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The European Alpha-1 Research Collaboration (EARCO) will promote international research in alpha-1 antitrypsin deficiencyhttp://ow.ly/DWwg30nwCj4

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.

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 : 47857.pdf (Publisher’s version ) (Closed access) The Capital Hip implant was a Charnley-based system which included a flanged and a roundback stem, both of which were available in stainless steel and titanium. The system was withdrawn from the market because of its inferior performance. However, all four of the designs did not produce poor rates of survival. Using a simulated-based, finite-element analysis, we have analysed the Capital Hip system. Our aim was to investigate whether our simulation was able to detect differences which could account for the varying survival between the Capital Hip designs, thereby further validating the simulation. We created finite-element models of reconstructions with the flanged and roundback Capital Hips. A loading history was applied representing normal walking and stair-climbing, while we monitored the formation of fatigue cracks in the cement. Corresponding to the clinical findings, our simulation was able to detect the negative effects of the titanium material and the flanged design in the Capital Hip system. Although improvements could be made by including the effect of the roughness of the surface of the stem, our study increased the value of the model as a predictive tool for determining failure of an implant.

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.

It is crucial for the quality of care of people with mental retardation that care providers experience their work as meaningful. A complexity, however, is the fact that this care is divided amongst a range of professions. This book addresses issues of meaning (meaning of care and meaning of life) from all the different professional perspectives involved. Such a multidisciplinary approach is unique and has never before been followed. The book contains the results of a series of interviews in which parents of people with mental retardation were asked what they conceive to be meaningful care. The results are placed in relation to experiences and conceptions of professional caregivers. Moreover, the study analyzes the cultural, philosophical, and theological significance of the concept, `meaningful care'. Finally, the book explores the relevance of this concept for practical professions such as medical care, social work, educational psychology, pedagogic counseling, and pastoral care. Scholarly depth is combined with experiential knowledge of professional practice. Hence, this book is an outstanding source of reflection for all those who work professionally with people with mental retardation.

Exacerbations of asthma have been associated with exposure to ozone or particles with a 50% cut-off aerodynamic diameter of 10 microm (PM10). We postulated in this study that the association of summertime air pollution (i.e. ozone and PM10) with acute respiratory symptoms, medication use and peak expiratory flow differs among patients grouped according to asthma severity. During the summer of 1995, effects of ambient air pollution on these parameters were studied in a panel of 60 nonsmoking patients with intermittent to severe persistent asthma. These patients were recruited from our Pulmonary Out-patient Clinic. Subgroup analysis was performed on the degree of hyperresponsiveness and lung steroid use before the start of the study, as indictors for the severity of asthma. Associations of the parameters studied with ozone, PM10, nitrogen dioxide (NO2), sulphur dioxide (SO2) and black smoke were evaluated using time series analysis. Several episodes with increased summertime air pollution occurred during the 96 day study period. Eight hour average ozone concentrations exceeded the World Health Organization (WHO) Air Quality Guidelines (120 microg x m(-3)) on 16 occasions. Daily mean levels of PM10 were moderately elevated (range 16-98 microg x m(-3)). Levels of the other measured pollutants were low. There was a consistent, positive association of the prevalence of shortness of breath (maximal relative risk (RRmax) 1.18) with ozone, PM10, black smoke and NO2. In addition, bronchodilator use was associated with both ozone and PM10 levels (RRmax 1.16). Stratification by airway hyperresponsiveness and steroid use did not affect the magnitude of the observed associations. No associations with peak expiratory flow measurements were found. We conclude that the severity of asthma is not an indicator for the sensitivity to air pollution

Alpha1-antitrypsin (α1-AT) deficiency is a common genetic disorder, with homozygous genotype Z as the most relevant deficient type for clinicians. In some parts of Europe, this phenotype is as prevalent as cystic fibrosis and for both disorders there is presently no cure for the disease, which has implications for genetic testing in many countries. In 2003, the European Respiratory Society and American Thoracic Society published a joint statement of standards for diagnosis and management of individuals with α1-AT deficiency 1. Recently, a full chapter on genetic testing addressed the pros and cons of this issue. In pulmonary practice, diagnostic testing of a single case with onset of symptoms related to chronic obstructive pulmonary disease (COPD) at early age is most frequently performed. Predispositional detection of the related family of the newly detected case is already more questionable and relates to the care that doctors can provide to cases detected by family screening. Case detection is somewhat different from screening, as screening activity is usually employed for subjects with no symptoms of disease. Public health authorities often only allow for (neonatal) screening if it …

In response to inflammatory mediators, polymorphonuclear leukocytes (PMN) are activated and release potent serine proteases, i.e. elastase, cathepsin G and proteinase 3. The aim of this study was to develop an assay to determine PMNmediated fibrinogenolysis in plasma, as a biochemical marker for activated PMN in vivo. On the basis of a special monoclonal antibody, generated against a neo-antigenic site in elastase degraded fibrinogen (EOF), we developed a highly specific plasma test for PMN-generated fibrin(ogen) derivatives. Intact fibrin(ogen) did not cross react in the assay, nor did plasmin-generated fibrin(ogen) derivatives. With this assay we showed, amongst others, that smoking did not affect the values of EDF-like degradation products in plasma of normal healthy volunteers (overall 8.2±1.6 ng/ml; n= 18) and that EDF-values are increased in patients with an ccl-proteinase inhibitor deficiency (18.6±5.3 ng/ml; n=12) and with sepsis (365.7±198.4 ng/ml; n=16). The assay was also applied to assess PMN-mediated fibrinogenolysis in synovial tissue extracts of patients with rheumatoid arthritis; these contained very high levels of EDF (98.2±59.3 ng/ml; n=15), in contrast to synovial tissue extracts of patients with osteoarthritis (6.3±2.7 ng/ml; n=12). The assay may be useful to identify patients with activated PMN, and to monitor drug-efficacy during therapy. This study was partly supported by grants from the Dutch Asthma Foundation (NAF 91.39 and 93.73) and the Praeventiefonds (002819180). © Pearson Professional Ltd 1996.