemical staining. In a subgroup of subjects (n = 28), MUC3A and MUC3B mRNAs were quantified in bronchial brushings using microarray. Non-parametric tests were used to perform correlation and group comparison analyses. A value of p < 0.05 was considered statistically significant. MUC3A and MUC3B immunohistochemical expression was localized to ciliated cells. MUC3B was also expressed in basal cells. MUC3A and MUC3B immunohistochemical expression was equal in all study groups but subjects with emphysema had higher MUC3A expression, compared to those without emphysema. Smokers had higher mRNA levels of MUC3A and MUC3B than non-smokers. MUC3A and MUC3B mRNA were higher in male subjects and correlated negatively with expiratory air flows. MUC3B mRNA correlated positively with total cell concentration and macrophage percentage, and negatively with CD4/CD8 T cell ratio in BALF. We concluded that MUC3A and MUC3B in large airways may be a marker of disease or may play a role in the pathophysiology of airway obstruction.

Consequences of Using Post- or Prebronchodilator Reference Values in Interpreting Spirometry.

Rationale: Postbronchodilator spirometry is used for the diagnosis of chronic obstructive pulmonary disease. However, prebronchodilator reference values are used for spirometry interpretation. Objectives: To compare the resulting prevalence rates of abnormal spirometry and study the consequences of using pre- or postbronchodilator reference values generated within SCAPIS (Swedish CArdioPulmonary bioImage Study) when interpreting postbronchodilator spirometry in a general population. Methods: SCAPIS reference values for postbronchodilator and prebronchodilator spirometry were based on 10,156 and 1,498 never-smoking, healthy participants, respectively. We studied the associations of abnormal spirometry, defined by using pre- or postbronchodilator reference values, with respiratory burden in the SCAPIS general population (28,851 individuals). Measurements and Main Results: Bronchodilation resulted in higher predicted medians and lower limits of normal (LLNs) for FEV1/FVC ratios. The prevalence of postbronchodilator FEV1/FVC ratio lower than the prebronchodilator LLN was 4.8%, and that of postbronchodilator FEV1/FVC lower than the postbronchodilator LLN was 9.9%, for the general population. An additional 5.1% were identified as having an abnormal postbronchodilator FEV1/FVC ratio, and this group had more respiratory symptoms, emphysema (13.5% vs. 4.1%; P < 0.001), and self-reported physician-diagnosed chronic obstructive pulmonary disease (2.8% vs. 0.5%, P < 0.001) than subjects with a postbronchodilator FEV1/FVC ratio greater than the LLN for both pre- and postbronchodilation. Conclusions: Pre- and postbronchodilator spirometry reference values differ with regard to FEV1/FVC ratio. Use of postbronchodilator reference values doubled the population prevalence of airflow obstruction; this was related to a higher respiratory burden. Using postbronchodilator reference values when interpreting postbronchodilator spirometry might enable the identification of individuals with mild disease and be clinically relevant.

Assessment of Spine Patient Preferences for the Location of Surgery Between a Hospital and an Ambulatory Surgical Center in the Time of COVID-19: An Analysis of Patient Surveys.

Introduction There has been a recent increase in the number of spinal procedures that can be performed in ambulatory surgical centers (ASCs). Studies have found that patients who undergo procedures at ASCs tend to have lower complication rates following procedures, including lower infection rates. Furthermore, ASCs offer significantly lower costs of procedures to patients and health insurance companies as compared to the costs of procedures performed in a hospital. Despite precautions and screening in place by ASCs, patients may be hesitant to undergo procedures outside of the hospital. Conversely, the ongoing COVID-19 pandemic has created hesitancy for many to go to the hospital for care due to the presence of COVID patients.  Objective To assess patient preferences in the location of elective spine procedures between ASCs and hospitals, the authors conducted a survey of spine surgery candidates in a single practice. Methods A survey measuring patient age, vaccination status, fear of contracting COVID-19, and preference of surgery location was given to spinal surgery candidates at a single practice between fall 2021 and winter 2022. Statistical differences between the means of response groups were measured by a two-sample Z-score test. Results A total of 58 surveys were completed by patients. No difference in preference was observed by age. A difference was observed between genders, with 66% of females preferring ASCs to 40% of males (α=0.03). Patients with a fear of contracting COVID-19 preferred to have their procedure performed in an ASC. No difference was observed in location due to vaccination status, but unvaccinated patients had a significantly lower fear of contracting COVID-19 (α=0.02). Conclusion The differences in patient preferences have no clear cause, highlighting the need for better patient education in regard to the risks and benefits of each location of surgery. The fear of contracting COVID-19 on the day of surgery appears to be more ideological than rational for unvaccinated patients, who had less fear of contracting COVID-19 than vaccinated patients, despite being more likely to contract COVID-19 than vaccinated patients.

Evaluation of the risk factors associated with emergency department boarding: A retrospective cross-sectional study.

PURPOSE: Boarding is a common problem in the emergency department (ED) and is associated with poor health care and outcome. Imam Khomeini Hospital is the main healthcare center in Urmia, a metropolis in the northwest of Iran. Due to the overcrowding and high patient load, we aim to characterize the rate, cause and consequence of boarding in the ED of this center. METHODS: All medical records of patients who presented to the ED of Imam Khomeini Hospital from August 1, 2017 to August 1, 2018 were retrospectively analyzed. Patients with uncompleted records were excluded. Boarding was defined as the inability to transfer the admitted ED patients to a downstream ward in ≥2 h after the admission order. Demographic data, boarding rate, mortality and triage levels (1-5) assessed by emergency severity index were collected and analyzed. The first present time of patients was classified into 4 ranges as 0:00-5:59, 6:00-11:59, 12:00-17:59 and 18:00-23:59. Descriptive, parametric and non-parametric statistical tests were performed and the risk of boarding was determined by Pearson Chi-square test. RESULTS: Demographic data analysis showed that 941 (58.5%) male and 667 (41.5%) female, altogether 1608 patients were included in this study. Five patients (0.3%) died. The distribution of patients with the triage levels 1-5 was respectively 79 (4.9%), 1150 (71.5%), 374 (23.3%), 4 (0.2%) and 0 (0%). Most patients were of level 2. Only 75 (4.7%) patients required intensive care. The majority of patients (84.2%) were presented at weekdays. The maximum patient load was observed between 12:00-17:59. Of the 1608 patients, 340 (21.1%) experienced boarding within a mean admission time of 13.70 h. Among the 340-boarded patients, 20.1% belonged to surgery, 12.1% to orthopedics, 10.9% to neurosurgery and 10.3% to neurology. The boarding rate was higher in females, patients requiring intensive care and those with low triage levels. Compared with the non-boarded, the boarded patients had a higher mean age. CONCLUSION: The boarding rate is higher in the older and female patients. Moreover, boarding is dependent on the downstream ward sections: patients requiring surgical management experience the maximum boarding rate.

Smoking-associated increase in mucins 1 and 4 in human airways.

RATIONALE: Smoking-related chronic obstructive pulmonary disease (COPD) is associated with dysregulated production of mucus. Mucins (MUC) are important both for mucus secretion and epithelial defense. We have examined the distribution of MUC1 and MUC4 in the airway epithelial cells of never-smokers and smokers with and without COPD. METHODS: Mucosal biopsies and bronchial wash samples were obtained by bronchoscopy from age- and sex-matched COPD-patients (n = 38; GOLD I-II/A-B), healthy never-smokers (n = 40) and current smokers with normal lung function (n = 40) from the Karolinska COSMIC cohort (NCT02627872). Cell-specific expressions of MUC1, MUC4 and regulating factors, i.e., epithelial growth factor receptor (EGFR) 1 and 2, were analyzed by immunohistochemistry. Soluble MUC1 was measured by quantitative immunodetection on slot blot. RESULTS: The levels of cell-bound MUC1 expression in basal cells and in soluble MUC1 in bronchial wash were increased in smokers, regardless of airway obstruction. Patients with chronic bronchitis had higher MUC1 expression. The expression of MUC4 in cells with goblet cell phenotype was increased in smokers. The expression of EGFR2, but not that of EGFR1, was higher in never-smokers than in smokers. CONCLUSIONS: Smoking history and the presence of chronic bronchitis, regardless of airway obstruction, affect both cellular and soluble MUC1 in human airways. Therefore, MUC1 may be a novel marker for smoking- associated airway disease.

Secretory anti-citrullinated protein antibodies in serum associate with lung involvement in early rheumatoid arthritis.

OBJECTIVE: A 'mucosal connection' in RA presently attracts increasing attention. We recently described the occurrence of secretory antibodies to citrullinated protein (SC-ACPA) in sera from patients with recent-onset RA. The current study was performed to evaluate possible associations between serum levels of secretory ACPA and signs of lung involvement in patients with early, untreated RA. METHODS: One hundred and forty-two RA patients were included as part of the 'LUng Investigation in newly diagnosed RA' study. One hundred and six patients were examined with high-resolution CT (HRCT) and 20 patients underwent bronchoscopy, where bronchial biopsies and bronchoalveolar lavage fluid (BALF) samples were obtained. SC-ACPA in serum and BALF were detected by an enzyme-linked immunoassay. Antibody levels were related to smoking history, pulmonary function, HRCT, BALF cell counts and findings in bronchial biopsies. RESULTS: SC-ACPA occurred in 16% of the serum samples and in 35% of the BALF samples. SC-ACPA levels in serum correlated with SC-ACPA levels in BALF (σ = 0.50, P = 0.027) and were higher among patients with HRCT parenchymal lung abnormalities (P = 0.022) or bronchiectasis (P = 0.042). Also, ever smoking was more frequent among serum SC-ACPA-positive patients (91% vs 67%, P = 0.023), and the SC-ACPA levels correlated with the number of pack-years (σ=0.20, P = 0.020). CONCLUSION: In early, untreated RA, serum levels of SC-ACPA reflect lung involvement in terms of local ACPA levels, smoking and lung abnormalities on HRCT. These findings strengthen the link between mucosal ACPA responses and the lungs in RA.

Construction of Epstein-Bar virus cocktail peptide fused with Fcγ of IgG: as a potential delivery system for vaccine development.

Epstein-Barr virus (EBV) associated with several diseases such as contagious mononucleosis chronic active EBV infection, and diverse sorts of malignant tumors. Therefore, using applicable vaccines could be advantageous for public health. Yet, the vaccine has been unavailable to protect from EBV so far. In the current study, to develop a multi-peptide vaccine for EBV and assess its expression in Pichia pastoris yeast system, three immunodominant sequences in glycoprotein (gp) 85, gp350 and latent membrane protein 1 (LMP1) were chosen. To construct fusion peptide, -GGGGS- liker was applied. After cloning the fusion peptide in the pPICZαA expression vector, this recombinant vector processed and transfected into Pichia pastoris host cells. The expression of high level of EBV fusion peptide was confirmed by dot blot and SDS-PAGE procedures. The Pichia pastoris is capable of supporting EBV fusion peptide expression. The application of this fusion peptide as a peptide vaccine to fight EBV is suggested.

Long-term smoking alters abundance of over half of the proteome in bronchoalveolar lavage cell in smokers with normal spirometry, with effects on molecular pathways associated with COPD.

BACKGROUND: Smoking represents a significant risk factor for many chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). METHODS: To identify dysregulation of specific proteins and pathways in bronchoalveolar lavage (BAL) cells associated with smoking, isobaric tags for relative and absolute quantitation (iTRAQ)-based shotgun proteomics analyses were performed on BAL cells from healthy never-smokers and smokers with normal lung function from the Karolinska COSMIC cohort. Multivariate statistical modeling, multivariate correlations with clinical data, and pathway enrichment analysis were performed. RESULTS: Smoking exerted a significant impact on the BAL cell proteome, with more than 500 proteins representing 15 molecular pathways altered due to smoking. The majority of these alterations occurred in a gender-independent manner. The phagosomal- and leukocyte trans endothelial migration (LTM) pathways significantly correlated with FEV1/FVC as well as the percentage of CD8+ T-cells and CD8+CD69+ T-cells in smokers. The correlations to clinical parameters in healthy never-smokers were minor. CONCLUSION: The significant correlations of proteins in the phagosome- and LTM pathways with activated cytotoxic T-cells (CD69+) and the level of airway obstruction (FEV1/FVC) in smokers, both hallmarks of COPD, suggests that these two pathways may play a role in the molecular events preceding the development of COPD in susceptible smokers. Both pathways were found to be further dysregulated in COPD patients from the same cohort, thereby providing further support to this hypothesis. Given that not all smokers develop COPD in spite of decades of smoking, it is also plausible that some of the molecular pathways associated with response to smoking exert protective mechanisms to smoking-related pathologies in resilient individuals. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02627872 ; Retrospectively registered on December 9, 2015.

Proteomic profiling of lung immune cells reveals dysregulation of phagocytotic pathways in female-dominated molecular COPD phenotype.

BACKGROUND: Smoking is the main risk factor for chronic obstructive pulmonary disease (COPD). Women with COPD who smoke experienced a higher risk of hospitalization and worse decline of lung function. Yet the mechanisms of these gender-related differences in clinical presentations in COPD remain unknown. The aim of our study is to identify proteins and molecular pathways associated with COPD pathogenesis, with emphasis on elucidating molecular gender difference. METHOD: We employed shotgun isobaric tags for relative and absolute quantitation (iTRAQ) proteome analyses of bronchoalveolar lavage (BAL) cells from smokers with normal lung function (n = 25) and early stage COPD patients (n = 18). Multivariate modeling, pathway enrichment analysis, and correlation with clinical characteristics were performed to identify specific proteins and pathways of interest. RESULTS: More pronounced alterations both at the protein- and pathway- levels were observed in female COPD patients, involving dysregulation of the FcγR-mediated phagocytosis-lysosomal axis and increase in oxidative stress. Alterations in pathways of the phagocytosis-lysosomal axis associated with a female-dominated COPD phenotype correlated well with specific clinical features: FcγR-mediated phagocytosis correlated with FEV1/FVC, the lysosomal pathway correlated with CT < -950 Hounsfield Units (HU), and regulation of actin cytoskeleton correlated with FEV1 and FEV1/FVC in female COPD patients. Alterations observed in the corresponding male cohort were minor. CONCLUSION: The identified molecular pathways suggest dysregulation of several phagocytosis-related pathways in BAL cells in female COPD patients, with correlation to both the level of obstruction (FEV1/FVC) and disease severity (FEV1) as well as emphysema (CT < -950 HU) in women. TRIAL REGISTRATION: No.: NCT02627872 , retrospectively registered on December 9, 2015.

Differences in regional air trapping in current smokers with normal spirometry.

We investigated regional air trapping on computed tomography in current smokers with normal spirometry. It was hypothesised that presence of regional air trapping may indicate a specific manifestation of smoking-related changes.40 current smokers, 40 patients with chronic obstructive pulmonary disease (COPD), and 40 healthy never- smokers underwent computed tomography scans. Regional air trapping was assessed on end-expiratory scans and emphysema, micronodules and bronchial wall thickening on inspiratory scans. The ratio of expiratory and inspiratory mean lung attenuation (E/I) was calculated as a measure of static (fixed) air trapping.Regional air trapping was present in 63% of current smokers, in 45% of never smokers and in 8% of COPD patients (p<0.001). Current smokers with and without regional air trapping had E/I ratio of 0.81 and 0.91, respectively (p<0.001). Forced expiratory volume in 1 s (FEV1) was significantly higher and emphysema less frequent in current smokers with regional air trapping.Current smokers with regional air trapping had higher FEV1 and less emphysema on computed tomography. In contrast, current smokers without regional air trapping resembled COPD. Our results highlight heterogeneity among smokers with normal spirometry and may contribute to early detection of smoking related structural changes in the lungs.

Gender differences in the T-cell profiles of the airways in COPD patients associated with clinical phenotypes.

T lymphocytes are believed to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). How T cells are recruited to the lungs and contribute to the inflammatory process is largely unknown. COPD is a heterogeneous disease, and discriminating disease phenotypes based on distinct molecular and cellular pathways may provide new approaches for individualized diagnosis and therapies. Bronchoalveolar lavage (BAL) and blood samples were obtained from 40 never-smokers, 40 smokers with normal lung function, and 38 COPD patients. T-cell chemokine receptor expression was analyzed with flow cytometry, and soluble BAL cytokines and chemokines were measured using a cytokine multiplex assay. Correlations with gender and clinical characteristics including lung imaging were investigated using multivariate modeling. Th1/Tc1- and Th2/Tc2-associated soluble analytes and T-cell chemokine receptors were analyzed as cumulative Th1/Tc1 and Th2/Tc2 immune responses. A higher expression of chemokine receptor CCR5 on CD8+ T cells in BAL and higher percentage of CXCR3+CD8+ T cells in blood was found in female smokers with COPD compared to those without COPD. CCR5 expression on CD4+ and CD8+ T cells was lower in BAL from male smokers with COPD compared to those without COPD. Among female smokers with COPD, Th1/Tc1 immune response was linked to BAL macrophage numbers and goblet cell density, and Th2/Tc2 response was associated with the measures of emphysema on high-resolution computed tomography. The highly gender-dependent T-cell profile in COPD indicates different links between cellular events and clinical manifestations in females compared to males. Our findings may reveal mechanisms of importance for the difference in clinical course in female COPD patients compared to males.

Linoleic acid-derived lipid mediators increase in a female-dominated subphenotype of COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality; however, the role of inflammatory mediators in its pathobiology remains unclear. The aim of this study was to investigate the influence of gender in COPD on lipid mediator levels.Bronchoalveolar lavage fluid (BALF) and serum were obtained from healthy never-smokers, smokers and COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage I-II/A-B) (n=114). 94 lipid mediators derived from the cytochrome-P450, lipoxygenase, and cyclooxygenase pathways were analysed by liquid chromatography-mass spectrometry.Multivariate modelling identified a 9-lipid panel in BALF that classified female smokers with COPD from healthy female smokers (p=6×10(-6)). No differences were observed for the corresponding male population (p=1.0). These findings were replicated in an independent cohort with 92% accuracy (p=0.005). The strongest drivers were the cytochrome P450-derived epoxide products of linoleic acid (leukotoxins) and their corresponding soluble epoxide hydrolase (sEH)-derived products (leukotoxin-diols). These species correlated with lung function (r=0.87; p=0.0009) and mRNA levels of enzymes putatively involved in their biosynthesis (r=0.96; p=0.003). Leukotoxin levels correlated with goblet cell abundance (r=0.72; p=0.028).These findings suggest a mechanism by which goblet cell-associated cytochrome-P450 and sEH activity produce elevated leukotoxin-diol levels, which play a putative role in the clinical manifestations of COPD in a female-dominated disease sub-phenotype.

A fatal case of JC virus meningitis presenting with hydrocephalus in a human immunodeficiency virus-seronegative patient.

JC virus (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV encephalopathy. Whether JCV can also cause meningitis has not yet been demonstrated. We report a case of aseptic meningitis resulting in symptomatic hydrocephalus in a human immunodeficiency virus-seronegative patient. Brain imaging showed enlargement of ventricles but no parenchymal lesion. She had a very high JC viral load in the cerebrospinal fluid (CSF) and developed progressive cognitive dysfunction despite ventricular drainage. She was diagnosed with pancytopenia and passed away after 5.5 months. Postmortem examination revealed productive JCV infection of leptomeningeal and choroid plexus cells, and limited parenchymal involvement. Sequencing of JCV CSF strain showed an archetype-like regulatory region. Further studies of the role of JCV in aseptic meningitis and in idiopathic hydrocephalus are warranted.

Lung density on high resolution computer tomography (HRCT) reflects degree of inflammation in smokers.

BACKGROUND: Smokers have increased cell concentration in the lower respiratory tract indicating a chronic inflammatory state, which in some individuals may lead to development of chronic obstructive pulmonary disease (COPD). Computer tomography (CT) imaging provides means of quantifying pulmonary structure and early signs of disease. We investigated whether lung density on high resolution CT differs between smokers and never-smokers and if this were associated to intensity of inflammation. METHODS: Forty smoking volunteers with normal pulmonary function, 40 healthy never-smokers and 40 patients with COPD of GOLD stage I-II, were included. Mean lung attenuation and percentage of pixels in the lung with attenuation between -750 and -900 HU (percentage higher density spectrum (%HDS)) were calculated on inspiratory CT-scans. Markers of systemic inflammation in blood and cell counts in bronchoalveolar lavage (BAL) fluid were recorded. RESULTS: Lung density expressed as %HDS was increased in smokers (44.0 ± 5.8%) compared to both never-smokers (38.3 ± 5.8%) and patients with COPD (39.1 ± 5.8%), (p < 0.001, for both). Females had denser lungs than males, which was dependent on body height. Cell concentration in BAL were correlated to lung density in smokers (r = 0.50, p < 0.001). CONCLUSIONS: Lung density on CT is associated with cell concentration in BAL in smokers and may mirror an inflammatory response in the lung. Gender difference in lung density is dependent on height. In COPD with emphysema, loss of lung tissue may counterbalance the expected increase in density due to inflammation. The findings may help to interpret high resolution CT in the context of smoking and gender and highlight the heterogeneity of structural changes in COPD.

Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis.

OBJECTIVE: It has been suggested that immunologic events in the lungs may be involved in triggering immunity, in particular production of anti-citrullinated protein antibodies (ACPAs) during early phases of rheumatoid arthritis (RA). The aim of this study was to investigate the structural and immunologic features of the lungs in incident cases of early RA in relation to ACPA presence and smoking status. METHODS: High-resolution computed tomography (HRCT) was used to examine the lungs of 105 patients with early, untreated RA (70 with ACPA-positive RA and 35 with ACPA-negative RA) and 43 healthy individuals. Bronchoscopy with collection of bronchoalveolar lavage (BAL) fluid and mucosal bronchial biopsy specimens was performed in 23 RA patients. The presence of citrullinated proteins in the bronchial tissue was detected by immunohistochemical staining. ACPAs (detected with an anti-cyclic citrullinated peptide 2 test) and total Ig levels were determined in the sera and BAL fluid of RA patients. RESULTS: HRCT imaging revealed that 63% of ACPA-positive RA patients had parenchymal lung abnormalities, compared with only 37% of ACPA-negative RA patients and 30% of healthy controls (each P < 0.05). These significant differences remained after adjustment for smoking status. Airway changes detected by HRCT were more frequent in RA patients than in healthy controls (66% versus 42%; P < 0.05), but there was no difference between ACPA-positive and ACPA-negative RA patients. Immunohistochemical studies of the bronchial tissue showed increased staining for citrullinated proteins in ACPA-positive RA patients compared with ACPA-negative RA patients (P < 0.05). ACPA levels were relatively higher in the BAL fluid as compared with the sera of ACPA-positive RA patients, suggesting that there is local production of ACPAs in the lungs of these patients. CONCLUSION: The presence of ACPAs is associated with parenchymal lung abnormalities, site-specific citrullination, and antibody enrichment in the lungs early in the development of ACPA-positive RA.

Distribution of T-cell subsets in BAL fluid of patients with mild to moderate COPD depends on current smoking status and not airway obstruction.

BACKGROUND: COPD is characterized by chronic inflammation. CD8+ T cells and CD4+ T cells have both been implicated in the inflammatory response. We investigated whether the lymphocyte and T-cell subpopulations in BAL differ between patients with COPD who are current smokers and those who are ex-smokers. METHODS: Forty never smokers, 40 smokers with normal lung function, and 38 patients with COPD, GOLD (Global Initiative for Chronic Obstructive Pulmonary Disease) stage I-II (27 smokers and 11 ex-smokers) underwent BAL. Using flow cytometry, cells were analyzed from BAL and blood for T-cell subsets, B cells, natural killer cells, and natural killer T (NKT)-like cells. The differentiation status of CD4+ T cells was also determined. RESULTS: Smokers with or without COPD had higher percentages of CD8+ T cells and NKT-like cells in BAL than did never smokers and ex-smokers with COPD. Most of the NKT-like cells were CD8+. In contrast, the percentages of CD4+ T cells were lower in the smoking than in the nonsmoking groups. In blood, the frequency of CD4+ T cells was increased in the two smoking groups. Current smokers also had increased numbers of activated (CD69+) naive and effector CD4+ T cells in BAL compared with nonsmokers, particularly in patients with COPD. In male smokers with COPD, the percentage of CD8+ T cells in BAL positively correlated with the number of cigarettes per day. CONCLUSIONS: Current smoking status has a greater impact than airway obstruction on the distribution of T-cell subsets in BAL of patients with mild to moderate COPD. This fact must be considered when the role of T cells in COPD is evaluated. Our results stress the importance of subgrouping patients with COPD in terms of smoking.

N2O ionization and dissociation dynamics in intense femtosecond laser radiation, probed by systematic pulse length variation from 7 to 500 fs.

We have made a series of measurements, as a function of pulse duration, of ionization and fragmentation of the asymmetric molecule N2O in intense femtosecond laser radiation. The pulse length was varied from 7 fs to 500 fs with intensity ranging from 4 × 10(15) to 2.5 × 10(14) W∕cm(2). Time and position sensitive detection allows us to observe all fragments in coincidence. By representing the final dissociation geometry with Dalitz plots, we can identify the underlying breakup dynamics. We observe for the first time that there are two stepwise dissociation pathways for N2O(3+): (1) N2O(3+) → N(+) + NO(2+) → N(+) + N(+) + O(+) and (2) N2O(3+) → N2 (2+) + O(+) → N(+) + N(+) + O(+) as well as one for N2O(4+) → N(2+) + NO(2+) → N(2+) + N(+) + O(+). The N2 (2+) stepwise channel is suppressed for longer pulse length, a phenomenon which we attribute to the influence which the structure of the 3+ potential has on the dissociating wave packet propagation. Finally, by observing the total kinetic energy released for each channel as a function of pulse duration, we show the increasing importance of charge resonance enhanced ionization for channels higher than 3+.

Gender differences in the bronchoalveolar lavage cell proteome of patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and is increasing, primarily among women. Underdiagnosis is common, and because of the heterogeneous disease characteristics, molecular markers of specific disease phenotypes and more efficacious treatment regimens are urgently needed. OBJECTIVE: In this study the soluble proteome of bronchoalveolar lavage cells, primarily consisting of macrophages, was investigated with the aim of identifying phenotypic differences in early disease development. METHODS: Two-dimensional difference gel electrophoresis was used for relative quantification of protein levels, and multivariate modeling was applied to identify proteins of interest that were subsequently identified by means of liquid chromatography-mass spectrometry. RESULTS: Significant gender differences were unveiled, with numerous alterations in the bronchoalveolar lavage cell proteome occurring in female but not male patients with COPD. Specifically, a subset of 19 proteins provided classification of female healthy smokers from female patients with COPD with 78% predictive power. Subsequent pathway analyses linked the observed alterations to downregulation of the lysosomal pathway and upregulation of the oxidative phosphorylation pathway, possibly linking dysregulation of macroautophagy to a female-dominated COPD disease phenotype. CONCLUSION: This investigation makes an important contribution to the elucidation of putative molecular mechanisms underlying gender-based differences in the pathophysiology of COPD, linking alterations of specific molecular pathways to previously observed gender differences in clinical COPD phenotypes. Furthermore, these results stress the importance of the gender-specific search for biomarkers, diagnosis, and treatment in COPD.

Persistent vestige of dorsal ophthalmic artery: a case report.

A rare case of a persistent dorsal ophthalmic artery is reported. An elderly woman presented with subarachnoid hemorrhage and hydrocephalus. A CT angiogram revealed findings consistent with a small aneurysm and the presence of a dorsal ophthalmic artery. This was confirmed with catheter diagnostic angiography. The radiological findings, embryology and anatomy of these dual ophthalmic arteries are discussed.