Airway eosinophilia is considered a central event in the pathogenesis of asthma. Eotaxin plays a key role in selective eosinophil accumulation in the airways and, subsequently, their activation and degranulation. The study was undertaken to evaluate eotaxin-1 levels in the exhaled breath condensate (EBC) of asthmatics with different degrees of asthma severity and to establish the possible correlation of these measurements with other recognized parameters of airway inflammation.EBC was collected from 46 patients with allergic asthma  and 12 healthy volunteers. Concentrations of eotaxin-1 were measured by ELISA.ENO) or serum eosinophil cationic protein (ECP) in the three studied groups of asthmatics. We also discovered a significantly positive correlation between eotaxin-1 in EBC and blood eosinophil count in the groups of patients with unstable asthma and steroid-naïve asthma.In the three groups of asthmatics, eotaxin-1 concentrations in EBC were significantly higher compared with healthy volunteers . Eotaxin-1 levels were significantly higher in patients with unstable asthma than in the two groups with stable disease. We observed statistically significant correlations between the concentrations of eotaxin-1 in EBC and exhaled nitric oxide (FMeasurements of eotaxin-1 in the EBC of asthma patients may provide another useful diagnostic tool for detecting and monitoring airway inflammation and disease severity. Asthma is a chronic inflammatory disease of the airways. Eosinophils play a crucial role in the pathogenesis of asthma, and eosinophil infiltrations prevail in sites of allergic inflammation. The most important factors taking part in the development of inflammatory infiltration are increased expression of adhesion molecules localized on the surface of endothelial cells (VCAM-1 - vascular cell adhesion molecule-1) and increased synthesis of chemotactic substances by eosinophils and Th2 lymphocytes . They acIn previous studies it was revealed that eotaxin levels in BAL fluid were higher in asthmatics than in healthy controls ,5. EotaxBy contrast, exhaled breath condensate (EBC), collected by cooling exhaled air, is a noninvasive, easily performed, and rapid method for obtaining samples from the lower respiratory tract. There has been increasing interest in measuring EBC, which is a very useful method in the pathophysiology and evaluation of new strategies for the treatment of asthma - especially for the assessment of inflammatory mediators related to the bronchial epithelium . HoweverPrevious studies have revealed that eotaxin can be measured in the EBC of patients with asthma -11. Ko eWe hypothesize that eotaxin-1 levels in EBC are associated with the level of severity of the disease and markers of airway inflammation in asthma.The aim of the study was to assess eotaxin-1 concentrations in the EBC of asthmatics with different degrees of asthma severity, and also to establish the possible correlation of these measurements with the other recognized parameters of airway inflammation.The study was performed upon groups of 14 steroid-naïve allergic asthma patients; 16 patients, treated with inhaled corticosteroids (ICS) with stable allergic asthma; and 16 ICS-treated patients with unstable allergic asthma. Asthma was diagnosed according to the criteria recommended by the GINA 2006 .The steroid-naïve asthmatics had not been treated with ICS. They were free from acute exacerbations and respiratory tract infections during the three months prior to the study. In this group of patients asthma was diagnosed recently, just before inclusion to the study .2-agonists), no exacerbations, and no use of systemic steroids in the previous 12 months. The patients with unstable asthma had required one or more hospitalizations for asthma and more than three oral steroid bursts in the last year. They had been taking high-doses of ICS and long-acting β2-agonists for at least six months. Patients who had respiratory tract infections in the last month before the study were excluded from this study. All the patients were atopic and sensitized to common perennial inhaled allergens, as evaluated by skin prick tests .The patients with unstable ICS-treated asthma and stable ICS-treated asthma had a many-year history of asthma and anti-asthmatic treatment. In these patients asthma was diagnosed several years ago on the basis of typical symptoms, positive reversibility tests, or bronchial provocation tests. The patients with stable ICS-treated asthma had been treated with low to medium doses of ICS at a constant dose for at least three months. Stable asthma was defined as a minimal need for rescue medications (short-acting βENO) levels, and no presence of eosinophilia in peripheral blood. Healthy volunteers also had a negative bronchial provocation test with histamine (PC20 > 32 mg/ml). All healthy volunteers were non atopic; all of them had negative skin prick tests. They were free of respiratory tract infection within three months prior to the study and from other significant illnesses known to affect FENO measurements. Asthma patients and healthy volunteers were non-smokers and during the last year had not been passive smokers.12 healthy subjects were recruited for the study as a negative control group. In this group, asthma was excluded on the basis of lack of symptoms of asthma and atopy, normal spirometric indices, low exhaled nitric oxide  and EBC samples were collected. After 30 min, the measurement of FThe study protocol was approved by the Ethics of Research Committee of the Medical University of Bialystok, number of agreement: R-I-002/265/2009. Informed consent was obtained from every patient entered in the study.ENO) was measured by the chemiluminescence technique using a Sievers 280i NO Analyzer . The measurements were performed at an expiratory flow of 50 ml/s according to ATS recommendations for on-line measurement of FENO in adults [Exhaled nitric oxide (Fn adults .1) was performed using a MasterScreen Pneumo PC spirometer , according to ATS standards [The spirometry  according to the current ATS/ERS guidelines . All meaThe longest storage time of EBC samples did not exceed two months. The samples were not concentrated prior to measurement. All measurements were performed in a blind fashion. All samples were run in duplicate. Because the marker used to correct the difference in the degree of dilution has not yet been established, in our study we made no attempt to assess the dilution of ALF in EBC. The results (eotaxin-1) were well repeatable {CV(%) = 4-7%}. We performed the preliminary study, in which we measured eotaxin-1 in EBC immediately after collection and after 1, 2, and 3 months of storage at -80°C and we did not observe important changes. Therefore, we suggest that eotaxin-1 in EBC stored at -80°C remains stable during at least three months.Serum total IgE concentrations and serum ECP were measured using ImmunoCAP™ Technology . The minimum detectable level of ECP was 2.0 μg/l. Blood eosinophil count was measured using a hematologic analyzer . The concentrations of eotaxin-1  in EBC were determined using an enzyme-linked immunosorbent assay. The minimum detectable level was 5.0 pg/ml.Statistical significance was analyzed by using analysis of variance (ANOVA) followed by Bonferroni's t test post hoc to determine statistical differences. All values were expressed as means ± SD; p values < 0.05 were considered significant. The relationship between studied parameters was assayed by correlation. Pearson's linear correlation coefficient was used.In the three groups of asthmatics, EBC concentrations of eotaxin-1 were significantly higher than those detected in healthy volunteers   against the mean, using Bland and Altman statistics in the studied groups of asthmatic patients and healthy volunteers are presented in figure Airway eosinophilia is recognized as a central event in the pathogenesis of asthma. The toxic components produced by eosinophils are thought to be important in inducing damage and dysfunction of bronchial mucosa . EvidencEotaxin is the most specific and the strongest factor which can affect the function of eosinophil. The effect of eotaxin can be observed at each stage of the life cycle of eosinophil, and therefore plays a very important role in the development of allergic reaction. This chemokine is responsible for the release of progenitors of eosinophils from the bone marrow, and, together with IL-5, increases the count of mature forms in peripheral blood. The consequence of these processes is peripheral and tissue eosinophilia . The couThose human cells which can produce eotaxin are the airway epithelium, endothelial cells, lymphocytes, macrophages, and eosinophils, as well as airway smooth muscle cells . EotaxinIn previous studies, the possibility of measuring of eotaxin levels in exhaled breath condensate was confirmed both in children  and in aThe results of this study have confirmed the possibility of using eotaxin-1 measurements in EBC. It is worth noting that, in this study, increased eotaxin-1 levels in EBC in all groups of asthmatic patients with different degrees of disease severity compared with healthy volunteers were revealed for the first time. These differences could be the consequence of performing this study in highly selected groups and the authors have taken efforts to make this selection as defined as has been possible. By contrast, in the previouly cited studies, the differences between studied groups could have been too minor, and these studies were performed both on atopic and nonatopic patients and healthy volunteers.This is the first report which demonstrates the differences in eotaxin-1 levels between patients with stable and unstable asthma and healthy volunteers. Our results are the first report in which it can be shown that concentrations of eotaxin-1 in EBC significantly correlate with exhaled nitric oxide levels - a more and more appreciable criterion for the evaluation of airway inflammation - in all studied groups of asthma patients -28. EotaThe results obtained here indicate the possibilities of wider use of eotaxin - 1 measurements in EBC in the assessment of airway inflammation. The correlations with other markers recognized in the evaluation of asthmatic inflammation suggest that, in this way, the possibilities of monitoring the course and treatment of asthma could be improved.202, adenosine, 8-isoprostane [EBC examination, being simple and non-invasive, could be exploited to detect specific levels of biomarkers and monitor the severity of disease in response to appropriate prescribed therapy . The anaprostane ,15.Because of the difference in methodological procedures and the effect of many factors described previously, the results (different concentrations of eotaxin-1) of our study may not be directly comparable with the results from other research groups. We suggest that in the assessment of measurements of concentrations of immunological markers, including chemokines, in EBC, the control group and analysis of observed changes between the studied groups, as well as changes in the studied parameters in time, should be taken into account.in vitro studies have demonstrated that dexamethasone inhibition of cytokine-induced eotaxin mRNA augmentation is associated with diminished eotaxin secretion in cell cultures [In contrast to our previous studies, in which we suggested the beneficial effect of inhaled corticosteroids treatment on downregulation of RANTES in the airways (using EBC) , analysicultures . FurtherThere are some limitations of the study. One of them is small number of patients in the studied groups. The number of patients in particular groups was based on our experiences from previous studies, in which in similar numbers of patients the possibility of obtaining statistically significant differences in studied parameters in EBC, as well as in peripheral blood, was revealed. Because of the small sizes of our studied groups, an analysis of the minimal number of the sample using statistical tests was not performed. The next limitation of our study worth noting is the difference in age between the studied groups of asthmatics and the healthy volunteers. These differences between studied groups are a consequence of the natural history of asthma, diagnosis at a young age, and the subsequent, sometimes severe, course of the disease. Previous studies published by Targowski et al have shown that age and sex significantly influence the serum eotaxin levels in healthy people and patients with rhinoconjunctivitis . HoweverIn conclusion, we have shown that eotaxin-1 levels in exhaled breath condensate are higher in asthmatic patients with different degrees of asthma severity when compared with controls. In patients with unstable asthma, these values are significantly higher compared with subjects with stable disease and correlate with other inflammatory parameters such as exhaled nitric oxide or serum ECP. Measurements of eotaxin-1 in EBC of asthma patients may provide another useful diagnostic tool for detecting and monitoring airway inflammation. However, taking the previously described methodological limitations of our study into account, future studies are needed for better assessment of the clinical significance and the possibility of the practical usefulness of eotaxin-1 measurements in EBC.The authors declare that they have no competing interests in the publication of the manuscript. This work was supported by research grant No 3-06513P from the Medical University of Bialystok, Poland.ZZ conceived the trial, participated in its design, study procedures, interpretation of results, performed the statistical analysis and helped to draft the manuscript. MMT-L participated in the study procedures and helped to draft the manuscript. RS participated in the study procedures, laboratory tests and helped to draft the manuscript. EZ helped to draft the manuscript. AB-L participated in study design, interpretation of results and helped to draft the manuscript. All of the authors read and approved the final manuscript.


Quality circles (QCs) are well established as a means of aiding doctors. New quality improvement strategies include benchmarking activities. The aim of this paper was to evaluate the efficacy of QCs for asthma care working either with general feedback or with an open benchmark.Twelve QCs, involving 96 general practitioners, were organized in a randomized controlled trial. Six worked with traditional anonymous feedback and six with an open benchmark; both had guided discussion from a trained moderator. Forty-three primary care practices agreed to give out questionnaires to patients to evaluate the efficacy of QCs.P = 0.19), and asthma steps improved (P = 0.02). Delivery of individual emergency plans increased (P = 0.008), and unscheduled emergency visits decreased (P = 0.064). There was no change in asthma education and peak flow meter usage. High medication guideline adherence was associated with reduced emergency visits . Use of theophylline was associated with hospitalization  and emergency visits . There was no difference between traditional and benchmarking QCs.A total of 256 patients participated in the survey, of whom 185 (72.3%) responded to the follow-up 1 year later. Use of inhaled steroids at baseline was high (69%) and self-management low . Guideline adherence in drug treatment increased (Quality circles working with individualized feedback are effective at improving asthma care. The trial may have been underpowered to detect specific benchmarking effects. Further research is necessary to evaluate strategies for improving the self-management of asthma patients. Asthma has a high prevalence as a chronic disease, affecting nearly 5% of the population in industrialized nations . It is aQuality circles (QCs) are well-established instruments for aiding a doctor's daily work by regular conjointly reflection on common practice with other colleagues . HoweverThe study was designed as a two-armed randomized controlled trial. One arm comprised a traditional QC without benchmark. The second arm comprised a QC working with an open benchmark and discussion of the results. After giving consent, the GPs were randomized to the ‘traditional’ arm vs. the study arm working with benchmarking. These GPs were grouped into a total of 12 QCs. Six QCs worked with an open benchmark, and the other six worked with the traditional discussion style. The study was approved by the Medical Ethics Committee of the Medical Faculty of the University of Heidelberg on 12 November 2004 (application number 371/2004).An individual feedback report about prescribing data from one's own practice is normally posted to each doctor a few days before they meet in QCs, so that the report can be read before the meeting. In the QCs, the doctors usually interpret their own data without exchanging their individual practice results with one another. The GPs also receive a feedback report with additional information about the group performance of the other doctors. This allows them to compare their own results with the variability of performance  of the other doctors. The GPs discuss problems of care under the guidance of a moderator, and the respective quality indicators serve as a basis for discussion. In the present study, the GPs in traditional QCs also received the baseline questionnaire results describing the number of patients with an individual emergency plan, an asthma diary and peak flow meter at home. Using this information, the doctors discussed the feasibility of a new set of asthma guidelines, the management of asthma education or prescribing management. The discussion was facilitated by comprehensive information on evidence-based asthma therapy, including examples of individual emergency plans and asthma diaries, and other indices of patient management.The basic structure is identical to that of traditional QCs: individual feedback reports were given to the participating GPs in these QCs, but with a comparison with a performance ‘benchmark’. These GPs received the name of and information about the GP who performed best in their QCs and information about the performance of the ‘best 10%’ of GPs in the benchmark arm. Under the guidance of the moderator, the GPs discussed with the identified GP how the best practice was achieved. In addition, practice details of the ‘overall best practice’ of the benchmarking arm were given to enable a comparison with the best benchmark. This multifaceted benchmark intervention was intended to allow learning from the best performer. The moderators of both arms were trained before the QC meetings to lead the group discussion.At the beginning of this study, 97 GPs in 87 general practices collaborating in this project were asked to participate in the survey. As the workload in these practices was particularly high because of the implementation of a new fee-for-service structure during the study period, only 42 practices agreed on handing out the questionnaires . The GPs were instructed in a leaflet to select patients with asthma as accurately as possible. The most relevant criteria to distinguish between asthma and COPD were explained in this leaflet. For example, the GPs were instructed to preferably select patients with varying symptoms, attacks of dyspnoea and wheezing, or with a known allergy. They were to avoid including heavy smokers, who were likely to have COPD.The GPs were asked to hand out a questionnaire consecutively to every asthma patient coming for consultation between May and July 2005 (T1). The patients were asked to fill in the questionnaire and to send it to the study centre, receiving assurances of the anonymous handling of their data. Three lots of €250 were raffled as an incentive for participation. One year later (T2), the patients received the same questionnaire directly from the study centre. Again, three lots of €250 were raffled as an incentive. Three reminders were sent out after 4, 8 and 12 weeks.Routine prescribing data as primary outcome measures are yet to be made available by the compulsory health insurance organization Allgemeine Ortskrankenkasse (AOK). However, these data will be obtained after careful control and anonymizing in February 2007 at the earliest. The secondary outcome measures were evaluated using the questionnaire.The patients were asked about their daily and nocturnal symptoms related to asthma, according to the international levels of asthma severity steps 1 to 4 . Currentspss 14.0. by Eyes & Hands® Forms, Version 5 . The plausibility of the data was checked manually, and baseline data were presented descriptively. Differences between men and women, and responders and non-responders were calculated with t-tests or χ2-tests where appropriate.The questionnaires were scanned and the data were imported automatically into To assess adherence to guidelines, the medication was checked manually for each patient. Full adherence to guidelines implied that the prescribed medication was consistent with the guidelines  and thatBefore–after differences of guideline adherence and asthma steps were calculated using the McNemar test, a non-parametric test for dependent samples. Predictive values related to hospitalization and unscheduled emergency visits were estimated using univariate logistic regression.A total of 314 patients, of whom 159 (62.5%) were female, received the questionnaire; the average age was 56.8 years. Two hundred and fifty-six (81.5%) patients sent back the questionnaire. Of the responders, 158 (61.7%) were female, and the average age was 56.3 years. There was no significant difference between responders and non-responders with regard to sex and age at baseline (data not shown). Nearly half of the patients reported symptoms corresponding to asthma step 3 or 4 . The useOne hundred and eighty-five patients (72.3%) responded to the follow-up 1 year later. Seventy-one were unable to be included at follow-up. Of these patients, 11 had an unknown address and one patient had died. There was no significant difference in sex, age and self-management between responders and non-responders at follow-up.P = 0.046) and patients with asthma step 2 increased (P = 0.055). The non-responders at follow-up seemed to be slightly healthier, as they had more favourable asthma steps; indeed the difference was not significant . As an overall effect, the change from the unfavourable group (asthma steps 3 and 4) into the beneficial group (asthma steps 1 and 2) was significant (P = 0.018). There was no group difference between benchmarking and traditional QCs in all of these categories.Clinical improvement was operationalized as change in asthma severity . The numThe improvement in asthma severity is slightly reflected in the improvement of asthma therapy. There was a trend towards an increase of full adherence to guidelines and decrease of under-dosing . HoweverP = 0.008), although this number remains low. There was a decrease in the number of patients with unscheduled emergency visits (P = 0.064) and a decrease in the number of visits (P = 0.096). Also, in these categories, there was no group difference between benchmarking and traditional QCs.There was no change in asthma education, peak flow meter at home and use of asthma diary . The numP = 0.09).The risk for hospitalization and unscheduled emergency visits over 1 year increased significantly with asthma severity . The numThe results of our trial indicate that QCs can be effective at improving outcomes for patients with asthma. While asthma steps improved significantly, which is slightly reflected in the improvement of drug treatment, few changes in clinical management were identified. Unscheduled emergency visits decreased, which might be associated with the effect on asthma severity. However, it was not possible with this randomized trial to demonstrate the superiority of using an open benchmark in QCs.Nearly 70% of patients received inhaled steroids and 8.2% had oral steroids. This is a high level of inhaled steroid usage compared with a huge European survey in which only 23% used inhaled steroids regularly . The quaThe association between use of theophylline, hospital stay and emergency visits remains to be discussed. On the one hand, this could indicate low guideline adherence in terms of prescribing, accompanied by under-use of inhaled steroids, which are vital to efficient asthma therapy  as they et al. also found a low usage of peak flow meter and therefore suggested the dissemination of guidelines to patients themselves [Another critical point is the low number of patients receiving education and support for self-management. The relevance of these measures for reducing disability and hospitalization has been demonstrated in several studies . Meng etemselves . Howeveremselves . Therefoet al., who found group education not effective [et al. included patients with asthma and COPD, following the ‘Dutch hypothesis’, which presumes a common aetiological factor in both diseases [et al., who tried to detect improvement of peak flow variability in asthma and COPD patients by improving care with a multifaceted intervention, including educational meetings [et al. tried to distinguish asthma from COPD and found a significant increase of acceptably treated asthma cases after peer-review meetings combined with feedback of prescribing data [However, all these measures together seemed to improve the health outcomes in terms of asthma severity and unscheduled emergency cases. This contrasts with the results of Smeele ffective . One readiseases . Newer ddiseases . Therefomeetings . Supporting data .Quality circles working with structured feedback have already been shown to improve rational prescribing in general practice . The corThe small increase in self-management behaviours reveals the limitation of QCs. It seems unlikely that more sophisticated performance of QCs would be able to solve this problem, in particular as this kind of patient management is strongly dependent on organization within the practice team. As there is still no ‘magic bullet’ in qualiOur trial has some limitations. Most important is that only 43 out of 96 practices agreed to distribute the questionnaires because of a high workload due to the implementation of a new fee-for-service structure during the study period. This could have led to a selection of highly motivated GPs and therefore an overestimation of the effectiveness of the QCs. Another critical point is that not all patients responded at follow-up. However, more than 70% did, and the non-responding patients seemed to be slightly healthier. This could also have led to some overestimation of the effectiveness. On the other hand, this underscores the high potential of QCs, as it may have been the more difficult patients who participated.


A prospective study was undertaken to evaluate the changes in portal venous pressure in patients withbenign biliary obstruction (BBO) but without overt clinical, endoscopic or radiological evidence of portalhypertension. Portal venous pressure was measured at laparotomy in 20 patients (10 each with eitherbenign biliary stricture or choledocholithiasis) before and after biliary decompression. Pressure was foundto be on the high side in seven patients .The mean fall of pressure was 3.4 cm of saline after biliary decompression. No correlation could, however,be found between portal venous pressure and duration of biliary obstruction, serum bilirubin or bile ductpressure. Liver histology showed mild to moderate cholestatic changes but maintained portal architecturein all. Benign biliary obstruction may therefore, lead to elevation of portal pressure, even though thepatient may not necessarily have any clinical, endoscopic or radiological manifestations of portal hypertension.The pathogenesis of this ‘latent’ portal hypertension is probably multifactorial. If biliary obstructionis left untreated the development of overt portal hypertension may become a possibility in the future.


KIT mutations. To evaluate the effectiveness of adjuvant imatinib after radical surgery, a consecutive series of patients with high-risk tumours (n=23) was compared with historic controls (n=48) who were treated with surgery alone. The mean follow-up period was over 3 years in both groups. Only 1 out of 23 patients (4%) in the adjuvant treatment group developed recurrent disease compared to 32 out of 48 patients (67%) in the control group. This preliminary study indicates that 1 year of adjuvant treatment with imatinib dramatically improves recurrence-free survival. Confirmation of these findings awaits the results of ongoing randomised studies.Palliative imatinib treatment has dramatically improved survival in patients with malignant gastrointestinal stromal tumours, particularly in patients with tumours harbouring activating  KIT exon 11 mutations, has improved dramatically since the introduction of imatinib mesylate into treatment protocols ) for 1 year in patients with high-risk GIST with no control arm, while ACOSOG Z9001 compares imatinib treatment with placebo in patients with tumours ⩾3 cm . EORTC 62024 is designed for patients with intermediate- and high-risk GIST treated with imatinib ) vs placebo for 2 years. Finally, SSG XVIII includes high-risk GIST treated with imatinib ) for either 1 or 3 years.The survival of patients with metastatic and inoperable malignant gastrointestinal stromal tumours (GIST), particularly those whose tumours have −1) for 1 year after R0 resection. These cases are compared with historical controls from a previous population-based series ) for 12 months after R0 resection. The mean follow-up after onset of imatinib treatment was 40 months . Mutational analyses of KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were performed with dHPLC and bidirectional direct sequencing in both patient groups  with high-risk GIST diagnosed between February 2001 and June 2005. The mean tumour size was 9.4 cm , and the mean Ki67 max% (maximum percentage of cells positive with Ki67 immunostains) was 7.0 . These patients received adjuvant imatinib . One patient had a GIST with duplication in KIT exon 9 and one patient's tumour had deletion in PDGFRA exon 18. Four patients had tumours that lacked KIT and PDGFRA mutations.The majority of patients  receiving adjuvant imatinib had tumours with mutations in KIT exon 11 mutations , one tumour had a missense mutation in PDGFRA exon 12 and 18 patients had tumours that were wild type (WT) in KIT and PDGFRA (There were 48 matched (with regard to tumour size and Ki67 max %) historical controls of high-risk GIST with R0 resections, including 25 women and 23 men with a mean age of 67 years . Mean tumour size was 12.3 cm , and mean Ki67 max% was 11.7  These patients had a mean follow-up of 36 months . Twenty-nine patients had tumours with d PDGFRA .. P<0.050 was considered statistically significant.Continuous data from the different groups were compared using the non-parametric Mann–Whitney test. Categorical data from different groups were compared using Fisher's exact test. Recurrence-free survival  was recorded from the time of initial diagnosis to the time of first recurrence or tumour-related death. Disease-free survival was calculated using the Kaplan–Meier method. Differences between groups were compared by the log–rank test. All statistical tests were two-sidedOnly high-risk GIST were included in this pilot adjuvant imatinib study, in contrast to ongoing adjuvant trials that also include intermediate-risk and even low-risk GIST. The selection of patients with high-risk GIST was based on follow-up data from our previously published population-based study of 233 GIST patients , she received adjuvant imatinib for 12 months. Twenty-two months after termination of imatinib treatment, a small lung metastasis was detected and removed. There is a distinct, rare subgroup of malignant GIST associated with a protracted clinical course despite multiple distant metastases over a long period of time. These have a distinct predilection for young females and have been shown to lack KIT mutation status is an independent prognostic factor in GIST in addition to tumour size and proliferative index ) treatment after R0 resections for high-grade GIST dramatically reduces the risk of recurrent disease. These results await confirmation with ongoing prospective adjuvant treatment trials.In summary, our study shows that 1 year of imatinib (400 mg day


High blood pressure (HBP) is a major risk factor for cardiovascular disease (CVD). European hypertension and cardiology societies as well as expert committees on CVD prevention recommend stratifying cardiovascular risk using the SCORE method, the modification of lifestyles to prevent CVD, and achieving good control over risk factors. The EDUCORE  project aims to determine whether the use of a cardiovascular risk visual learning method - the EDUCORE method - is more effective than normal clinical practice in improving the control of blood pressure within one year in patients with poorly controlled hypertension but no background of CVD;This work describes a protocol for a clinical trial, randomised by clusters and involving 22 primary healthcare clinics, to test the effectiveness of the EDUCORE method. The number of patients required was 736, all between 40 and 65 years of age (n = 368 in the EDUCORE and control groups), all of whom had been diagnosed with HBP at least one year ago, and all of whom had poorly controlled hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic ≥ 90 mmHg). All personnel taking part were explained the trial and trained in its methodology. The EDUCORE method contemplates the visualisation of low risk SCORE scores using images embodying different stages of a high risk action, plus the receipt of a pamphlet explaining how to better maintain cardiac health. The main outcome variable was the control of blood pressure; secondary outcome variables included the SCORE score, therapeutic compliance, quality of life, and total cholesterol level. All outcome variables were measured at the beginning of the experimental period and again at 6 and 12 months. Information on sex, age, educational level, physical activity, body mass index, consumption of medications, change of treatment and blood analysis results was also recorded;The EDUCORE method could provide a simple, inexpensive means of improving blood pressure control, and perhaps other health problems, in the primary healthcare setting;http://ClinicalTrials.gov].The trial was registered with ClinicalTrials.gov, number NCT01155973 [ In the year 2000, the worldwide prevalence of high blood pressure (HBP) among the adult population was 26.4% . The higThe control of HBP in Europe is far from optimum -8, and iComité Español Interdisciplinario para la Prevención Cardiovascular: CEIPC) .In recent years, many studies have investigated the use of tables based on the Framingham study -19 (e.g.: CEIPC) , recomme: CEIPC) ,23. The on 2009)  recommenIn randomised clinical trials, several strategies aimed at health professionals and patients have been shown capable of improving compliance with antihypertension therapy  and of rAs a strategy, improving the perception of risk is closely related to making behavioural changes that affect health . Leal etIt is unclear which communication format  is the best to use in educational interventions, although each type has its own advantages . Some auAffective communication can improve the perception of risk in high risk patients, and alleviate concerns in those whose risk is low . The EDUThe aim of the present work is to determine whether the EDUCORE method for communicating cardiovascular risk in patients with poorly controlled HBP, but no history of CVD, is more effective than normal practice in terms of improving the control of blood pressure at one year.Comunidad de Madrid) took part. The recruitment of these centres was undertaken between March and May 2009. The research group was comprised of 166 persons: 148 general practitioners and nurses , and 19 scientific researchers . A member of the clinical assistance team at each participating centre was appointed as liaison officer between the centre and the technical group.The present work involves a two-year community, parallel clinical trial, randomised by clusters. Twenty two primary healthcare centres (PHCC) in the Madrid Region (Comité de Ética de Investigación Clínica del Área 3) (2009/24/06), and met all good clinical practice demands. The trial was registered with ClinicalTrials.gov, number NCT01155973 [http://ClinicalTrials.gov].The study protocol was approved by the Area 3 Research Ethics Committee  at least one year ago, with analytical  and ECG results available, whose blood pressure was poorly controlled (last determination systolic ≥ 140 mmHg and/or diastolic ≥ 90 mmHg), and for whom information on organ involvement was available.b. Aged 40-65 years.c. To be able to meet the demands of the trial, i.e., to have no intention of moving, to be localisable for the next year, and to have the capacity to understand the questionnaires presented.d. To have given signed, informed consent to be included in the study, and to meet no exclusion criterion.Exclusion criteria. Patients were required not to have suffered a major cardiovascular event , or to be suffering diabetes mellitus, a serious chronic disease with a notable impact on physical or psychological status , or to be unable to collaborate (patients with dementia or other psychopathologies).2. Sampling was performed by clusters, the PHCCs being the randomisation units. This minimised possible contamination effects between centres. An independent statistician randomly assigned the 22 PHCCs (each of which were randomly assigned a code) to either the EDUCORE method group or a control  group (11 centres in each group) using Epidat 3.1 software.Consecutive patients were chosen to minimise the risk of bias in their selection. Figure Method of calculation. For an alpha of 0.05, a power of 80%, and in order to detect an increase in good control of blood pressure of 15% in the EDUCORE group, the overall sample size required was 354 patients (177 in each arm of the study). Since randomisation was by clusters, the sample size had to be larger than if simple randomisation had been performed, in order to take into account the design effect (DE). The DE was calculated as follows: DE = 1 + (nc - 1) * ICC   [The criteria followed for the assessment and control of CVR were those published by the Madrid Regional Health Service .b. Calculation of the projected CVR at 60 years of age for all patients under this age.Use of visual impact images. Patients were shown images embodying different stages of a high risk action using the consultation room's computer with the aim of increasing consciousness regarding risk-entailing habits.2. Handing the patient a pamphlet. This pamphlet contained advice on how to maintain cardiovascular health plus the low risk SCORE table with the patient's current score marked.3. The main outcome variable measured in both groups was the control of blood pressure (systolic blood pressure < 140 mmHg and dyastolic blood pressure < 90 mmHg). The blood pressure was determined using the Riva-Rocci method and listening for Korotkoff sounds, using validated and calibrated sphygmomanometers). The secondary outcome variables recorded were: CVR (measured using the low risk SCORE table), total cholesterol level, the use of tobacco, therapeutic compliance (measured using the Morisky-Green treatment compliance questionnaire) , and quaThese included sex, age and level of education . Patient physical activity was measured using a questionnaire  .2), use of tobacco , total cholesterol and LDL-cholesterol (mg/dl), serum creatinine (mg/dl) and microalbuminuria/creatinine (mg/g). The consumption of cardiovascular medication  at the beginning and end of the study was also recorded. Changes in medication were also recorded, as were the reasons for such change, including secondary effects and ineffectiveness. The type of change made to antihypertension treatment was also recorded, including increasing/reducing dose, drug associations, suspensions and substitutions.These included body mass index (weight in kg/height in cmAll data (excluding patient identification data) were recorded in an electronic database  searchable only by the EDUCORE group via a corporative intranet system. This centralised the collection of data, facilitating later analysis.These included sex, age, professional category , the date of qualification, and the PHCC where services were rendered. This facilitated the description of the clinical assistance personnel associated with each cluster.The number of patients who declined to participate was recorded, as required by the CONSORT statement .The causes of all losses and withdrawals  were recorded. When patients failed to attend an appointment, two attempts were made to enter into contact by telephone.http://www.educore.es.A web page was used to facilitate the monitoring of the work performed and to make the project more visible The use of randomisation by clusters conditions the statistical analysis that can be employed, especially in the calculation of confidence intervals and the testing of hypotheses. The following analyses were undertaken:Descriptive analysis and the description of the profile of patients who abandoned the study plus their reason for withdrawal.1. Baseline comparison of the two intervention groups in terms of the analytical variables measured, prognostic factors and descriptive variables, using appropriate bivariate statistical tests.2. Effect of the EDUCORE method on blood pressure control (main outcome variable): i.e., a comparison of the proportion of patients with good/bad control in the two study arms using the Chi-squared test, and the calculation of confidence intervals at 6 months and 1 year after patient inclusion. Logistic regression with random effects was used to adjust for prognostic factors; the dependent variable was good/bad control of patient blood pressure, and the independent variable the intervention group to which each patient belonged. Confounding factors or factors that might alter the effect recorded were taken into account in this analysis.3. Effect of the EDUCORE method on secondary outcome variables  using appropriate statistical tests.4. © v.18 software.All statistical tests were performed with intention to treat. The 'last observation carried forward' was used for missing data . SignifiEducational intervention strategies aimed at either patients or health professionals can provide benefits in the control of HBP ,31,33. TThe study design used in this work is, however, subject to certain limitations. Firstly, the intervention cannot be masked, which could influence the assessment of its effect. Certainly, the possibility of contamination exists if the patients involved communicate with one another . For thiIn practice, the percentage of patients with good control of their HBP that can be reached, though improvable, is limited. Thus, achieving a very large impact with the EDUCORE method might be difficult. For this very reason, any positive effect achieved - even though small in magnitude - could be understood to represent success, especially in this disease of such great pubic health importance.The conclusions drawn from this study might influence clinical practice and research into blood pressure control. In the clinical setting, the reduction of CVR in patients with HBP could have an important effect on health and quality of life.Comité Español Interdisciplinario para la Prevención Cardiovascular; DE: Design effect; EDUCORE: Education and Coronary Risk Evaluation; ECG: Electrocardiogram; GP: General practitioner; HBP: High blood pressure; ICC: Intracluster correlation coefficient; nc: Number of individuals in a cluster; SCORE: Systematic Coronary Risk Evaluation;CVD: Cardiovascular disease; CVR: Cardiovascular risk; CEIPC: The authors declare that they have no competing interests.IRS conceived of the study and participated in its design. EEM participated in the design and coordination of the study. IRS and EEM carried out the EDUCORE method. MRB, RRF, AAS, ICG, LCB, SGE and RRB (senior authors) participated in the design of the study. EEM, IRS, MRB, RRF and AAS directed the writing of the manuscript. Contributions were made by the remaining authors. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/10/449/prepub


Circulatory dysfunction in cirrhotic patients may cause a specific kind of functional renal failure termed hepato-renal syndrome (HRS). It contributes to the high incidence of renal failure in cirrhotic intensive care unit (ICU) patients. Fluid therapy may aggravate renal failure by increasing ascites and intra-abdominal pressure (IAP). This study investigates the short-term effects of paracentesis on haemodynamics and kidney function in volume resuscitated patients with HRS.Nineteen consecutive cirrhotic patients with HRS were studied. Circulatory parameters and renal function were analysed before and after plasma expansion and paracentesis. Haemodynamic monitoring was performed by transpulmonary thermodilution.-2 (693 to 862) (median and 25th to 75th percentile) to 844 ml m-2 (751 to 933). Cardiac index (CI) increased from 4.1 l min-1 m-2 (3.6 to 5.0) to 4.7 l min-1 m-2 (4.0 to 5.8), whereas systemic vascular resistance index (SVRI) decreased from 1,422 dyn s cm-5 m-2  to 1,171 dyn s cm-5 m-2 . Creatinine clearance (CC) and fractional excretion of sodium (FeNa) were not affected. During paracentesis, IAP decreased from 22 mmHg (18 to 24) to 9 mmHg (8 to 12). MAP decreased from 81 mmHg (74 to 100) to 80 mmHg (71 to 89), and CI increased from 4.1 l min-1 m-2 (3.2 to 4.3) to 4.2 l min-1 m-2 (3.6 to 4.7), whereas SVRI decreased from 1,639 dyn s cm-5 m-2  to 1,301 dyn s cm-5 m-2 . CC during the 12-hour interval after paracentesis was significantly higher than during the 12 hours before (33 ml min-1 (16 to 50) compared with 23 ml min-1 (12 to 49)). CC remained elevated for the rest of the observation period. FeNa increased after paracentesis but returned to baseline levels after 24 hours.After infusion of 200 ml of 20% human albumin solution, mean arterial pressure (MAP) and central venous pressure remained unchanged. Global end-diastolic volume index (GEDVI) increased from 791 ml mParacentesis with parameter-guided fluid substitution and maintenance of central blood volume may improve renal function and is safe in the treatment of ICU patients with hepato-renal failure. According to the hypothesis of arterial vasodilation, portal hypertension in cirrhotic patients leads to arterial vasodilation in extra-renal vascular beds, especially in the splanchnic system, and to the abdominal pooling of blood ,2. TheseWhereas the role of fluid resuscitation has been extensively investigated in non-cirrhotic patients with sepsis-associated circulatory failure, data on fluid resuscitation in cirrhotic patients with this specific type of pre-renal kidney failure are scarce. One problem with fluid expansion in cirrhotic patients lies in the loss of infused volume to the intra-peritoneal space, where it increases intra-abdominal pressure (IAP). The presence of ascites itself is closely related to the development of renal failure, and 20% of cirrhotic patients with tense ascites develop HRS. Intra-abdominal pressure may impair renal perfusion by decreasing the renal perfusion pressure (RPP) and filtration gradient (FG) . In addiSeveral studies focused on the prevention of post-paracentesis circulatory dysfunction -8 or on The present study was undertaken in cirrhotic intensive care patients with advanced cirrhosis, tense ascites and acute renal failure that persisted after fluid resuscitation but without evidence of intrinsic kidney disease. The aim was to investigate the single and combined haemodynamic and renal effects of plasma expansion by infusion of albumin and of the decrease in intra-abdominal pressure by paracentesis under the condition of parameter-guided maintenance of central volume.-1 and HRS 2 by a slow increase in creatinine to above 133 μmol l-1, the classification of patients with an acute renal failure who do not reach a serum creatinine over 221 μmol l-1 is difficult to do adequately. Likewise, the delimitation from septic kidney failure is fuzzy. For the purpose of this study, HRS was defined as kidney failure in cirrhotic patients who had documented normal serum creatinine values before ICU admission and who had suffered an acute increase in serum creatinine to values above 133 μmol l-1 within less than 14 days that persisted despite resolution of the precipitating event and despite adequate haemodynamic management and who showed no evidence of intrinsic kidney disease or current infection.The – recently amended – definition of HRS has known setbacks and is especially difficult to apply in ICU patients. The two groups, HRS 1 and HRS 2, are delineated by criteria that are not congruent: whereas HRS 1 is defined by an acute increase in serum creatinine to a level above 221 μmol l-1) with a previously normal kidney function (serum creatinine < 98 μmol l-1), caused by an acute condition treated in our intensive care department and if they had a stable serum creatinine (less than 10% change per 24 hours) in the 24 hours preceding the study period. Patients had to be haemodynamically stable without vasopressors or positively inotropic substances for 2 days after treatment of the condition leading to ICU admission without an improvement in kidney function, and they had to fulfil the diagnostic criteria established by the International Ascites Club in 1994 , which works by the injection of a cold bolus of normal saline through a central venous line that is detected after passing through the cardiac chambers, pulmonary vasculature and part of the aorta by a thermistor-tipped arterial line inserted into one of the femoral arteries and advanced to the aortic bifurcation. The mean transit time and the slope of the temperature curve at the thermistor permit the assessment of cardiac output as well as that of the amount of intra-thoracic volume that has been passed through and also the pulmonary blood volume. Subtracting pulmonary blood volume from intra-thoracic blood volume provides an estimation of the largest volume of blood contained in the four heart chambers, called, after indexing by body surface area, the global end-diastolic volume index (GEDVI). All measurements were made in triplicate and averaged. They were performed at 12-hour intervals and immediately before and after the infusion of a fluid load and before and after paracentesis.Intra-abdominal pressure was measured at the beginning and end of paracentesis by connecting the drainage tube to a pressure transducer with the zero level set at the mid-axillary line. Measurements were recorded after some equilibration time and after verification of ventilatory modulation of the readings, at end-expiration. RPP and renal FG were determined from RPP = MAP - IAP and FG = MAP - (2 × IAP) , where MUrinary output was recorded and urine was collected over 12-hour intervals corresponding to those of haemodynamic measurements, and blood was taken at the end of each 12-hour interval. After biochemical analysis, FeNa and creatinine clearance (CC) were calculated from standard formulae.Immediately after inclusion, patients received an infusion of 200 ml of 20% human albumin solution. Haemodynamic measurements by transpulmonary thermodilution were performed before and after infusion and after 12 hours. After this first 12-hour interval, paracentesis was performed with measurements of intra-abdominal pressure and haemodynamic parameters before and after paracentesis. Thereafter, patients received albumin solution up to a total of 8 g of albumin per litre of ascites removed, and saline thereafter. Fluid therapy was titrated so as to keep GEDVI and cardiac index (CI) constant. Urine was collected over four 12-hour intervals for the determination of CC and FeNa. Thereafter, paracentesis could be repeated if clinically indicated (for example by dyspnoea or pain) and if there had been no increase in serum creatinine after the first intervention. Monitoring and measurements were performed as before. Follow-up measurements of serum creatinine were made 7 and 12 days after the last paracentesis , chronic hepatitis C (n = 2), chronic hepatitis B (n = 1) or cryptogenic (n = 2). The acute conditions leading to ICU admission were spontaneous bacterial peritonitis (n = 7), sepsis of other origin (n = 6) and variceal haemorrhage (n = 5). One patient was admitted because of hepatic encephalopathy, hypotension and acute kidney failure. Patients' baseline parameters are presented in Table Nineteen consecutive patients  were included between September 2004 and August 2005. 14 of these were listed for liver transplantation. Cirrhosis was due to alcohol  as well as with the relative decrease in MAP immediately after paracentesis . The decrease in IAP was correlated with the relative change in SVRI after paracentesis .Twenty-seven paracenteses were performed. One patient received five paracenteses, in four patients two paracenteses each were performed and one was performed in each of the remaining 14 patients. During the procedures, 6 litres 5.3 to 8.0) of ascites were removed. IAP fell from a median of 22 mmHg to a median of 9 mmHg .Repeat paracenteses were performed 60 hours (48 to 72) after the first paracentesis. IAP on repeat paracentesis was not significantly lower than on the respective previous paracentesis (23 mmHg (21 to 26) versus 25 mmHg (21 to 30), Fluid substitution after paracentesis was guided by transpulmonary thermodilution, with GEDVI used as reference variable. Including the volume load before paracentesis, patients received a total of 8 g (6.8 to 8.7) of albumin per litre of ascites removed. In addition, after paracentesis there was an hourly net fluid balance of +89 ml (61 to 101), resulting in infusion over 48 hours of 64% of the volume removed at paracentesis. GEDVI was kept constant despite a decrease in CVP that, however, failed to reach the level of significance. CI and MAP remained unchanged Table .-1 (167 to 450) to 176 μmol l-1 (88 to 256) in all patients. Values deteriorated in only two patients, in both after the first paracentesis. Both received terlipressin but did not respond and had to be dialysed. One was allotted a liver transplant and his renal function recovered thereafter; the other developed pneumonia and died in septic shock.The period of haemodynamic monitoring lasted for between 60 and 252 hours, depending on the number of paracenteses. Overall, there was decrease of serum creatinine from 300 μmol l-1, 6 had a serum creatinine of less than 221 μmol l-1, and two had a serum creatinine value of less than 133 μmol l-1. Four of them had a decrease in serum creatinine levels of more than 50%. On day 12, seven had a serum creatinine value of less than 221 μmol l-1, and three had a serum creatinine value of less than 133 μmol l-1. In five patients, the decrease in serum creatinine levels was larger than 50%.On day 7 after the last paracentesis, of the remaining 10 patients with an initial serum creatinine value of at least 221 μmol l-1 had serum creatinine values of less than 133 μmol l-1 on days 5 and 10 after the last paracentesis; in four, serum creatinine had normalized . The decrease in SVRI seen in our patients after plasma expansion may have been due to a decrease in activation of endogenous vasopressor systems. Several studies have described the circulatory dysfunction of cirrhotic patients as a primary peripheral arterial vasodilation and mesenteric blood pooling, resulting in a low effective arterial blood volume and compensatory stimulation of endogenous vasopressor systems. We did not measure the activity of vasopressor systems in our study, but decreased levels of renin and aldosterone have been reported in patients with Child–Pugh grade C cirrhosis after plasma expansion [2O was obtained [2O) in our patients, possibly indicating a larger central blood volume. However, CVP has been found to be unreliable as an indicator of preload and may be even less accurate in conditions with elevated intra-abdominal pressure [The patients in our study had persistent acute kidney failure despite adequate fluid resuscitation according to common criteria, as demonstrated by the fact that CVP and GEDVI were in the normal range. Nevertheless, after plasma expansion with 200 ml of a 20% human albumin solution, there was a further increase in GEDVI, indicating an increase in central blood volume, with the higher cardiac preload resulting in an increase in CI. Whereas MAP remained virtually unchanged, there was a substantial decrease in SVRI. This finding is in contrast with results of other studies investigating the effects of plasma expansion on haemodynamics in patients with cirrhosis. One actually reported an increase in SVRI after plasma expansion  and has xpansion . Despiteobtained . This copressure -19. The Intra-abdominal hypertension was present in all patients, and paracentesis resulted in a substantial decrease in intra-abdominal pressure. Because the concomitant decrease in MAP was small, this resulted in a major increase in APP and FG. Simultaneously, CI increased while CVP and SVRI were reduced. This is in keeping with the results of previous studies assessing the effect of paracentesis on systemic haemodynamics -22. ThesThe elevation of CC seen already during the first 12 hours after paracentesis was maintained over 48 hours while central blood volume, as indicated by GEDVI, was kept constant. The improved serum creatinine values seen at 7 and 12 days after the last paracentesis also indicate that renal function remained above baseline in most of the patients. As has previously been shown, post-paracentesis circulatory dysfunction is most pronounced after 6 days [This study indicates that the expansion of central blood volume is possible even in patients with advanced cirrhosis. The ensuing circulatory changes are small, however, and renal effects were not visible with the amount of albumin solution used in our study. After paracentesis there was a marked decrease in IAP and RPP. Under substitution of albumin and fluids to maintain central blood volume, there was a simultaneous improvement of renal function that may be relevant in patients with end-stage liver disease.• Cardiac index in cirrhotic patients with hepato-renal syndrome may be fluid-responsive despite normal central venous pressure and global end-diastolic volume.• Intra-abdominal hypertension, caused by ascites, can be reduced by paracentesis, resulting in a net increase in renal perfusion pressure.• After paracentesis, fluid substitution can be titrated to keep global end-diastolic volume constant, and creatinine clearance and fractional excretion of sodium may increase.• In cirrhotic intensive care patients with intra-abdominal hypertension caused by ascites resulting from fluid therapy, paracentesis is a safe procedure.CI = cardiac index; CVP = central venous pressure; CC = creatinine clearance; FG = filtration gradient; FeNa = fractional excretion of sodium; GEDVI = global end-diastolic volume index; HRS = hepato-renal syndrome; IAP = intra-abdominal pressure; ICU = intensive care unit; MAP = mean arterial pressure; RPP = renal perfusion pressure; SVRI = systemic vascular resistance index.Andreas Umgelter and Wolfgang Huber have been speakers for Pulsion Medical Systems, Munich. The other authors declare no conflict of interest. There were no grants received for this study.The study was designed by AU and WH, who also co-wrote the manuscript. WR, KW, MF and KS were involved in patient management, acquisition and processing of data and revision of the manuscript. RMS was involved in designing the study and revised the manuscript. All authors read and approved the final manuscript.


Overproduction of pro-inflammatory cytokines is a well established factor in the progression of chronic heart failure (CHF). Changes in cellular immunity have not been widely studied, and the impact of standard medication is uncertain. Here we investigate whether a leukocyte redistribution occurs in CHF and whether this effect is influenced by beta-blocker therapy.in vitro, analysed subsets of lymphocytes using flow cytometry, and assessed plasma levels of the pro-inflammatory markers interleukin 1, 6, tumor necrosis factor-α, and soluble tumor necrosis factor receptors 1 and 2.We prospectively studied 75 patients with systolic CHF  and 20 age-matched healthy control subjects (age: 63±10 years). We measured the response of cells to endotoxin exposure While no differences in the number of leukocytes were noted between patients with CHF and healthy controls, we detected relative lymphopenia in patients with CHF (p<0.001 vs. control), mostly driven by reductions in T helper cells and B cells (both p<0.05). The number of neutrophils was increased (p<0.01). These effects were pronounced in patients who were beta-blocker naïve . Increased plasma levels of soluble tumor necrosis receptor-1 correlated with the relative number of lymphocyte subsets.i.e. an increase in neutrophils with relative lymphopenia. These effects were pronounced in patients who were beta-blocker naïve. The underlying mechanism remains to be elucidated.In patients with CHF, we detected a redistribution of leukocyte subsets,  Chronic heart failure (CHF) is a multisystem disorder that affects not only the cardiovascular system but many other body organs and functions. The involvement of these systems can be explained by overproduction of neuroendocrine mediators and cytokines, which are a key mechanism for the progression of CHF. Elevated levels of catecholamines, among others, have long been recognized to play a role in this syndrome Few studies have investigated the interplay between pro-inflammatory cytokines and the redistribution of leukocyte subsets in patients with CHF and no studies have sought to elucidate the role of standard medical therapy. We measured the distribution of leukocyte subsets and their relation to markers of inflammatory activation in patients with CHF. We also assessed the impact of treatment with β-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), aldosterone antagonists, and statins.We prospectively studied 75 patients with CHF who were recruited from the Royal Brompton Hospital outpatients' department between April 2004 and September 2005. The diagnosis of CHF was based on symptoms, clinical signs, and documented left ventricular impairment measured by echocardiography (left ventricular ejection fraction≤45%). All patients were on unchanged medication for at least four weeks. At the time of assessment no patients were taking non-steroidal anti-inflammatory drugs or steroid hormones. Subjects with clinical signs of infection, rheumatoid arthritis, or cancer were excluded. In addition, we enrolled 20 age-matched healthy control subjects . At the time of assessment none of the control subjects were taking any medication. The ethics committee on human research of the Royal Brompton Hospital, London, UK, approved the study, and all subjects provided written informed consent. The study was performed in adherence to the Declaration of Helsinki.® and CellQuest® software (both from Becton Dickinson). The following antibodies (with the respective isotype controls) were used in the following combinations: (i) fluorescein isothiocyanate (FITC) labelled monoclonal mouse-anti-human CD4 IgG1 antibody (Ab) (Sigma-Aldrich)/R-phycoerythrin (PE) labelled monoclonal mouse-anti-human CD8 IgG2a Ab (Sigma-Aldrich)/Peridinin-chlorophyll-protein Complex (PerCP) labelled monoclonal mouse-anti-human CD3 IgG1 Ab (Becton Dickinson), (ii) FITC labelled monoclonal mouse-anti-human CD14 IgG2a Ab (Sigma-Aldrich)/PE labelled monoclonal mouse-anti-human CD19 IgG1 Ab (Sigma-Aldrich), (iii) PE labelled monoclonal mouse-anti-human HLA-DR IgG2a Ab (BD PharMingen). In addition, an untreated (i.e. no Ab staining) sample was analysed for each patient.Venous EDTA blood was drawn after 15 minutes of semi-supine rest in the morning. Samples of 100 µl were incubated for 25 minutes at +4°C in the dark with the respective antibody combinations. Red blood cells were lysed using FACS lysing solution  according to the manufacturer's instructions. Cells were then washed using phosphate buffered saline (PBS), supplemented with 2% fetal calf serum and 0.01% sodium azide . 30,000 cells were analysed per sample using a FACSort2). Pilot experiments had demonstrated a maximal TNFα secretion after 6 hours incubation (data not shown). Upon centrifugation, supernatants were harvested and frozen immediately at −80°C for later analysis. Cell viability was>90% as assessed using trypan blue exclusion.A substudy was performed in 42 patients with CHF and 11 healthy controls of the above described cohort. Venous citrated blood was drawn as described above. Whole blood samples were diluted 1∶1 with RPMI 1640  supplemented with 10 U/mL heparin . Afterwards, 1 mL aliquots were placed in 1.5 mL Eppendorf tubes . E. coli-derived LPS  was added to achieve a final concentration of 0.1, 1, 10, or 100 ng/mL. LPS was diluted in RPMI 1640. The addition of RPMI 1640 alone served as a control. Dilutions, aliquoting and stimulations were carried out under sterile conditions. Following the addition of endotoxin , all samples were incubated for 6 hours in a humidified atmosphere  kits according to the manufacturer's instructions . The detection limit was 15 pg/mL. All samples were frozen at −80°C until analysis.Serum levels of TNFα, soluble TNF receptor-1 and 2 (sTNFR-1 and sTNFR-2), IL-6, and IL-1β were determined using the respective Quantikine HS immunoassay kits . The lower limits of detection are 0.106 pg/mL, 7.8 pg/mL, 7.8 pg/mL, 0.039 pg/mL, and 0.057 pg/mL, respectively.t-tests, simple regression, and the chi-square test were used as appropriate. The effect of beta-blocker therapy was assessed using the ANOVA method of testing. A p-value<0.05 was considered significant.Data are presented as mean±SD. All data were checked for normal distribution using the Kolmogorov-Smirnov test. Non-normally distributed variables were log-transformed to achieve normal distribution before further analysis. Analysis of variance (ANOVA) with Fisher's post hoc test, repeated measures ANOVA, Student's unpaired and paired vs. control, There were no significant differences between healthy control subjects and patients with CHF in terms of age, sex, weight, number of smokers, or body mass index. As expected there were differences in standard biochemistry . PatientWhole blood from both healthy subjects and patients with CHF produced substantial levels of TNFα and IL-6 when stimulated with 0.1, 1, 10, or 100 ng/mL LPS . There w9/L or 4.9±1.1%; CHF: 0.38±0.12×109/L or 5.2±1.6%, both p>0.3), eosinophils , or basophils . However, both the absolute and the relative number of neutrophils were increased in patients with CHF . The results for β-blockers are presented in Our data show that the distribution of lymphocyte subsets and neutrophils is significantly altered in patients with CHF as compared to healthy age-matched controls. Whilst no change in the absolute number of white blood cells was noted, we found decreases in the number of lymphocytes, mainly driven by reductions in T helper cells and B cells. These effects were most pronounced in β-blocker naïve patients who also presented with lower relative numbers of cytotoxic T cells as compared to patients who were on such a drug . Thus, i2-adrenergic receptors are most abundantly expressed, but their number and their sensitivity vary significantly between cell types 2-agonist, has been shown to decrease the number of circulating lymphocytes mainly in those subsets with the greatest β-adrenergic sensitivity in vitro2-adrenergic receptors but, it has also been reported that increases in granulocytes involve β-adrenergic receptor stimulation i.e. an early increase in non-specific granulocytes In view of these findings, one possible explanation for leukocyte redistribution, among others, is linked to elevated levels of catecholamines, which have been described by many independent researchers in patients with CHF Alternatively, higher cortisol levels may be responsible for the observed effects in patients with CHF. Cortisol may induce granulocytosis and relative lymphopenia. Moreover, disturbed intestinal microcirculation and barrier function in CHF may induce a state of chronic endotoxinemia which may yield lymphopenia.Nevertheless, a vast array of factors contributes to the release of catecholamines in patients with CHF, and one important factor is the influence of pro-inflammatory cytokines. It was shown decades ago that IL-1, IL-6, and TNFα can trigger the activation of the sympathetic nervous system in the brain Some limitations of this analysis demand further discussion, among these the fact that the number of study patients is rather limited. Moreover, our results may be influenced by the fact that the patients not receiving β-blockers might have been sicker which may have led physicians not to prescribe β-blockers as eg. they had a lower blood pressure. Furthermore, as stated before, we did not assess catecholamine levels. As chronic lymphopenia may theoretically yield an increased rate of infection, it is tempting to speculate that the mortality benefit provided by the use of β-blockers in CHF may in part be explained by the effects observed here. This, however, needs to be interpreted with caution. The results presented here need to be confirmed in a larger analysis.In conclusion, we found a significant redistribution of leukocyte subsets with an increase in granulocytes and relative lymphopenia in patients with stable CHF. This finding is in line with previous studies


The aim of this study was to evaluate asthma control after the introduction of a leukotriene modifier (Montelukast), in addition to the current controller asthma therapies, in patients with inadequately controlled mild-to-moderate persistent asthma. Asthma control and patient perception were assessed prior to, and 4 weeks after, the introduction of Montelukast, and the pre-introduction and post-introduction results were compared.A cross-sectional, observational study collected information on 1,490 eligible adult asthmatic patients in Saudi Arabia. The eligibility criteria included patients aged 15 years or more with symptomatic mild-to-moderate persistent asthma despite treatment with inhaled corticosteroids with or without long-acting beta agonist; also, the patient should attend the initial visit and follow-up visits after at least 4 weeks.Of the 1,490 eligible patients, 79.5% received inhaled corticosteroids alone, and the remaining 20.5% received combination of inhaled corticosteroids and long-acting bronchodilator. Despite the treatment with daily controller medications, asthma symptoms persisted in more than two-thirds of the study population. Upon adding Montelukast, more than 80% of patients reported improvement in symptoms, which was consistent in all patients irrespective of corticosteroid type or dose (stratum) or the addition of long-acting β2-agonist. At the follow-up visit, 92.2% of patients reported that they felt better on Montelukast.Leukotriene modifier Montelukast has significant additive benefits in the management of patients who suffer from mild-to-moderate asthma and who are inadequately controlled on inhaled corticosteroids therapy with or without long-acting bronchodilator. Asthma is a complex respiratory disorder characterized by reversible airflow obstruction and bronchial hyper-reactivity. In recenNot all asthmatics can be adequately controlled with high-dose inhaled corticosteroid (ICS) alone or in combination with long-acting bronchodilators (LABA). The Global Initiatives for Asthma (GINA) recommended leukotriene modifiers as add-on therapy in patients with uncontrolled moderate persistent asthma and also as alternative to long-acting bronchodilator in moderate persistent asthma. This wasThe objective of this observational cross-sectional survey was to evaluate asthma control and patient perception after the introduction of a leukotriene modifier, Montelukast, in addition to the current controller asthma therapies, in patients with inadequately controlled mild-to-moderate persistent asthma. Asthma control and patient perception were assessed prior to, and 4 weeks after, the introduction of Montelukast, and the pre-introduction and post-introduction results were compared.This observational, cross-sectional, prospective survey recruited asthmatic patients from the general practice setting in the major cities of the Kingdom of Saudi Arabia: Riyadh, Jeddah, Mecca, Medina, Dammam, Abha, Kamis Mushate, Jubail, Qasim, Yanbu and Jizan. The study was conducted in the period between December 2003 and July 2004. Recruited patients were above the age of 15, with mild-to-moderate persistent asthma, who were still uncontrolled despite ICS therapy at any dose with or without LABA. Patients were selected by physicians in the general practice setting, where both parties volunteered and were unpaid. Patients on Montelukast were excluded. It was mandatory for the patients to attend the initial first and second visits and complete the questionnaires in order to be eligible for the final analysis.The patients were evaluated twice. At the first visit, the current asthma symptoms were recorded and described by (a) asthma-related difficulty in sleeping, (b) early morning awakening, (c) limitation of activities and (d) short-acting β2-agonist (SABA) use twice or more per week. Patients were informed about the cross-sectional survey objectives and the leukotriene modifiers as one of the recommended standard option for a patient with uncontrolled mild and moderate persistent asthma. All patiThe second visit was scheduled at the discretion of the participants. However, it was recommended to be performed at least 4 weeks after the first visit. At the second visit, the patients were asked to fill in a report, commenting on the change of their symptoms  in regard to (a) early morning awakening, (b) difficulty with sleep due to asthma, (c) limitations of activities due to asthma and (d) SABA use twice or more times a week. Patients were classified into three strata based on the dose of ICS: stratum I with ICS ≤400 μg/day, stratum II with dose between 401 and 800 μg/day and stratum III with dose ≥800 μg/day.P’ value was calculated by Chi-square test. P value more than 0.05 was considered not significant. P value of less than 0.05 but more than 0.01 was rated as significant, 0.01 to 0.001 as highly significant and <0.001 as very highly significant.‘Of the 1,687 patients recruited in the study, 1,490 patients (88.3%) were eligible and attended the second visit. At the second visit after adding Montelukast, 1,296 out of 1,490 (87%) patients reported improvement. The observed improvement was consistent for all symptoms addressed, i.e., early morning awakening, difficulty in sleeping, limitations of activities and SABA use twice or more times a week . Figure P = 0.009). P < 0.001).At the second visit after adding Montelukast, there was reported symptomatic improvement regardless of the type of ICS. The improvement was universal to all the reported symptoms by the patients . HoweverP = 0.007). When Montelukast was combined with ICS alone, 1,103 patients (93.2%) reported feeling better at the second visit, while 271 patients (88.4%) felt better after adding Montelukast to the combination of ICS and LABA  to evaluate the impact of Montelukast on the control of asthma symptoms, after at least 4 weeks of treatment.[The results in our study were consistent with those of Malonne reatment. Of the preatment. Moreoverreatment.Our study is an observational survey, and its results should be considered as such. The important limitation for all observational studies is the lack of control and blind randomization. In our study, we did not account for patient's adherence to therapy, the presence of comorbid conditions such as allergic rhinitis, gastroesophageal reflux or the presence of any occupational or environmental triggers. However, despite these limitations, the importance of observational data is the reflection of reality, far from the ‘unreal’ strict patients' monitoring that usually takes place in randomized controlled trials.


As the effect of renin-angiotensin system (RAS) blockade on β-cells in clinical situations remains unclear, new evidence has been presented that angiotensin-converting enzyme (ACE) inhibitors and angiotensin ‖ receptor blockers (ARBs) may delay or prevent the development of insulin resistance and diabetes through novel mechanisms. This study aimed to determine the effects of ARBs on insulin excretion by β-cells. Hypertensive patients with impaired glucose tolerance were randomly divided into two groups: group A (n = 6), which received 8 mg/day of oral candesartan for three months, and controls (n = 6). Before and after administration, a 75 g oral glucose tolerance test was conducted to compare various parameters. No significant differences in age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose, or fasting immunoreactive insulin (IRI) were identified between the groups before administration. After three months, there were no significant changes in BMI, SBP, and DBP for the controls and in BMI and DBP for group A. However, SBP was significantly decreased from 144 ± 2.6 mmHg to 125 ± 4.6 mmHg in group A. Insulinogenic index tended to be slightly decreased for controls, but was significantly increased from 0.32 ± 0.0 to 0.47 ± 0.1 for group A. No significant changes in HOMA-R were identified in either group. To the best of our knowledge, no previous studies have documented a RAS inhibitor improving early-phase insulin response; thus, the present study may be the first of its kind. Recent trials have suggested that inhibitors of the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin ‖ receptor blockers (ARBs), may reduce the incidence of new-onset of diabetes in patients with or without hypertension and at a higher risk of developing diabetes . This reHypertensive patients with IGT were enrolled in this study at Saiseikai Niigata Second Hospital. None of the enrolled patients with IGT had received pharmacologic treatment before the study. Hypertension was defined by systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg. A standard oral glucose tolerance test (OGTT) with 75 g of glucose was performed before and after administration. Interpretations of OGTT data were based on the World Health Organization definition , and theThe present results show that three months of candesartan therapy improved early-phase insulin response in IGT patients with hypertension. RAS blockade in animal models of type 2 diabetes significantly restores β-cell mass, which could be interpreted as representing a potentially reparative mechanism, possibly by decreasing oxidative stress and apoptosis, in addition to attenuating profibrotic pathways ,5,10. ThMajor limitations of the present study were that we examined only a small number of patients and the study period was relatively short . Therefore, larger studies are needed to further elucidate the insulin secretory effect of candesartan during long-term follow-up.


Studies relating blood pressure to cancer risk have some shortcomings and have revealed inconsistent findings. In 17 498 middle-aged London-based government employees we related systolic and diastolic blood pressure recorded at baseline examination (1967–1970) to the risk of cancer mortality risk at 13 anatomical sites 25 years later. Following adjustment for potential confounding and mediating factors, inverse associations between blood pressure and mortality due to leukaemia and cancer of the pancreas (diastolic only) were seen. Blood pressure was also positively related to cancer of the liver and rectum (diastolic only). The statistically significant blood pressure–cancer associations seen in this large-scale prospective investigation offering high power were scarce and of sufficiently small magnitude as to be attributable to chance or confounding. Examination of the predictive value of blood pressure for later mortality has a long research pedigree: among the earliest investigations of risk were those undertaken by the US life insurance industry over four decades ago . The finThe potential link between blood pressure and cancer risk was first examined by Against this background of inconsistent findings and study limitations we examined the relation of blood pressure to cancer risk at 13 anatomical sites using a 25-year mortality surveillance of 18 403 male government workers in the original Whitehall study, a prospective investigation.1)  were traced and ‘flagged’, using the procedures of the Office for National Statistics (Southport), until 31 January 1995. Death certificates were coded according to the eighth revision of the International Classification of Diseases (ICD) . The catOur analyses are based on 17 498 men without missing data and exclude 26 men for whom the cause of death was unknown. In analyses of baseline characteristics according to levels of blood pressure, the prevalence of these characteristics were adjusted for age (5-year age groups) by the direct standardisation method. Trends in these proportions were tested for statistical significance using the Mantel–Haenszel test. For baseline characteristics expressed as continuous variables, least-squares means were used to present the age-adjusted means, and tests for trend across blood pressure groups were computed by fitting a linear trend term.1, cholesterol) variables. Age, cholesterol, body mass index, triceps skinfold thickness, and height-adjusted FEV1 were fitted as continuous variables, whereas employment grade (five levels), marital status (four), blood pressure-lowering medication (two), smoking status (four)  and disease at entry (two) were fitted as categorical variables. Disease at entry was defined as a positive response to enquiries regarding one or more of the following at study entry: unexplained weight loss in the preceding year, bronchitis, diabetes (based on self-report and blood glucose levels), ischaemia (based on self-report and ECG trace), intermittent claudication, dyspnoea, or care of a general practitioner for raised blood pressure or heart problems.These models were initially adjusted for age and then for other potential confounding  and mediating , tumour presence may elevate blood pressure so generating a positive blood pressure–cancer association. To address this issue of reverse causality, we excluded deaths in the first 10 years of follow-up and repeated our analyses. In doing so, we reasoned that a large proportion of deaths attributable to cancer, if present at study induction, would have occurred within this time frame .The relation of components of blood pressure to baseline physical characteristics is presented in In this cohort there were 7460 deaths over 25 years of follow-up. A total of 2226 deaths were ascribed to all-cancers, the most common site being that of the lung (30% of cancer deaths). Rate ratios for the association of systolic and diastolic blood pressure with mortality from all cancers and site-specific cancers are depicted in Tables 2P [trend]=0.07).Both systolic and diastolic blood pressure were essentially unrelated to total cancer mortality. In age-adjusted analyses, inverse associations of cancer of the lung, and pancreas, and leukaemia with blood pressure were seen at conventional levels of statistical significance. Following multiple adjustment, the relationship with lung cancer was lost. Blood pressure was positively related to cancer of the rectum (diastolic only) and liver; confidence intervals latter, confidence intervals were wide owing to the low number of deaths. In the analyses in which we excluded deaths occurring in the first 10 years of follow-up, a positive association between diastolic, but not systolic, blood pressure and lymphoma emerged  and leukaemia was seen after adjustment for potential confounding and mediating factors. After exclusion of deaths in the first decade of follow-up, the relation for leukaemia was lost. Both systolic and diastolic blood pressure were positively related to cancer of the liver, rectum and, after exclusion of early deaths, lymph nodes.per se that is generating the association. However, few investigators have data on medication and blood pressure levels to allow them to explore this issue. In the present study, the already weak blood pressure–cancer associations seen after controlling for age were generally little altered when we added other factors to our regression models. While information on those men taking medication for high blood pressure was available, the prevalence at baseline was very low (1.5%), and there were insufficient cancer deaths in this group to examine either the predictive value of blood pressure-lowering drugs for cancer risk or explore their potential confounding effect.The interpretation of the findings of several studies of the blood pressure–cancer relation is complicated by issues of confounding and reverse causality. The effect of potentially important confounding variables such as social circumstances, alcohol consumption and anti-hypertensive medications is rarely explored. Anti-hypertensive medications have been linked to increased risk of malignancy in some (P [trend]=0.01). This suggests that the positive blood pressure–liver cancer relation may be confounded by alcohol consumption; however, we only have data on alcohol intake for a 10% subsample of the cohort – too few to investigate this possibility. We are unaware of any other studies to have examined the link between blood pressure and liver cancer, a scarcity that is also apparent for pancreatic cancer and leukaemia.We observed a positive relation between blood pressure and liver cancer. Many of these malignancies would have been attributable to alcohol-induced cirrhosis of the liver, a precipitating condition. Both systolic and diastolic blood pressure were positively and incrementally related to liver cirrhosis deaths rates  to two components of blood pressure, it is highly plausible that these latter two associations are attributable to the play of chance, or, because of their small magnitude, confounding by unmeasured factors, residual confounding by measured factors, or both.In the present study, systolic and diastolic blood pressure were measured on a single occasion, raising concerns about validity. We addressed this issue by relating these exposures to coronary heart disease and stroke mortality, both of which have been shown to be positively associated with systolic and diastolic blood pressure in a pooling of individual level data for one million subjects (In conclusion, in this large-scale prospective investigation of male government employees offering a large number of cases, an inverse association between blood pressure and mortality from cancer of the pancreas and leukaemia was seen, while blood pressure was positively related to liver and rectal cancer risk. That these relationships were few among the many analyses we conducted, and of small magnitude, suggests that they are likely to be due to chance and/or confounding rather than being real effects.