Phase-contrast virtual chest radiography.

Respiratory X-ray imaging enhanced by phase contrast has shown improved airway visualization in animal models. Limitations in current X-ray technology have nevertheless hindered clinical translation, leaving the potential clinical impact an open question. Here, we explore phase-contrast chest radiography in a realistic in silico framework. Specifically, we use preprocessed virtual patients to generate in silico chest radiographs by Fresnel-diffraction simulations of X-ray wave propagation. Following a reader study conducted with clinical radiologists, we predict that phase-contrast edge enhancement will have a negligible impact on improving solitary pulmonary nodule detection (6 to 20 mm). However, edge enhancement of bronchial walls visualizes small airways (< 2 mm), which are invisible in conventional radiography. Our results show that phase-contrast chest radiography could play a future role in observing small-airway obstruction (e.g., relevant for asthma or early-stage chronic obstructive pulmonary disease), which cannot be directly visualized using current clinical methods, thereby motivating the experimental development needed for clinical translation. Finally, we discuss quantitative requirements on distances and X-ray source/detector specifications for clinical implementation of phase-contrast chest radiography.

Feasibility of monitoring the resolution of acute pulmonary embolism with non-contrast-enhanced magnetic resonance imaging at one day, one week, one, three, and six months.

BACKGROUND: Pulmonary embolism (PE) is a common cause of death with an incidence of approximately 1-2 cases per 1000 inhabitants in Europe and the United States. Treatment for PE is the administration of anticoagulants for at least three months. PURPOSE: To assess the feasibility of following the resolution rate of PE over time using repeated imaging with a non-contrast-enhanced magnetic resonance imaging (MRI) protocol. MATERIAL AND METHODS: Patients (n = 18) diagnosed with acute PE via computed tomography pulmonary angiography (CTPA) underwent non-contrast-enhanced MRI at two tertiary hospitals. The first MRI was performed within 36 h of CTPA, with follow-up at one week, one, three, and six months. The MRI sequence used was a non-contrast-enhanced standard two-dimensional steady-state free precession under free-breathing and without respiratory or cardiac gating. All MRI scans were then compared to the initial CTPA. The emboli were assessed visually for location and size, and clot burden was calculated using the Qanadli score. RESULTS: MRI revealed complete resolution in seven cases at one week, in five cases at one month, and in three cases at three months. The most significant resolution of emboli occurred within the first few weeks, with only 10% of the diagnosed emboli persisting at the one-month examination. CONCLUSION: The use of MRI imparts the ability to visualize PE without radiation and thus allows multiple examinations to be made, for example in studies investigating the resolution of PE or the evaluation of drug effect in clinical trials.

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.

Lung perfusion disturbances in nonhospitalized post-COVID with dyspnea-A magnetic resonance imaging feasibility study.

BACKGROUND: Dyspnea is common after COVID-19. Though the underlying mechanisms are largely unknown, lung perfusion abnormalities could contribute to lingering dyspnea. OBJECTIVES: To detect pulmonary perfusion disturbances in nonhospitalized individuals with the post-COVID condition and persistent dyspnea 4-13 months after the disease onset. METHODS: Individuals with dyspnea and matched healthy controls were recruited for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), a 6-min walk test, and an assessment of dyspnea. The DCE-MRI was quantified using two parametric values: mean time to peak (TTP) and TTP ratio, reflecting the total lung perfusion resistance and the fraction of lung with delayed perfusion, respectively. RESULTS: Twenty-eight persons with persistent dyspnea (mean age 46.5 ± 8.0 years, 75% women) and 22 controls (mean age 44.1 ± 10.8 years, 73% women) were included. There was no systematic sex difference in dyspnea. The post-COVID group had no focal perfusion deficits but had higher mean pulmonary TTP (0.43 ± 0.04 vs. 0.41 ± 0.03, p = 0.011) and TTP ratio (0.096 ± 0.052 vs. 0.068 ± 0.027, p = 0.032). Post-COVID males had the highest mean TTP of 0.47 ± 0.02 and TTP ratio of 0.160 ± 0.039 compared to male controls and post-COVID females (p = 0.001 and p < 0.001, respectively). Correlations between dyspnea and perfusion parameters were demonstrated in males (r = 0.83, p < 0.001 for mean TTP; r = 0.76, p = 0.003 for TTP ratio), but not in females. CONCLUSIONS: DCE-MRI demonstrated late contrast bolus arrival in males with post-COVID dyspnea, suggestive of primary vascular lesions or secondary effects of hypoxic vasoconstriction. Since this effect was not regularly observed in female patients, our findings suggest sex differences in the mechanisms underlying post-COVID dyspnea, which warrants further investigation in dedicated trials.

Extending hypofractionated stereotactic body radiotherapy to tumours larger than 70cc - effects and side effects.

BACKGROUND AND PURPOSE: Stereotactic body radiotherapy (SBRT) for tumours ≥5 cm is poorly studied and its utility and feasibility is uncertain. We here report the Karolinska experience of SBRT in this setting. MATERIAL AND METHODS: All patients had a gross tumour volume (GTV) ≥70 cc, a prescribed physical dose of at least 40 Gy and received treatment between 1995-2012. RESULTS: We included 164 patients with 175 tumours located in the thorax (n = 86), the liver (n = 27) and the abdomen (n = 62) and treated with a median prescribed dose (BEDα/ß 10Gy) of 80 Gy (71.4-113). One- and 2- year local control rates were 82% and 61%. In multivariate analyses, minimum dose to the GTV and histological subtype were associated with local control. Renal cell carcinoma (RCC) histology showed the most favourable local control - 94% at 2 years for all histologies. Thirty-seven patients experienced grade 3-5 toxicity most likely related to SBRT. Seven of the ten patients with grade 5 toxicity, had a centrally located tumour in the thorax. CONCLUSION: SBRT of tumours >5 cm in diameter may be an option for peripherally located lung and abdominal tumours. Histological origin and tumour location should be considered before treatment.

Two methods of evaluating mandibular trabecular pattern in intraoral radiographs and the association to fragility fractures during a 47-year follow up.

In this longitudinal cohort study, we explored the association of fragility fractures to sparse trabecular bone pattern in intraoral radiographs using two methods, a visual and a semi-automated. Our aim was to study both sexes and to include younger age-groups, during a follow-up time of 47 years. The cohort consisted of 837 men and women aged 18-65 years, with intraoral radiographs from 1970-1971. The trabecular pattern was assessed in the mandibular premolar region with a visual and a semi-automated method. Data on fragility fractures were acquired from the Swedish National Patient Register for 47 years of follow-up time. Sparse trabecular pattern was found in 2.2% of the cohort using the visual method, and 18% were deemed at 'risk of osteoporosis' using the semi-automated method. A total of 132 individuals suffered at least one fragility fracture during the follow-up period. We found no significant association between fractures and sparse trabecular pattern using either method. This study shows that visual assessment, as a predictor of future fractures, may not be a suitable method for individuals of all ages and sexes. As for the semi-automated method, there is still very limited evidence for its fracture predictive ability.

Negative effects of iodine-based contrast agent on renal function in patients with moderate reduced renal function hospitalized for COVID-19.

BACKGROUND: Kidney disease and renal failure are associated with hospital deaths in patients with COVID - 19. We aimed to test if contrast enhancement affects short-term renal function in hospitalized COVID - 19 patients. METHODS: Plasma creatinine (P-creatinine) was measured on the day of computed tomography (CT) and 24 h, 48 h, and 4-10 days after CT. Contrast-enhanced (n = 142) and unenhanced (n = 24) groups were subdivided, based on estimated glomerular filtration rates (eGFR), > 60 and ≤ 60 ml/min/1.73 m2. Contrast-induced acute renal failure (CI-AKI) was defined as ≥27 µmol/L increase or a > 50% rise in P-creatinine from CT or initiation of renal replacement therapy during follow-up. Patients with renal replacement therapy were studied separately. We evaluated factors associated with a > 50% rise in P-creatinine at 48 h and at 4-10 days after contrast-enhanced CT. RESULTS: Median P-creatinine at 24-48 h and days 4-10 post-CT in patients with eGFR> 60 and eGFR≥30-60 in contrast-enhanced and unenhanced groups did not differ from basal values. CI-AKI was observed at 48 h and at 4-10 days post contrast administration in 24 and 36% (n = 5/14) of patients with eGFR≥30-60. Corresponding figures in the eGFR> 60 contrast-enhanced CT group were 5 and 5% respectively, (p < 0.037 and p < 0.001, Pearson χ2 test). In the former group, four of the five patients died within 30 days. Odds ratio analysis showed that an eGFR≥30-60 and 30-day mortality were associated with CK-AKI both at 48 h and 4-10 days after contrast-enhanced CT. CONCLUSION: Patients with COVID - 19 and eGFR≥30-60 had a high frequency of CK-AKI at 48 h and at 4-10 days after contrast administration, which was associated with increased 30-day mortality. For patients with eGFR≥30-60, we recommend strict indications are practiced for contrast-enhanced CT. Contrast-enhanced CT had a modest effect in patients with eGFR> 60.

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.

A case-report of widespread pulmonary embolism in a middle-aged male seven weeks after asymptomatic suspected COVID 19 infection.

BACKGROUND: Pulmonary embolism (PE) is seen in high frequency in hospital-treated patients with Covid-19. We present a case of suspected Covid-19 with long-term dyspnea and widespread PE. CASE PRESENTATION: A 51- year old male, with no prior medical history, no medication, and non-smoker arrived at the emergency department with exercise induced dyspnea during 4-5 weeks and for the last 48 h dyspnea at rest. Seven weeks before hospitalization, he felt difficulties taking deep breaths for some days but no other symptoms. Oxygen saturation at rest was 93%. Troponin T was 1200 mg/L (ref < 15 mg/L). CT angiography revealed widespread bilateral segmental pulmonary embolism. Additional findings were ground glass opacities that could match Covid-19. The patient tested negative for SARS -CoV-2. Full dose tinzaparin was given for 2 days in hospital, followed by apixaban for 6 months. Recovery has been uneventful so far. CONCLUSIONS: Long-term breathing difficulties might be relatively common after non-hospitalized symptomatic Covid-19. The frequency of PE in this group is unknown. We report a case of suspected covid-19 with widespread PE and a long history of dyspnea but no other symptoms. In our case slight hypoxia and laboratory testing indicated significant disease, which was proven with contrast angiography. This case shows that PE is a differential diagnosis in non-hospitalized symptomatic Covid-19 with persisting breathing problems.

Pulmonary outcomes in adults with a history of Bronchopulmonary Dysplasia differ from patients with asthma.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a risk factor for respiratory disease in adulthood. Despite the differences in underlying pathology, patients with a history of BPD are often treated as asthmatics. We hypothesized that pulmonary outcomes and health-related quality of life (HRQoL) were different in adults born preterm with and without a history of BPD compared to asthmatics and healthy individuals. METHODS: We evaluated 96 young adults from the LUNAPRE cohort ( clinicaltrials.gov/ct2/show/NCT02923648 ), including 26 individuals born preterm with a history of BPD (BPD), 23 born preterm without BPD (preterm), 23 asthmatics and 24 healthy controls. Extensive lung function testing and HRQoL were assessed. RESULTS: The BPD group had more severe airway obstruction compared to the preterm-, (FEV1- 0.94 vs. 0.28 z-scores; p ≤ 0.001); asthmatic- (0.14 z-scores, p ≤ 0.01) and healthy groups (0.78 z-scores, p ≤ 0.001). Further, they had increased ventilation inhomogeneity compared to the preterm- (LCI 6.97 vs. 6.73, p ≤ 0.05), asthmatic- (6.75, p = 0.05) and healthy groups (6.50 p ≤ 0.001). Both preterm groups had lower DLCO compared to healthy controls (p ≤ 0.001 for both). HRQoL showed less physical but more psychological symptoms in the BPD group compared to asthmatics. CONCLUSIONS: Lung function impairment and HRQoL in adults with a history of BPD differed from that in asthmatics highlighting the need for objective assessment of lung health.

Pulmonary artery imaging under free-breathing using golden-angle radial bSSFP MRI: a proof of concept.

PURPOSE: To evaluate the feasibility of an improved motion and flow robust methodology for imaging the pulmonary vasculature using non-contrast-enhanced, free-breathing, golden-angle radial MRI. METHODS: Healthy volunteers (n = 10, age 46 ± 11 years, 50% female) and patients (n = 2, ages 27 and 84, both female) were imaged at 1.5 T using a Cartesian and golden-angle radial 2D balanced SSFP pulse sequence. The acquisitions were made under free breathing without contrast agent enhancement. The radial acquisitions were reconstructed at 3 temporal footprints. All series were scored from 1 to 5 for perceived diagnostic quality, artifact level, and vessel sharpness in multiple anatomical locations. In addition, vessel sharpness and blood-to-blood clot contrast were measured. RESULTS: Quantitative measurements showed higher vessel sharpness for golden-angle radial (n = 76, 0.79 ± 0.11 versus 0.71 ± 0.16, p < .05). Blood-to-blood clot contrast was found to be 23% higher in golden-angle radial in the 2 patients. At comparable temporal footprints, golden-angle radial was scored higher for diagnostic quality (mean ± SD, 2.3 ± 0.7 versus 2.2 ± 0.6, p < .01) and vessel sharpness (2.2 ± 0.8 versus 2.1 ± 0.5, p < .01), whereas the artifact level did not differ (3.0 ± 0.9 versus 3.0 ± 1.0, p = .80). The ability to retrospectively choose a temporal resolution and perform sliding-window reconstructions was demonstrated in patients. CONCLUSION: In pulmonary artery imaging, the motion and flow robustness of a radial trajectory does both improve image quality over Cartesian trajectory in healthy volunteers, and allows for flexible selection of temporal footprints and the ability to perform real-time sliding window reconstructions, which could potentially provide further diagnostic insight.

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.

Implementation of lung cancer CT screening in the Nordic countries.

INTRODUCTION: We review the current knowledge of CT screening for lung cancer and present an expert-based, joint protocol for the proper implementation of screening in the Nordic countries. MATERIALS AND METHODS: Experts representing all the Nordic countries performed literature review and concensus for a joint protocol for lung cancer screening. RESULTS AND DISCUSSION: Areas of concern and caution are presented and discussed. We suggest to perform CT screening pilot studies in the Nordic countries in order to gain experience and develop specific and safe protocols for the implementation of such a program.

Detection of pulmonary embolism using repeated MRI acquisitions without respiratory gating: a preliminary study.

Background Pulmonary embolism (PE) is a severe medical condition with non-specific clinical findings. Computed tomography angiography (CTA) using iodinated contrast agents is the golden standard for diagnosis, but many patients have contraindications for CTA. Purpose To investigate the diagnostic accuracy of repeated acquisitions of magnetic resonance imaging (MRI), without respiratory gating or breath holding, in diagnosing PE using CTA as the reference standard. Material and Methods Thirty-three patients with clinically suspected PE underwent MRI within 48 h after diagnostic CTA. A control group of 37 healthy participants underwent MRI and was matched with an equal number of negative CTA exams. The MRI protocol was based on free-breathing steady-state free precession producing 4.5 mm slices in axial, sagittal, and coronal planes. Instead of respiratory or cardiac gating five repetitive slices were obtained in each anatomical position to compensate for movement and artifacts. Clinical assessment including d-dimer and Well's score was performed prior to imaging. One radiologist reviewed the CTA exams and two radiologists reviewed the MRI scans. Results All 70 MRI exams were of diagnostic quality and the total acquisition time for each MRI scan was 9 min 34 s. On CTA, 29 patients were diagnosed with PE and the MRI readers detected 26 and 27 of those, respectively. Specificity was 100% for both readers. Sensitivity was 90% and 93%, respectively. Inter-reader agreement using Cohen's kappa was 0.97. Conclusion Our unenhanced MRI protocol shows a high sensitivity and specificity for PE, but further studies are required before considering it as a safe diagnostic test.

Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis.

OBJECTIVES: Events in the lungs might contribute to generation of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). We investigated if signs of immune activation are present in bronchial biopsies and bronchoalveolar lavage (BAL) of patients with early-untreated RA without clinical signs of lung involvement. METHODS: Twenty-four patients with RA with symptom duration <1 year and naïve to disease-modifying antirheumatic drugs were subjected to bronchoscopy where BAL and mucosal bronchial biopsies were retrieved. For comparison, 15 bronchial biopsies and 79 BAL samples from healthy volunteers were available. Histological examination was performed to evaluate lymphocyte infiltration, presence of immune cells (T and B cells, plasma cells, dendritic cells and macrophages) and immune activation markers. Cell composition of BAL samples was analysed by differential counting and T cell subsets by flow cytometry. RESULTS: Lymphocyte infiltration was more frequently found in ACPA-positive patients (50%) as compared with ACPA-negative patients (17%) and controls (13%). Germinal centres, B cells and plasma cells were only found in ACPA-positive patients. The frequency of T cells in bronchial biopsies of patients with ACPA-positive RA was positively associated with expression of immune activation markers. BAL samples of patients with ACPA-positive, but not ACPA-negative, RA had significantly higher relative numbers of lymphocytes and expressed higher levels of activation markers compared with controls. CONCLUSIONS: Signs of immune cell accumulation and activation are present both in the bronchial tissue and in BAL of untreated patients with early RA without concomitant lung disease, strengthening the role of the lung compartment as an important player in ACPA-positive RA.

High Serum Insulin-Like Growth Factor-Binding Protein 1 (IGFBP-1) is Associated with High Fracture Risk Independent of Insulin-Like Growth Factor 1 (IGF-I).

High serum levels of IGFBP-1 are related both to low body mass index (BMI) and to low insulin-like growth factor 1 (IGF-I), which both in turn are related to low bone mineral density (BMD) and to increased fracture risk. However, we have found no previous prospective studies on IGFBP-1 and fracture risk. Despite its name, IGFBP-1 is not only just a binding protein but also has its own IGF-independent effects, e.g., stimulating osteoclast differentiation. IGFBP-1 might have an IGF-related and/or an IGF-independent association to fracture risk. This is a population-based prospective cohort study with a ten-year follow-up of 351 women aged 69-79 at inclusion. Fracture and mortality data were collected from national health care registers. IGFBP-1 had a positive linear relation to the risk of both hip fractures and "major osteoporotic fractures" including fractures of the hip, spine, shoulder, and wrist. The age-adjusted hazard ratio (HR) for a hip fracture was 1.46 (95 % CI 1.08-1.99) for one SD increase in IGFBP-1. The corresponding age-adjusted HR for major osteoporotic fractures was 1.33 (95 % CI 1.05-1.69). The relation between IGFBP-1 and fracture risk was not confounded by either IGF-I or BMI. Femoral neck BMD, however, mediated 56 % of the total "effect" of IGFBP-1 on hip fracture risk. In conclusion, IGFBP-1 had a positive linear relation to fracture risk, partly mediated by BMD but not related to IGF-I or BMD. This implies that IGFBP-1 might be an important factor in bone turnover and that further studies on this would be valuable.

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.

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.