Biomedical subjects

Jan-Willem J Lammers

Publications and source records attributed to Jan-Willem J Lammers.

At least 19 recordsLinked to original sources

PubMed2007

Diffusing capacity for nitric oxide: reference values and dependence on alveolar volume.

Nitric oxide (NO) has a much stronger affinity for hemoglobin than carbon monoxide (CO); therefore, the DL(NO) (diffusing capacity for NO) is less influenced by changes in capillary blood volume than the DL(CO) (diffusing capacity for CO), and represents the true membrane diffusing capacity. We measured the combined single breath DL(NO)/DL(CO) in 124 healthy subjects, and generated reference equations for the DL(NO) and K(NO). In a subset of 21 subjects the measurements were performed on different inspiratory levels. The reference equation for DL(NO) in females is 53.47*H(height)0.077*A(age)-48.28(RSD5.22) and for males 59.84*H-0.25*A-44.20(RSD6.39). Reference equations for K(NO) in females is -2.03*H-0.025*A+11.52(RSD0.48) and for males -0.15*H-0.045*A+9.47(RSD0.65). The K(CO) (DL(CO)/V(A)) increases when V(A) (alveolar volume) decreases, probably due to an increase of blood volume per unit lung volume. The DL(NO) was much stronger related to the V(A), the K(NO) was almost independent of V(A). Because of the relative independence of the K(NO) on V(A), the K(NO) appears to be a much better index for the diffusion capacity per unit lung volume (transfer coefficient) than the K(CO).

Adult↗

PubMed2007

Fracture risk with intermittent high-dose oral glucocorticoid therapy.

OBJECTIVE: To evaluate the risk of fracture in patients receiving intermittent therapy with high-dose oral glucocorticoids (GCs). METHODS: The study group comprised 191,752 patients from the UK General Practice Database who were 40 years of age and older and received therapy with GCs. The followup time period was divided into the categories of "current" and "no exposure." The daily dose and cumulative dose for each time period were determined. Relative risks were estimated using Cox proportional hazards models, adjusted for age, sex, body mass index, smoking, disease history, and drug history. Fractures of the radius/ulna, humerus, rib, femur/hip, pelvis, or vertebrae were included in the evaluation. RESULTS: Patients who intermittently received high-dose GCs (daily dose > or =15 mg) and had no or little previous exposure to GCs (cumulative exposure < or =1 gm) had a small increased risk of osteoporotic (but not hip/femur) fracture; this risk increased substantially with increasing cumulative exposure. Among patients who received a daily dose > or =30 mg and whose cumulative exposure was >5 gm, the relative risk (RR) of osteoporotic fracture was 3.63 (95% confidence interval [95% CI] 2.54-5.20), the RR of fracture of the hip/femur was 3.13 (95% CI 1.49-6.59), and the RR of vertebral fracture was 14.42 (95% CI 8.29-25.08). CONCLUSION: Intermittent use of high-dose oral GCs (daily dose > or =15 mg and cumulative exposure < or =1 gm) may result in a small increased risk of osteoporotic fracture. Conversely, patients who receive several courses of high-dose GCs (daily dose > or =15 mg and cumulative exposure >1 gm) have a substantially increased risk of fracture.

Adult↗

PubMed2007

Use of beta-2 agonists and risk of hip/femur fracture: a population-based case-control study.

INTRODUCTION: Administration of beta-2 agonists decreased bone mineral density in rats. But the association between bronchodilators and fracture risk has not been studied in humans. OBJECTIVES: To examine the association between use of beta-2 agonists and risk of hip/femur fracture. METHODS: We conducted a population-based case-control study (6763 cases) in the Dutch PHARMO database. Current beta-2 agonist use was compared to never use. We adjusted for severity of the underlying respiratory disease and disease and drug history. RESULTS: A hospitalisation for asthma/COPD in the year before index date increased risk of hip/femur fracture: crude OR 2.17 (95% CI, 1.41-3.34). Patients using higher doses of beta-2 agonists had increased risk of hip/femur fracture: crude OR 1.94 (95% CI, 1.41-2.66) for daily dosages of >or=1600 microg albuterol equivalent. The excess fracture risk reduced after adjustment for disease severity (1.46; 95% CI, 1.02-2.08) and after exclusion of oral glucocorticoid users (1.31; 95% CI, 0.80-2.15). Risk of hip/femur fracture was similar between users of beta-2 agonists, inhaled glucocorticoids and anticholinergics. CONCLUSION: We found increases in the risk of hip/femur fracture in patients using higher doses of beta-2 agonists. However, the excess risk of hip/femur fracture substantially reduced after exclusion of oral glucocorticoid users and after adjustment for the underlying disease. Risk of hip/femur fracture was similar between users of beta-2 agonists, inhaled glucocorticoids and anticholinergics. The severity of the underlying disease, rather than the use of beta-2 agonists, may play an important role in the aetiology of hip/femur fractures in patients using beta-2 agonists.

Adrenergic beta-2 Receptor Agonists↗

PubMed2006

Effectiveness of early switch from intravenous to oral antibiotics in severe community acquired pneumonia: multicentre randomised trial.

OBJECTIVES: To compare the effectiveness of an early switch to oral antibiotics with the standard 7 day course of intravenous antibiotics in severe community acquired pneumonia. DESIGN: Multicentre randomised controlled trial. SETTING: Five teaching hospitals and 2 university medical centres in the Netherlands. PARTICIPANTS: 302 patients in non-intensive care wards with severe community acquired pneumonia. 265 patients fulfilled the study requirements. INTERVENTION: Three days of treatment with intravenous antibiotics followed, when clinically stable, by oral antibiotics or by 7 days of intravenous antibiotics. MAIN OUTCOME MEASURES: Clinical cure and length of hospital stay. RESULTS: 302 patients were randomised (mean age 69.5 (standard deviation 14.0), mean pneumonia severity score 112.7 (26.0)). 37 patients were excluded from analysis because of early dropout before day 3, leaving 265 patients for intention to treat analysis. Mortality at day 28 was 4% in the intervention group and 6% in the control group (mean difference 2%, 95% confidence interval -3% to 8%). Clinical cure was 83% in the intervention group and 85% in the control group (2%, -7% to 10%). Duration of intravenous treatment and length of hospital stay were reduced in the intervention group, with mean differences of 3.4 days (3.6 (1.5) v 7.0 (2.0) days; 2.8 to 3.9) and 1.9 days (9.6 (5.0) v 11.5 (4.9) days; 0.6 to 3.2), respectively. CONCLUSIONS: Early switch from intravenous to oral antibiotics in patients with severe community acquired pneumonia is safe and decreases length of hospital stay by 2 days. TRIAL REGISTRATION: Clinical Trials NCT00273676 [ClinicalTrials.gov].

Administration, Oral↗

PubMed2006

IL-5-mediated eosinophil survival requires inhibition of GSK-3 and correlates with beta-catenin relocalization.

Interleukin (IL)-5 is a hematopoietic cytokine able to regulate differentiation, survival, and effector functions of eosinophils. It binds specifically to its receptor, which is composed of a cytokine-specific alpha-chain and a beta-chain shared with the receptors for IL-3 and the granulocyte macrophage-colony stimulating factor. The molecular mechanisms by which IL-5 modulates eosinophil survival remain unclear. In this study, we demonstrate that IL-5 withdrawal induces eosinophil apoptosis through a mitochondria-dependent pathway, independently of Fas receptor activation. The lipid kinase phosphatidylinositol-3 kinase plays a crucial role in the maintenance of eosinophil survival, as inhibition of its activity results in apoptosis. IL-5 induces phosphorylation and thus, inhibition of the Forkhead transcription factor FOXO3a and glycogen synthase kinase 3 (GSK-3). We analyzed expression of FOXO3a-dependent transcriptional targets: Fas ligand or Bim (a proapoptotic Bcl-2 family member), but neither was detected in apoptotic eosinophils. We further show that GSK-3 is activated after IL-5 withdrawal, and inhibition of its activity rescues eosinophils from apoptosis. beta-catenin, a direct GSK-3 substrate, is present in the nucleus of IL-5-stimulated eosinophils, but it is translocated to the plasma membrane in the absence of cytokine in a GSK-3-dependent manner. This is the first report describing a potential role for GSK-3 and beta-catenin in regulating eosinophil survival and suggests a novel mechanism by which IL-5 inhibits the constitutive apoptotic program in these cells.

Apoptosis↗

PubMed2006

A comparison of lung function equipment with emphasis on interchangeability and methods.

The replacement of lung function equipment may not result in changing values: transitions should be seamless. We compared the equipment of two manufacturers (ZAN and Jaeger) to estimate the differences in spirometry, bodyplethysmography and diffusion capacity derived parameters elicited by equipment differences, and also compared calibration systems. From Jaeger (1) a Masterlab bodyplethysmograph, (2) a Pneumoscreen pneumotachograph, (3) a Masterscreen CS-FRC and (4) a Masterlab CompactTransfer (the latter two measure the diffusion capacity) were compared, and from ZAN a bodyplethysmograph system encompassing spirometry, flow-volume curve and diffusion capacity measurements. In vitro (a 2 litre calibration syringe at three flows, a fixed flow generator (0.5 l s(-1), 1.67 l s(-1) and 5 l s(-1)) and a wave form generator) studies and an in vivo cross-over study (N = 59) were used to compare the pneumotachographs. Other parameters were compared only via the in vivo study. The calibration syringe study showed no differences between the pneumotachographs: all volumes in all systems were within 3% of the reference. The fixed flow generator showed no flow differences either: again within 3% of the reference. The wave form generator showed PEF, MEF(75/50/25) differences up to 10-15% from the reference, but none in FEV(1) and FVC. The in vivo study found similar system differences in PEF, MEF(75/50/25): up to 29%. FEV(1), VC and FVC differed by small amounts (in all cases <3% between systems). R(0.5), TLC, V(A) and RV differed by small amounts between the systems (in all cases <3%), but T(L,CO) up to 9%. This study showed that between and within manufacturers, significant differences can exist between pneumotachographs and that using calibration syringes or fixed flow generators these frequently go unnoticed. These approaches insufficiently test the dynamic features of pneumotachographs. For other parameters, in vivo calibration is the only option and accuracy is only achieved with rather large samples, so more research is needed into suitable in vitro systems.

Equipment Design↗

PubMed2006

Heart failure and chronic obstructive pulmonary disease: An ignored combination?

AIMS: To quantify the prevalence of heart failure and left ventricular systolic dysfunction (LVSD) in chronic obstructive pulmonary disease (COPD) patients and vice versa. Further, to discuss diagnostic and therapeutic implications of the co-existence of both syndromes. METHODS AND RESULTS: We performed a Medline search from 1966 to March 2005. The reported prevalence of LVSD among COPD patients varied considerably, with the highest prevalence (10-46%) among those with an exacerbation. One single study assessed the prevalence of heart failure in COPD patients. A prevalence of 21% of previously unknown heart failure was reported in patients with a history of COPD or asthma. We did not find any report on COPD in heart failure or LVSD patients. Diagnosing heart failure in COPD patients or vice versa is complicated by overlap in signs and symptoms, and diminished diagnostic value of additional investigations. In general, pulmonary and heart failure 'drug cocktails' can be administered safely to patients with concomitant COPD and heart failure, although (short acting) beta2-adrenoreceptor agonists and digitalis have potentially deleterious effects on cardiac and pulmonary function, respectively. CONCLUSION: Although knowledge about the prevalence of concomitant heart failure in COPD patients and vice versa is scarce, it seems that the combined presence is rather common. In view of diagnostic and therapeutic implications, more attention should be paid to the concomitant presence of both syndromes in clinical practice and research.

Adrenergic beta-Agonists↗

PubMed2006

Expression of priming-associated cellular markers on neutrophils during an exacerbation of COPD.

Chronic inflammation of the airways is a hallmark of chronic obstructive pulmonary disease (COPD). We investigated the kinetics of priming of inflammatory cells in peripheral blood during exacerbations of COPD and during the resolution phase. Modulation of the leukocyte compartment as a consequence of systemic activation by cytokines/chemokines was determined by measuring the expression of priming-associated epitopes by novel antibodies designated A17 and A27. Furthermore, H2O2 was determined in breath condensate as a read out for local inflammation. Leukocytes were obtained from COPD patients (GOLD II-IV) during and after an exacerbation of their disease. During an exacerbation the expression of priming epitopes on leukocytes was increased. This priming phenotype disappeared upon treatment with intravenous corticosteroids. Similarly, H2O2 levels in breath condensate were also increased during an exacerbation and decreased upon treatment. We conclude that the activation status of neutrophils in the systemic compartment can be used as a read-out for systemic innate immune signals involved in the pathogenesis of COPD. The correlation between H2O2 in exhaled air with A27 priming on neutrophils showed that local inflammation has systemic effects on cells of the innate immune system.

Female↗

PubMed2006

Are patient characteristics helpful in recognizing mild COPD (GOLD I) in daily practice?

OBJECTIVE: To determine whether in a high-risk group of middle-aged male current smokers, patient characteristics are useful to recognize mild COPD (GOLD stage I). DESIGN: In a cross-sectional study spirometry was performed according to the American Thoracic Society criteria. COPD was defined according to the GOLD criteria for COPD. SETTING: Primary care. SUBJECTS: Male smokers, aged 40-65 years, without documented lung disease in the population at large. MAIN OUTCOME MEASURES: Medical records were scrutinized to collect patient characteristics. Multiple logistic regression analysis was used to identify independent determinants of mild COPD. RESULTS: A total of 567 subjects participated. COPD, defined by a FEV1/FVC ratio < 0.7, was detected in 170 subjects (30.0%, 95% CI 26.2-33.9%). In 149 subjects (26.3%; 22.7-30.1%) COPD was mild (GOLD stage I) and in 21 subjects (3.7%; 2.3-5.6%) moderate (GOLD stage II). Only age and cough were independently associated with the presence of mild COPD. The ability of these determinants to discriminate between subjects with or without mild COPD was relatively poor (ROC area 0.65). Therefore no prediction rule was developed. CONCLUSION: Our results indicate that patient characteristics are not helpful to recognize mild COPD (GOLD stage I) in middle-aged male smokers.

Adult↗

PubMed2006

Relevant and redundant lung function parameters in discriminating asthma from COPD.

A relevant set of lung function parameters, derived from spirometry, flow-volume curves, diffusion capacity and bodyplethysmography, to discriminate asthma from COPD was established via logistic regression analysis. All new patients, referred to the outpatient clinic and later defined as asthma or COPD, underwent extensive lung function testing with reversibility testing. Logistic regression was used to calculate the probability to be a COPD or asthma patient. Selection of relevant parameters was done via 1] forward-, 2] backward-, 3] stepwise selection and 4] the best score method. All four methods were supplemented by bootstrapping to obtain a validated selection and estimation of the logistic regression parameters. The area under the ROC curve (mean+/-sd) for respectively the forward, backward, stepwise and best score selection method is 0.9348+/-0.0115, 0.9346+/-0.0115, 0.9348+/-0.0115 and 0.9296+/-0.0121. The TLCO, VA and the postdilator MEF50, VC and PEF were selected as the most relevant parameters in discriminating asthma from COPD: they appeared most often as relevant discriminators in 500 bootstrapped samples: TLco was present in all bootstrapped samples and VA, postdilator MEF50, VC and PEF in resp. 70.8%, 46.2%, 42.8% and 36.8%. Bodyplethysmography derived parameters turned out to be of limited value. Diffusion capacity testing and spirometry/flow-volume curve after administration of bronchodilators are the methods of choicewhen having to chose between asthma or COPD.

Adult↗

PubMed2006

Incidence and determinants of moderate COPD (GOLD II) in male smokers aged 40-65 years: 5-year follow up.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major health problem with an estimated prevalence of 10-15% among smokers. The incidence of moderate COPD, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), is largely unknown. AIM: To determine the cumulative incidence of moderate COPD (forced expiratory volume in 1 second/forced vital capacity ratio [FEV1/FVC] <0.7 and FEV1 <80% predicted) and its association with patient characteristics in a cohort of male smokers. DESIGN: Prospective cohort study. SETTING: The city of IJsselstein, a small town in the Netherlands. METHOD: Smokers aged 40-65 years who were registered with local GPs, participated in a study to identify undetected COPD. Baseline measurements were taken in 1998 of 399 smokers with normal spirometry (n = 292) or mild COPD (FEV1/FVC <0.7 and FEV1 >or=80% predicted, n = 107) and follow-up measurements were conducted in 2003. RESULTS: After a mean follow-up of 5.2 years, 33 participants developed moderate COPD (GOLD II). This showed an estimated cumulative incidence of 8.3% (95% CI = 5.8 to 11.4) and a mean annual incidence of 1.6%. No participant developed severe airflow obstruction. The risk of developing moderate COPD in smokers with baseline mild COPD (GOLD I) was five times higher than in those with baseline normal spirometry (one in five versus one in 25). CONCLUSIONS: In a cohort of middle-aged male smokers, the estimated cumulative incidence of moderate COPD (GOLD II) over 5 years was relatively high (8.3%). Age, childhood smoking, cough, and one or more GP contacts for lower respiratory tract problems were independently associated with incident moderate COPD.

Adult↗

PubMed2005

Recognising heart failure in elderly patients with stable chronic obstructive pulmonary disease in primary care: cross sectional diagnostic study.

OBJECTIVE: To determine which clinical variables provide diagnostic information in recognising heart failure in primary care patients with stable chronic obstructive pulmonary disease (COPD) and whether easily available tests provide added diagnostic information. DESIGN: Cross sectional diagnostic study. SETTING: 51 primary care practices. PARTICIPANTS: 1186 patients aged > or = 65 years with COPD diagnosed by their general practitioner who did not have a diagnosis of heart failure confirmed by a cardiologist. MAIN OUTCOME MEASURES: Independent diagnostic variables for concomitant heart failure in primary care patients with stable COPD. RESULTS: 405 patients (34% of eligible patients) underwent a systematic diagnostic investigation, which resulted in 83 (20.5%) receiving a new diagnosis of concomitant heart failure. Independent clinical variables for concomitant heart failure were a history of ischaemic heart disease, high body mass index, laterally displaced apex beat, and raised heart rate (area under the receiver operating characteristic curve (ROC area) 0.70, 95% confidence interval 0.64 to 0.76). Addition of measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) to the reduced "clinical model" had the largest added diagnostic value, with a significant increase of the ROC area to 0.77 (0.71 to 0.83), followed by electrocardiography (0.75, 0.69 to 0.81). C reactive protein and chest radiography had limited added value. A simplified diagnostic model consisting of the four independent clinical variables plus NT-proBNP and electrocardiography was developed. CONCLUSIONS: A limited number of items easily available from history and physical examination, with addition of NT-proBNP and electrocardiography, can help general practitioners to identify concomitant heart failure in individual patients with stable COPD.

Aged↗

PubMed2005

Discriminating asthma and COPD based on bronchodilator data: an improvement of the methods.

The degree of bronchodilation is usually expressed as a percentage of the predicted or baseline value. It has been shown that the relation between pre- and post-dilation lung function values is not adequately described by this approach: the sensitivity/specificity in separating asthmatics from cases of chronic obstructive pulmonary disease (COPD) could be improved. The alternative method we investigate is based on a logistic regression approach incorporating pre- and post-dilation lung function, age, sex and height. The discriminatory power of forced expiratory volume in one second (FEV1) increase as a percentage of the predicted or baseline FEV1 is compared to our approach using two databases containing bronchodilator data and diagnoses (asthma, chronic bronchitis or emphysema, the latter two grouped as (OPD). The increase as a percentage of the predicted or baseline approach and our alternative method show areas under the receiver operator curve (ROC) (males/females) of 0.552/0.629, 0.523/0.550 and 0.867/0.879 in one database. In the other database the same trend is present although less obvious: 0.628/0.730, 0.592/0.737 and 0.709/0.749. This increase in discriminatory power is obtained in the optimal use of all available information, especially age, which is not used in the increase of the predicted/baseline FEV1 rule.

Adult↗

PubMed2005

Prevalence of undetected persistent airflow obstruction in male smokers 40-65 years old.

BACKGROUND: Airflow obstruction in smokers is often diagnosed relatively late. Earlier detection of airflow obstruction and smoking cessation may result in significant health gain. OBJECTIVE: To determine the prevalence of previously undetected persistent airflow obstruction according to WHO/GOLD criteria in male smokers aged 40 to 65 years and its correlation with age, smoking history and the presence of coughing. METHODS: In a cross-sectional study among 805 male smokers aged 40-65 years spirometry was performed according to ATS recommendations. In participants with low lung function (FEV1 < 85% predicted) a bronchodilator test was performed. RESULTS: In 702 participants [mean age 50 years (SD 6.6), mean number of pack years 24.7 (SD 9.6)] with acceptable spirometric curves, previously undetected airflow obstruction was found in 210 subjects (29.9%; 95% CI 26.5-33.4): mild airflow obstruction (GOLD stage 1) in 182 subjects (25.9%; 22.7-29.3) and moderate airflow obstruction (GOLD stage 2) in 28 (4.0%; 2.7-5.7). In the older age group (>55 years) airflow obstruction (GOLD 1 or higher) was found in 45% versus 21% in the youngest age group (40-44 years). In subjects with > or =30 pack years the prevalence of airflow obstruction was 45% versus 20% among those with <20 pack years. In smokers reporting coughing the prevalence was 47% versus 25% in those not reporting this symptom. CONCLUSION: The prevalence of undetected persistent airflow obstruction in middle-aged smokers is high. Targeted screening therefore, especially in smokers aged 40-65 years needs to be considered.

Adult↗

PubMed2005

Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease.

AIMS: To establish the prevalence of unrecognized heart failure in elderly patients with a diagnosis of chronic obstructive pulmonary disease, in a stable phase of their disease. METHODS AND RESULTS: In a cross-sectional study, patients >/=65 years of age, classified as having chronic obstructive pulmonary disease by their general practitioner and not known with a cardiologist-confirmed diagnosis of heart failure, were invited to our out-patient clinic. Four hundred and five participants underwent an extensive diagnostic work-up, including medical history and physical examination, followed by chest radiography, electrocardiography, echocardiography, and pulmonary function tests. As reference (i.e. 'gold') standard the consensus opinion of an expert panel was used. The panel based the diagnosis of heart failure on all available results from the diagnostic assessment, guided by the diagnostic principles of the European Society of Cardiology (ESC) for heart failure (i.e., symptoms and echocardiographic systolic and/or diastolic dysfunction). The diagnosis of chronic obstructive pulmonary disease was based on the diagnostic criteria of the Global Initiative (GOLD) for chronic obstructive pulmonary disease. Of 405 participating patients with a diagnosis of chronic obstructive pulmonary disease, 83 (20.5%, 95% CI 16.7-24.8) had previously unrecognized heart failure (42 patients systolic, 41 'isolated' diastolic, and none right-sided heart failure). In total, 244 (60.2%) patients had chronic obstructive pulmonary disease according to the GOLD criteria and 50 (20.5%, 95% CI 15.6-26.1) patients combined with unrecognized heart failure. CONCLUSION: Unrecognized heart failure is very common in elderly patients with stable chronic obstructive pulmonary disease. Closer co-operation among general practitioners, pulmonologists, and cardiologists is necessary to improve detection and adequate treatment of heart failure in this large patient population.

Age Distribution↗

PubMed2005

Characterization of the role of CaMKI-like kinase (CKLiK) in human granulocyte function.

Activation of granulocyte effector functions, such as induction of the respiratory burst and migration, are regulated by a variety of relatively ill-defined signaling pathways. Recently, we identified a novel Ca2+/calmodulin-dependent kinase I-like kinase, CKLiK, which exhibits restricted mRNA expression to human granulocytes. Using a novel antibody generated against the C-terminus of CKLiK, CKLiK was detected in CD34+-derived neutrophils and eosinophils, as well as in mature peripheral blood granulocytes. Activation of human granulocytes by N-formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF), but not the phorbol ester PMA (phorbol 12-myristate-13-acetate), resulted in induction of CKLiK activity, in parallel with a rise of intracellular Ca2+ [Ca2+]i. To study the functionality of CKLiK in human granulocytes, a cell-permeable CKLiK peptide inhibitor (CKLiK297-321) was generated which was able to inhibit kinase activity in a dose-dependent manner. The effect of this peptide was studied on specific granulocyte effector functions such as phagocytosis, respiratory burst, migration, and adhesion. Phagocytosis of Aspergillus fumigatus particles was reduced in the presence of CKLiK297-321 and fMLP-induced reactive oxygen species (ROS) production was potently inhibited by CKLiK297-321 in a dose-dependent manner. Furthermore, fMLP-induced neutrophil migration on albumin-coated surfaces was perturbed, as well as beta2-integrin-mediated adhesion. These findings suggest a critical role for CKLiK in modulating chemoattractant-induced functional responses in human granulocytes.

Antigens, CD34↗

PubMed2005

Differential regulation of granulopoiesis by the basic helix-loop-helix transcriptional inhibitors Id1 and Id2.

Inhibitor of DNA binding (Id) proteins function as inhibitors of members of the basic helix-loop-helix family of transcription factors and have been demonstrated to play an important role in regulating lymphopoiesis. However, the role of these proteins in regulation of myelopoiesis is currently unclear. In this study, we have investigated the role of Id1 and Id2 in the regulation of granulopoiesis. Id1 expression was initially up-regulated during early granulopoiesis, which was then followed by a decrease in expression during final maturation. In contrast, Id2 expression was up-regulated in terminally differentiated granulocytes. In order to determine whether Id expression plays a critical role in regulating granulopoiesis, Id1 and Id2 were ectopically expressed in CD34(+) cells by retroviral transduction. Our experiments demonstrate that constitutive expression of Id1 inhibits eosinophil development, whereas in contrast neutrophil differentiation was modestly enhanced. Constitutive Id2 expression accelerates final maturation of both eosinophils and neutrophils, whereas inhibition of Id2 expression blocks differentiation of both lineages. Transplantation of beta2-microglobulin(-/-) nonobese diabetic severe combined immunodeficient (NOD/SCID) mice with CD34(+) cells ectopically expressing Id1 resulted in enhanced neutrophil development, whereas ectopic expression of Id2 induced both eosinophil and neutrophil development. These data demonstrate that both Id1 and Id2 play a critical, although differential role in granulopoiesis.

Animals↗

PubMed2005

Flow-volumes indices as means to discriminate between intra- and extrapulmonary restrictive disease.

Restrictive lung disease comes in two major categories: (1) intrapulmonary (= parenchymal) disease caused by fibrotic reactions or (2) extrapulmonary (= compression), like in heart failure. In the first category the conducting airways, tethered in stiffened structures, are less likely to be compressed during forceful expiration and expiratory flows hence are expected to remain high. This could serve as a cheap and easy diagnostic, avoiding more complicated measures. A database was build containing 624 patients suffering from either intra- and extrapulmonary disease. The flow-volume curve indices of restrictive patients (with a total lung capacity < -1.96 sd of reference) were compared and it was shown that in primary fibrotic disease and in leukaemia, indeed, the PEF and MEF(75/50/25) were significantly higher compared to the heart failure group (P < or = 0.001). The diabetes mellitus vs. heart failure differences were much less (P > 0.05). The area under the ROC to discriminate extra- from intrapulmonary disease was a low 0.607 and 0.606 for the PEF and MEF75, respectively. For the peakflow an optimal cut-off point was found at 65.8% of the reference value. The positive/negative predictive value of a peakflow < 65.8% to detect extrapulmonary disease was 30.1% and 82.2%, respectively.

Adult↗