A unique protein profile of peripheral neutrophils from COPD patients does not reflect cytokine-induced protein profiles of neutrophils in vitro

Contains fulltext : 96603.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Inflammation, both local and systemic, is a hallmark of chronic obstructive pulmonary disease (COPD). Inflammatory mediators such as TNFalpha and GM-CSF are secreted by lung epithelium, alveolar macrophages and other inflammatory cells and are thought to be important contributors in the pathogenesis of COPD. Indeed, neutrophils are activated by these cytokines and these cells are one of the major inflammatory cell types recruited to the pulmonary compartment of COPD patients. Furthermore, these inflammatory mediators are found in the peripheral blood of COPD patients and, therefore, we hypothesized that TNFalpha/GM-CSF-induced protein profiles can be found in peripheral neutrophils of COPD patients. METHODS: Using fluorescence 2-dimensional difference gel electrophoresis we investigated differentially regulated proteins in peripheral neutrophils from COPD patients and healthy age-matched control subjects. Furthermore, protein profiles from COPD patients were compared with those of neutrophils of healthy age-matched controls that were stimulated with TNFalpha and/or GM-CSF in vitro. Protein gels were compared using DeCyder 7.0 software. RESULTS: We identified 7 significantly regulated protein spots between peripheral neutrophils from COPD patients and age-matched healthy control subjects. Stimulation of peripheral neutrophils with TNFalpha, GM-CSF or TNFalpha + GM-CSF in vitro resulted in 13, 20 and 22 regulated protein spots, respectively. However, these cytokine-induced protein differences did not correspond with the protein differences found in neutrophils from COPD patients. CONCLUSION: These results show that neutrophils from COPD patients have a unique protein profile compared to neutrophils from healthy age-matched controls. Furthermore, the neutrophil profiles of COPD patients do not reflect putative dominant signals induced by TNFalpha, GM-CSF or their combination. Our results indicate that systemic neutrophil responses in COPD patients are caused by a unique but subtle interplay between multiple inflammatory signals

Distribution of emphysema in heavy smokers: Impact on pulmonary function

SummaryPurposeTo investigate impact of distribution of computed tomography (CT) emphysema on severity of airflow limitation and gas exchange impairment in current and former heavy smokers participating in a lung cancer screening trial.Materials and MethodsIn total 875 current and former heavy smokers underwent baseline low-dose CT (30mAs) in our center and spirometry and diffusion capacity testing on the same day as part of the Dutch–Belgian Lung Cancer Screening Trial (NELSON). Emphysema was quantified for 872 subjects as the number of voxels with an apparent lowered X-ray attenuation coefficient. Voxels attenuated <−950HU were categorized as representing severe emphysema (ES950), while voxels attenuated between −910HU and −950HU represented moderate emphysema (ES910). Impact of distribution on severity of pulmonary function impairment was investigated with logistic regression, adjusted for total amount of emphysema.ResultsFor ES910 an apical distribution was associated with more airflow obstruction and gas exchange impairment than a basal distribution (both p<0.01). The FEV1/FVC ratio was 1.6% (95% CI 0.42% to 2.8%) lower for apical predominance than for basal predominance, for Tlco/VA the difference was 0.12% (95% CI 0.076–0.15%). Distribution of ES950 had no impact on FEV1/FVC ratio, while an apical distribution was associated with a 0.076% (95% CI 0.038–0.11%) lower Tlco/VA (p<0.001).ConclusionIn a heavy smoking population, an apical distribution is associated with more severe gas exchange impairment than a basal distribution; for moderate emphysema it is also associated with a lower FEV1/FVC ratio. However, differences are small, and likely clinically irrelevant

FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity

Survival signals elicited by cytokines include the activation of phosphatidylinositol 3-kinase (PI3K), which in turn promotes the activation of protein kinase B (PKB). Recently, PKB has been demonstrated to phosphorylate and inactivate forkhead transcription factor FKHR-L1, a potent inducer of apoptosis. To explore the mechanisms underlying the induction of apoptosis after cytokine withdrawal or FKHR-L1 activation, we used a cell line in which FKHR-L1 activity could be specifically induced. Both cytokine withdrawal and FKHR-L1 activation induced apoptosis, which was preceded by an upregulation in p27KIP1 and a concomitant decrease in cells entering the cell cycle. Induction of apoptosis by both cytokine withdrawal and activation of FKHR-L1 correlated with the disruption of mitochondrial membrane integrity and cytochrome c release. This was preceded by upregulation of the pro-apoptotic Bcl-2 family member Bim. Ectopic expression of an inhibitory mutant of FKHR-L1 substantially reduced the levels of apoptosis observed after cytokine withdrawal. Activation of PKB alone was sufficient to promote cell survival, as measured by maintenance of mitochondrial integrity and the resultant inhibition of effector caspases. Furthermore, hematopoietic stem cells isolated from Bim−/− mice exhibited reduced levels of apoptosis upon inhibition of PI3K/PKB signaling

鼠毒証

Information and communications technology (ICT) has the potential to contribute to the quality of life of older adults. The aim of this study was to analyze the use of a broad array of ICT devices and services among Dutch older adults and to determine whether demographics and health outcomes are associated with this use. A questionnaire was dispensed among a group of Dutch older adults (≥65 years). A univariate analysis of covariance was used to analyse results. Two hundred ninety-one subjects filled out the questionnaire. Reported use of newer technologies was lower compared with older technologies. Increased age (p = 0.048, Confidence Interval [CI]: -0.73: -0.004), lower degree of education (p = 0.008, CI: -59.64: -5.59), birthplace outside of Europe (p = 0.024, CI: -21.99: -0.73), lower income (p = 0.005, CI: -46.44:25.38), less arthrosis of the hands (p = 0.042, CI: -1.38:21.11), and a lower physical functioning (p = 0.008, CI: 1.43:9.41) resulted in a lower ICT use score with an adjusted R2 of 0.311. Older adults are slower to adapt to newer technologies. It appears it is not the degree of physical restrictions, but rather the degree of adaptability to these restrictions that influence the use of ICT.status: publishe

Inter-observer and inter-examination variability of manual vertebral bone attenuation measurements on computed tomography

Objective: To determine inter-observer and inter-examination variability of manual attenuation measurements of the vertebrae in low-dose unenhanced chest computed tomography (CT). Methods: Three hundred and sixty-seven lung cancer screening trial participants who underwent baseline and repeat unenhanced low-dose CT after 3 months because of an indeterminate lung nodule were included. The CT attenuation value of the first lumbar vertebrae (L1) was measured in all CTs by one observer to obtain inter-examination reliability. Six observers performed measurements in 100 randomly selected CTs to determine agreement with limits of agreement and Bland-Altman plots and reliability with intraclass correlation coefficients (ICCs). Reclassification analyses were performed using a threshold of 110 HU to define osteoporosis. Results: Inter-examination reliability was excellent with an ICC of 0.92 (p < 0.001). Inter-examination limits of agreement ranged from -26 to 28 HU with a mean difference of 1 ± 14 HU. Inter-observer reliability ICCs ranged from 0.70 to 0.91. Inter-examination variability led to 11.2 % reclassification of participants and inter-observer variability led to 22.1 % reclassification. Conclusions: Vertebral attenuation values can be manually quantified with good to excellent inter-examination and inter-observer reliability on unenhanced low-dose chest CT. This information is valuable for early detection of osteoporosis on low-dose chest CT. Key Points: • Vertebral attenuation values can be manually quantified on low-dose unenhanced CT reliably.• Vertebral attenuation measurements may be helpful in detecting subclinical low bone density.• This could become of importance in the detection of osteoporosis

The predictive value of the CTA Vasospasm Score on delayed cerebral ischaemia and functional outcome after aneurysmal subarachnoid hemorrhage

Background and purpose: Delayed cerebral ischaemia (DCI) is a severe complication of aneurysmal subarachnoid hemorrhage that can significantly impact clinical outcome. Cerebral vasospasm is part of the pathophysiology of DCI and therefore a computed tomography angiography (CTA) Vasospasm Score was developed and an exploration was carried out of whether this score predicts DCI and subsequent poor outcome after aneurysmal subarachnoid hemorrhage. Methods: The CTA Vasospasm Score sums the degree of angiographic cerebral vasospasm of 17 intradural arterial segments. The score ranges from 0 to 34 with a higher score reflecting more severe vasospasm. Outcome measures were cerebral infarction due to DCI (CI-DCI), radiological and clinical DCI, and unfavorable functional outcome defined as a modified Rankin Scale >2 at 6 months. Receiver operating characteristic analyses were used to assess predictive value and to determine optimal cut-off scores. Inter-rater reliability was evaluated by Cohen's kappa coefficient. Results: This study included 59 patients. CI-DCI occurred in eight patients (14%), DCI in 14 patients (24%) and unfavorable outcome in 12 patients (20%). Median CTA Vasospasm Scores were higher in patients with (CI-)DCI and poor outcome. Receiver operating characteristic analysis revealed the highest area under the curve on day 5: CI-DCI 0.89 (95% confidence interval [CI] 0.79–0.99), DCI 0.68 (95% CI 0.50–0.87) and functional outcome 0.74 (95% CI 0.57–0.91). Cohen's kappa between the two raters was moderate to substantial (0.57–0.63). Conclusions: This study demonstrates that the CTA Vasospasm Score on day 5 can reliably identify patients with a high risk of developing (CI-)DCI and unfavorable outcome

The Systematic Development of an Online Career-Oriented People Management Training for Line Managers of Professionals: A Pilot Field Intervention Study

This study systematically develops an online training program improving line managers’ career-oriented people management behavior, including a pilot test. This program was developed based on the six steps of the Intervention Mapping protocol. Interviews were held with line managers and physicians to understand their needs and challenges with regard to people management. The program aimed to create (self-)awareness, enhance knowledge, support the exchange of experiences, and stimulate reflection on career-oriented people management behavior and leadership style and skills. Eight senior line managers of medical professionals employed in a large Dutch academic public hospital followed the training as part of the pilot test. The program was evaluated through observations, follow-up interviews, and a survey. This study makes a methodological and theoretical contribution to the human resource management literature. It shows how career-oriented people management behavior of line managers can be enhanced, which is important as earlier studies have demonstrated the benefits of this behavior. Systematically developing this program is relevant as studies have shown that the effectiveness of leadership programs is limited because of research design issues. Moreover, this study contributes to leadership development programs as this training could be offered as part of leadership programs

Technology use by older adults in the Netherlands and its associations with demographics and health outcomes

Information and communications technology (ICT) has the potential to contribute to the quality of life of older adults. The aim of this study was to analyze the use of a broad array of ICT devices and services among Dutch older adults and to determine whether demographics and health outcomes are associated with this use. A questionnaire was dispensed among a group of Dutch older adults (≥65 years). A univariate analysis of covariance was used to analyse results. Two hundred ninety-one subjects filled out the questionnaire. Reported use of newer technologies was lower compared with older technologies. Increased age (p = 0.048, Confidence Interval [CI]: -0.73: -0.004), lower degree of education (p = 0.008, CI: -59.64: -5.59), birthplace outside of Europe (p = 0.024, CI: -21.99: -0.73), lower income (p = 0.005, CI: -46.44:25.38), less arthrosis of the hands (p = 0.042, CI: -1.38:21.11), and a lower physical functioning (p = 0.008, CI: 1.43:9.41) resulted in a lower ICT use score with an adjusted R2 of 0.311. Older adults are slower to adapt to newer technologies. It appears it is not the degree of physical restrictions, but rather the degree of adaptability to these restrictions that influence the use of ICT

Detecting exacerbations using the Clinical COPD Questionnaire

BACKGROUND: Early treatment of COPD exacerbations has shown to be important. Despite a non-negligible negative impact on health related quality of life, a large proportion of these episodes is not reported (no change in treatment). Little is known whether (low burden) strategies are able to capture these unreported exacerbations. METHODS: The Clinical COPD Questionnaire (CCQ) is a short questionnaire with great evaluative properties in measuring health status. The current explorative study evaluates the discriminative properties of weekly CCQ assessment in detecting exacerbations. RESULTS: In a multicentre prospective cohort study, 121 patients, age 67.4 ± 10.5 years, FEV(1 )47.7 ± 18.5% pred were followed for 6 weeks by daily diary card recording and weekly CCQ assessment. Weeks were retrospectively labeled as stable or exacerbation (onset) weeks using the Anthonisen symptom diary-card algorithm. Change in CCQ total scores are significantly higher in exacerbation-onset weeks, 0.35 ± 0.69 compared to -0.04 ± 0.37 in stable weeks (p < 0.001). Performance of the Δ CCQ total score discriminating between stable and exacerbation onset weeks was sufficient (area under the ROC curve 0.75). At a cut off point of 0.2, sensitivity was 62.5 (50.3-73.4), specificity 82.0 (79.3-84.4), and a positive and negative predictive value of 43.5 (35.0-51.0) and 90.8 (87.8-93.5), respectively. Using this cut off point, 22 (out of 38) unreported exacerbations were detected while 39 stable patients would have been false positively 'contacted'. CONCLUSIONS: Weekly CCQ assessment is a promising, low burden method to detect unreported exacerbations. Further research is needed to validate discriminative performance and practical implications of the CCQ in detecting exacerbations in daily care

Number needed to treat with ursodeoxycholic acid therapy to prevent liver transplantation or death in primary biliary cholangitis

Objective: The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC. Methods: The NNT was calculated based on the untreated LT-free survival and HR of UDCA with respect to LT or death as derived from inverse probability of treatment weighting-adjusted Cox proportional hazard analyses within the Global PBC Study Group database. Results: We included 3902 patients with a median follow-up of 7.8 (4.1-12.1) years. The overall HR of UDCA was 0.46 (95% CI 0.40 to 0.52) and the 5-year LT-free survival without UDCA was 81% (95% CI 79 to 82). The NNT to prevent one LT or death within 5 years (NNT5y) was 11 (95% CI 9 to 13). Although the HR of UDCA was similar for patients with and without cirrhosis (0.33 vs 0.31), the NNT5y was 4 (95% CI 3 to 5) and 20 (95% CI 14 to 34), respectively. Among patients with low alkaline phosphatase (ALP) (≤2× the upper limit of normal (ULN)), intermediate ALP (2-4× ULN) and high ALP (>4× ULN), the NNT5y to prevent one LT or death was 26 (95% CI 15 to 70), 11 (95% CI 8 to 17) and 5 (95% CI 4 to 8), respectively. Conclusion: The absolute clinical efficacy of UDCA with respect to LT or death varied with baseline prognostic characteristics, but was high throughout. These findings strongly emphasise the incentive to promptly initiate UDCA treatment in all patients with PBC and may improve patient compliance