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Background: Inhaled corticosteroids (ICSs) and long-acting β2-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) Setting: 2 university medical centers in The Netherlands. Patients: 114 steroid-naive current or former smokers with moderate to severe COPD. Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 μg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 μg twice daily, and salmeterol, 50 μg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3+ cells (-55% [95% CI, -74% to -22%]; P - 0.004), CD4- cells (-78% [CI, -88% to 60%]; P < 0.001), CD8+ cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV1 decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3+ cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV1 level. Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. Primary Funding Source: Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of The Netherlands, University Medical Center Groningen, and Leiden University Medical Center.

Contains fulltext : 48199.pdf (Publisher’s version ) (Closed access) The beneficial effect of porosity reduction on the fatigue life of bone cement has been demonstrated in numerous experimental studies. Clinically, however, it seems that the beneficial effect of porosity reduction of cement around total hip replacement components can only be found in large follow-up studies. Little is known about the actual mechanical effect of a pore on fatigue crack formation in cement mantles. We studied the effect of pores on the crack formation process in a finite element model of a transverse slice of a total hip reconstruction. We created models with a single large pore and models with multiple pores at levels of 2, 4, and 9%. The models were cyclically torque-loaded, causing macrocracks to appear in the cement mantle. In all models, we found that pores acted as microcrack initiators. However, pores could have both a detrimental and a beneficial effect on the macrocrack propagation in the cement mantle. Both effects were seen in the models with a single large pore and in the models with multiple pores. Pores would either accelerate, deviate, or decelerate the macrocrack propagation in the cement mantle. The effect of the pores depended on the location of the pores with respect to the stress intensities in the model, but was independent of the pore size or the level of porosity. The results may explain why the beneficial effect of vacuum mixing is difficult to demonstrate clinically. Stress intensities that are present in a cement mantle in an in vivo situation may overshadow the detrimental effect of a pore, while the beneficial effect may become more pronounced.

Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV1 and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV1 level. Eleven out of 17 SNPs were associated with FEV1 decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.

Alpha-1 antitrypsin (AAT) acts as an important neutrophil elastase inhibitor in the lung. Although the hepatocyte is considered as the primary source of AAT, local production by monocytes, macrophages and epithelial cells may contribute to the formation of an anti-elastase screen. Since monocytes can differentiate into a heterogeneous population of macrophages with subpopulations ranging from pro-inflammatory properties (MΦ-1) to anti-inflammatory properties (MΦ-2) and into dendritic cells (DC), we studied whether lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα) and oncostatin M (OSM) enhance AAT production differentially in cultured MΦ-1, MΦ-2 and DC. Monocytes from healthy blood donors were cultured for 7 days in the presence of GM-CSF, M-CSF, or GM-CSF and IL-4 to obtain MΦ-1, MΦ-2 and immature(i)DC, respectively. Next, cells were stimulated with LPS, TNFα or OSM and synthesis of AAT was assessed by quantitative RT-PCR, immunocytochemistry and ELISA. Spontaneous release of AAT was higher in MΦ-1 than in MΦ-2 and iDC and only LPS significantly increased AAT production in MΦ-1, MΦ-2 and DC, whereas TNFα and OSM did not affect AAT secretion. The secretion levels of the related protease inhibitors alpha-1 antichymotrypsin (ACT) and secretory leucocyte proteinase inhibitor (SLPI) were below the limits of detection by ELISA. In contrast to the protein data, analysis by quantitative RT-PCR showed that 24h LPS exposure caused a maximal 2.1-fold AAT mRNA increase in MΦ-1, a 21-fold increase in MΦ-2 and 11-fold increase in DC. These data suggest that cellular differentiation is a regulator of local AAT production.

The traditional Hessian-related vessel filters often suffer from the problem of handling non-cylindrical objects. To remedy the shortcoming, we present a shape-tuned strain energy density function to measure vessel likelihood in 3D images. Based on the tensor invariants and stress-strain principle in mechanics, a new shape discriminating and vessel strength measure function is formulated. The synthetical and clinical data experiments verify the performance of our method in enhancing complex vascular structures including branches, bifurcations, and feature details.

BACKGROUND: Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. METHODS: To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. RESULTS: Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. CONCLUSIONS: Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.

Background Chronic Obstructive Pulmonary Disease (COPD) is associated with bronchial epithelial changes, including squamous cell metaplasia and goblet cell hyperplasia. These features are partially attributed to activation of the epidermal growth factor receptor (EGFR). Whereas smoking cessation reduces respiratory symptoms and lung function decline in COPD, inflammation persists. We determined epithelial proliferation and composition in bronchial biopsies from current and ex-smokers with COPD, and its relation to duration of smoking cessation. Methods 114 COPD patients were studied cross-sectionally: 99 males/15 females, age 62 ± 8 years, median 42 pack-years, no corticosteroids, current (n = 72) or ex-smokers (n = 42, median cessation duration 3.5 years), postbronchodilator FEV1 63 ± 9% predicted. Squamous cell metaplasia (%), goblet cell (PAS/Alcian Blue+) area (%), proliferating (Ki-67+) cell numbers (/mm basement membrane), and EGFR expression (%) were measured in intact epithelium of bronchial biopsies. Results Ex-smokers with COPD had significantly less epithelial squamous cell metaplasia, proliferating cell numbers, and a trend towards reduced goblet cell area than current smokers with COPD (p = 0.025, p = 0.001, p = 0.081, respectively), but no significant difference in EGFR expression. Epithelial features were not different between short-term quitters ( Conclusion Ex-smokers with COPD had less bronchial epithelial remodelling than current smokers, which was only observed after long-term smoking cessation (>3.5 years). Trial registration NCT00158847

Berichten over de huidige stand van zaken van een roofmijten-proef en een GNO-proef uitgevoerd in proefkassen door PPO Glastuinbouw, en van het praktijkonderzoek op vijf chrysantenbedrijven door van Iperen en Syngenta bioline.

Contains fulltext : 19219_compprtef.pdf (Publisher’s version ) (Open Access) Despite the success of cemented total hip replacement (THR), high failure rates are occasionally reported for cemented hip implants that are introduced on the orthopaedic market. Rigorous pre-clinical testing of hip implants could prevent these disasters, by detecting unsafe implant designs at a pre-clinical stage. The failure risk of the implant should be assessed, by testing against the most dominant failure scenarios for cemented reconstructions. At present no dependable pre-clinical tests exist. Failure of the femoral component in THR is often believed to related to the damage accumulation failure scenario. According to this scenario, repetitive loading of the reconstruction produces creep and microcrack accumulation in the cement and along the interfaces. This leads to implant migration, peri-prosthetic osteolysis, and to gross loosening of the implant. This thesis is aimed at developing a validated pre-clinical test for cemented hip prostheses against this failure scenario, based on computer finite element (FEA) simulation. An extensive description is given of the FEA simulation developed to simulate the mechanical failure processes involved: creep and microcrack accumulation in the cement. The FEA tool can be used to predict cement crack formation and implant migration, when applied to models of cemented THR reconstructions. Research is performed to determine the loading conditions in the pre-clinical test. It is found that the loading configuration should include a hip joint force and an additional set of abductor forces. The forces should represent not only walking, but also stair climbing, as this latter task is shown to be more critical for failure in cemented THR. Finally, the thesis describes the successful validation of the FEA-based pre-clinical test, relative to the results of experimental fatigue tests on cemented THR reconstructions and relative to clinical survival data. For the first time, an FEA simulation is able to detect inferior implants, based on accurate predictions of the failure mechanisms occurring in real reconstructions 191 p.

Item does not contain fulltext Prosthetic migration has been identified as a marker for future revision of cemented total hip reconstructions. This could be tested at a pre-clinical stage with dynamic loading experiments. The purpose of this study was to assess the effects of resting periods, which are a considerable part of the daily activity cycle, on the migration characteristics of femoral cemented stems. Ten polished Exeter stems were implanted in composite femurs and loaded either with a continuous load or a discontinuous load. Continuous loading involved 345,600 loading cycles at 1 Hz, whereas the discontinuous loading involved loading at 1 Hz for 2.5 hours and a resting period of 21.5 hours for a period of four days. Hence, a total of 36,000 loading cycles were applied to these reconstructions. The subsidence patterns of the prostheses were considerably affected by the resting periods. The prostheses exhibited a step-wise migration pattern with migration steps of about 50 microns after every resting period, whereas the continuously loaded prostheses showed a more gradual migration pattern. The final subsidence of the specimens when loaded with resting periods was significantly less than the subsidence measured without resting periods. However, these specimens were loaded with fewer loading cycles. If this was taken into account, the discontinuously loaded specimens had a four fold higher average migration per loading cycle than the specimens that were loaded continuously. In conclusion, the resting periods had a considerable effect on the migration patterns, which should be realized when these stems are analyzed with pre-clinical tests.

Onderzoek uitgevoerd in opdracht van de Directie Coordinatie Emancipatiebeleid van het Ministerie van Sociale zaken en Werkgelegenheid.Het onderzoek sluit aan bij een longitudinaal onderzoek (JOA of Jongeren en Arbeid) waarbij jongeren vanaf 1988 gevolgd werden bij hun keuzeprocessen op het gebied van opleiding, arbeid, relatievorming en zorgtaken. In dit onderzoek zijn de (toen inmiddels) 27-31- jarigen uitvoerig geinterviewd over hun arbeid-zorg trajecten, over de arbeid-zorgverdeling tussen partners en onderhandelingen hierover, over de invloed van verdiensituaties (inkomen, arbeidstijden enz.) op het al dan niet gebruik maken van kinderopvang en ouderschapsverlof. In het rapport wordt onderscheid gemaakt in de taakverdelingen van standaardbiografisch en keuzebiografisch georienteerde ouders. De keuze voor een ongelijke arbeid- zorgverdeling blijkt vaak al gemaakt te zijn voordat vrouwen zwanger zijn van hun eerste kind. (Verwachtingen over) de kwaliteit van de levensstandaard en levenswijze, kosten voor levensonderhoud, ongelijke verdiensituaties van mannen en vrouwen dragen eraan bij dat vaders - ondanks eerdere opvattingen over gelijke verdeling van arbeid en zorg -fulltime werken. Ervaringen met lange wachtlijsten, geringe flexibiliteit en te hoge kosten voor kinderopvang, en het ontbreken van verlofregelingen c.q. slechte voorlichting hierover ontmoedigen moeders om zorg te combineren met ambitieus werk. Het rapport bevat casestudies over keuzes die de verschillende groepen ouders tussen hun 16e en 31e levensjaar maken en bijstellen.