Circulating Levels (circulating + level)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Impact of TLR-4 Polymorphisms on Circulating Levels of Antibodies Against Helicobacter pylori

HELICOBACTER, Issue 5 2010
Anastassios C. Manolakis
No abstract is available for this article. [source]


Leptin,a predictor of abnormal glucose tolerance and prognosis in patients with myocardial infarction and without previously known Type 2 diabetes

DIABETIC MEDICINE, Issue 8 2008
M. Wallander
Abstract Aims High levels of leptin and low adiponectin are associated with Type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease. We studied the prognostic implications of leptin and adiponectin in patients with acute myocardial infarction (AMI) without previously known Type 2 DM. Methods One hundred and eighty-one patients were included. Based on an oral glucose tolerance test at hospital discharge (day 4,5), 168 (67% men) had normal or abnormal glucose tolerance (AGT), defined as impaired glucose tolerance or T2DM. Sex- and age-matched healthy persons served as control subjects (n = 185). The associations between fasting serum leptin and adiponectin (day 2) and newly discovered AGT and CV events (CV mortality, non-fatal stroke, reinfarction or severe heart failure) during a median follow-up of 34 months were investigated. Results Compared with control subjects, patients of both genders had significantly higher levels of leptin 2 days after an AMI. These levels were higher than those obtained at hospital discharge and 3 months later. Circulating levels of (ln) leptin 2 days after the AMI predicted AGT at discharge (odds ratio 2.03, P = 0.042). Ln leptin at day 2 was the only biochemical variable that significantly predicted CV events both on univariate [hazard ratio (HR) 1.60, P = 0.018] and on multivariate analysis (HR 1.75, P = 0.045). Adiponectin levels did not differ between patients and control subjects and did not relate to AGT or CV events. Conclusions Elevated circulating levels of leptin on the first morning after an AMI are associated with the presence of AGT at discharge and with a poorer long-term prognosis. [source]


Circulating levels of copeptin, a novel biomarker, in lower respiratory tract infections

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2007
B. Müller
Abstract Background, Vasopressin has haemodynamic as well as osmoregulatory effects, and reflects the individual stress response. Copeptin is cosynthesized with vasopressin, directly mirroring vasopressin levels, but is more stable in plasma and serum. Both levels are increased in patients with septic shock. Lower respiratory tract infections (LRTI) are a precursor of sepsis. Thus, we investigated circulating levels and the prognostic use of copeptin for the severity and outcome in patients with LRTI. Materials and methods, Five hundred and forty-five consecutive patients with LRTI and 50 healthy controls were evaluated. Serum copeptin levels were measured with a new chemiluminescens sandwich immunoassay. Results, Of the 545 patients, 373 had community-acquired pneumonia (CAP), 60 acute exacerbations of chronic obstructive pulmonary disease (COPD), 59 acute bronchitis, 13 exacerbations of asthma and 40 other final diagnoses. Copeptin levels were significantly higher in patients with LRTI as compared to controls (P < 0·001) with highest levels in patients with CAP. Copeptin levels increased with increasing severity of CAP, as classified by the pneumonia severity index (PSI) (P < 0·001). In patients who died, copeptin levels on admission were significantly higher as compared to levels in survivors [70·0 (28·8,149·0) vs. 24·3 (10·8,43·8) pmol L,1, P < 0·001]. The area under the receiver operating curve (AUC) for survival was 0·75 for copeptin, which was significantly higher as compared to C-reactive protein (AUC 0·61, P = 0·01), leukocyte count (AUC 0·59, P = 0·01) and similar to procalcitonin (AUC 0·68, P = 0·21). Conclusions, Copeptin levels are increased with increasing severity of LRTI namely in patients with CAP and unfavourable outcome. Copeptin levels, as a novel biomarker, might be a useful tool in the risk stratification of patients with LRTI. [source]


Role of vascular endothelial growth factor and angiopoietin systems in serum of Crohn's disease patients

INFLAMMATORY BOWEL DISEASES, Issue 1 2008
Inés D. Pousa
Abstract Background: The purposes of this study were to determine soluble angiogenic factors in Crohn's disease (CD) patients and to compare these factors according to the pathological behavior of the disease in order to establish a possible relationship with its evolution in patients with CD. Methods: Blood samples were collected from 70 patients with CD, grouped according to their phenotypic behavior, and from 30 healthy controls. Vascular endothelial growth factor (VEGF), placental growth factor (PlGF), angiopoietin 1 (Ang1), angiopoietin 2 (Ang2), and their cognate receptors [VEGFR1, VEGFR2, and angiopoietin receptor tyrosine kinase (Tie2)] were assayed by ELISA. Results: Circulating levels of VEGF, PlGF, VEGFR1, Ang2, and Tie2 were significantly higher in CD patients than in healthy controls (489 ± 271 versus 335 ± 118 pg/mL, P < 0.001; 31 ± 9 versus 23 ± 9 pg/mL, P < 0.001; 1.7 ± 0.4 versus 1.0 ± 0.3 ng/mL, P < 0.001; 4.8 ± 2.0 versus 3.9 ± 2.0 ng/mL, P < 0.05; and 36 ± 5 versus 22 ± 7 ng/mL, P < 0.001, respectively). Conversely, CD patients showed significantly lower serum levels of Ang1 than healthy controls (40 ± 12 versus 67 ± 22 ng/mL; P < 0.001). No differences between the groups were found in VEGFR2 serum level. The circulating levels of the angiogenic factors did not differ significantly when the CD patients were classified according to pathological phenotype. Conclusions: In comparison with healthy controls, CD patients were found to have an active angiogenic profile, as detected by significant alterations in levels of angiogenesis soluble markers. These patients did not differ in serum levels of angiogenic factors according to phenotypic disease behavior. (Inflamm Bowel Dis 2007) [source]


Low adiponectin levels are associated with renal cell carcinoma: A case-control study

INTERNATIONAL JOURNAL OF CANCER, Issue 7 2007
Themistoklis N. Spyridopoulos
Abstract Adiponectin is a novel endogenous insulin sensitizer, secreted by mature adipocytes. Circulating levels of adiponectin are inversely associated with obesity and insulin resistance. Because obesity is a risk factor for renal cell carcinoma (RCC), we hypothesized that low adiponectin levels are associated with RCC. To evaluate this hypothesis, we conducted a case- control study of 70 patients with histologically confirmed RCC and 280 healthy controls matched by gender, age and county of residence. Study subjects were interviewed and blood samples were collected during a 32-month period in Athens, Greece. Serum adiponectin levels were statistically, significantly and inversely associated with RCC when compared with controls (OR = 0.76, p = 0.05) and this association remained practically unchanged after controlling for BMI; the introduction of waist to hip ratio along with adiponectin in the multiple logistic regression analysis model rendered the association between adiponectin and RCC risk insignificant, indicating that altered levels of adiponectin may mediate the effect of central or intra-abdominal obesity on RCC. Prospective studies as well as studies exploring underlying mechanisms are needed to fully explore the role of adiponectin in predicting future risk of RCC in humans. © 2006 Wiley-Liss, Inc. [source]


Circulating levels of pro-atrial natriuretic peptide in lower respiratory tract infections

JOURNAL OF INTERNAL MEDICINE, Issue 6 2006
B. MÜLLER
Abstract. Objective., To analyse the mid region of plasma N-terminal pro-atrial natriuretic peptide (MR-proANP) levels in patients with lower respiratory tract infections to evaluate its prognostic use for the severity of disease and outcome. Design., Prospective observational study. Setting., Emergency department of a university hospital. Subjects., A total of 545 consecutive patients with lower respiratory tract infections and 50 healthy controls. Interventions., MR-proANP was measured in serum from all patients using a new sandwich immunoassay. Results., MR-proANP levels (median [IQR], in pmol L,1) were significantly higher in patients with lower respiratory tract infections when compared with controls (138.0 [74.1,279.0] vs. 72.7 [62.5,89.5], P < 0.001), with highest levels in patients with community-acquired pneumonia (CAP). MR-proANP, but not C-reactive protein (CRP) levels, gradually increased with increasing severity of CAP, classified according to the pneumonia severity index (PSI) score (P < 0.001). On admission, MR-proANP levels were significantly higher in nonsurvivors when compared with survivors (293.0 [154.0,633.0] vs. 129.0 [71.4,255.0], P < 0.001). In a receiver operating characteristic (ROC) analysis for the prediction of survival of patients with CAP the area under the ROC curve (AUC) for MR-proANP was 0.69, similar when compared with the PSI (AUC 0.74, P = 0.31), and better when compared with other biomarkers, i.e. procalcitonin (AUC 0.57, P = 0.08), CRP (AUC 0.52, P = 0.02), and leucocyte count (AUC 0.56, P = 0.07). Conclusions., MR-proANP levels are increased in lower respiratory tract infections, especially in CAP. Together with other clinical, radiographic and laboratory findings, MR-proANP levels might be helpful for the risk stratification in CAP. [source]


Decreased Pulmonary Inflammation Following Ethanol and Burn Injury in Mice Deficient in TLR4 but not TLR2 Signaling

ALCOHOLISM, Issue 10 2010
Melanie D. Bird
Background:, Clinical and laboratory evidence suggests that alcohol consumption prior to burn injury leads to dysregulated immune function and subsequent higher rates of morbidity and mortality. Our laboratory previously observed higher levels of pro-inflammatory cytokines and leukocyte infiltration in the lungs of mice following ethanol and burn injury. To understand the mechanism of the increased inflammatory response, we looked at different signaling initiators of inflammation including toll-like receptors 2 and 4 (TLR2 and 4) pathways. Methods:, Wild-type, TLR2, and TLR4 knockout mice were treated with vehicle or a single binge dose of ethanol (1.11 g/kg) and subsequently given a sham or burn injury. Twenty-four hours postinjury, systemic and pulmonary levels of pro-inflammatory cytokines were quantified, and differences in neutrophil infiltration were determined by histological examination. Results:, Higher numbers of neutrophils were observed in the lungs of wild-type mice following the combined insult of ethanol and burn injury relative to either injury alone. This increase in leukocyte accumulation was absent in the TLR4 knockout mice. Circulating levels of IL-6 and tumor necrosis factor-, were also elevated in wild-type mice but not in TLR4 knockout mice. Consistent with these findings, pulmonary levels of KC and IL-6 were increased in wild-type mice following burn and ethanol compared to burn injury alone as well as to their TLR4 knockout counterparts. In contrast, TLR2 knockout mice displayed similar levels, to wild-type mice, of neutrophil infiltration as well as IL-6 and KC in the lung. Conclusions:, These data suggest that TLR4 signaling is a crucial contributory component in the exuberant inflammation after ethanol and burn injury. However, TLR2 does not appear to play a vital role in the aberrant pulmonary inflammation. [source]


Leptin and Cellular and Innate Immunity in Abstinent Alcoholics and Controls

ALCOHOLISM, Issue 11 2003
Sarosh J. Motivala
Background: Basic studies indicate that in vitro and in vivo doses of leptin modulate cellular immune responses. Given evidence that concentrations of leptin are altered in alcoholics who also show immune abnormalities, this study examined the relationships between circulating levels of leptin and markers of cellular and innate immunity. Methods: Circulating levels of leptin, natural killer cell (NK) activity, interleukin-2 (IL-2),stimulated NK activity, and concanavalin A,stimulated production of IL-2, IL-6, IL-10, and IL-12 were compared between abstinent DSM-IV alcohol-dependent men (n= 27) and age- and gender-matched controls (n= 34). Results: As compared with controls, alcoholics showed lower NK activity (p < 0.01) and a trend for lower levels of leptin (p= 0.055). In the total sample, leptin predicted NK activity (,= 0.33; p < 0.05) after controlling for the confounding influence of body mass index, alcohol intake, and smoking. Leptin was not correlated with any of the cytokine measures. To examine whether the effects of leptin were mediated by its direct action on NK, additional studies examined in vitro effects of leptin on NK activity in healthy volunteers (n= 10); leptin doses (0.1, 1, and 10 nM) yielded levels of NK activity comparable to those with media alone. Conclusions: These data show that circulating levels of leptin are associated with NK activity in humans and suggest that abnormal in vivo concentrations of leptin may contribute to the declines of NK activity in alcoholics who are at risk for infectious diseases. [source]


Elevated thrombopoietin in plasma of burned patients without and with sepsis enhances platelet activation

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2009
E. LUPIA
Summary.,Background:,Thrombopoietin (TPO) is a humoral growth factor that does not induce platelet aggregation per se, but enhances platelet activation in response to several agonists. Circulating levels of TPO are increased in patients with sepsis and are mainly related to sepsis severity. Objectives:,To investigate the potential contribution of elevated TPO levels in platelet activation during burn injury complicated or not by sepsis. Methods: We studied 22 burned patients, 10 without and 12 with sepsis, and 10 healthy subjects. We measured plasma levels of TPO, as well as leukocyte-platelet binding and P-selectin expression. The priming activity of plasma from burned patients or healthy subjects on platelet aggregation and leukocyte-platelet binding, and the role of TPO in these effects were also studied in vitro. Results:,Burned patients without and with sepsis showed higher circulating TPO levels and increased monocyte-platelet binding compared with healthy subjects. Moreover, TPO levels, monocyte-platelet binding and P-selectin expression were significantly higher in burned patients with sepsis than in burned patients without sepsis. In vitro, plasma from burned patients without and with sepsis, but not from healthy subjects, primed platelet aggregation, monocyte-platelet binding and platelet P-selectin expression. The effect of plasma from burned patients with sepsis was significantly higher than that of plasma from burned patients without sepsis. An inhibitor of TPO prevented the priming effect of plasma from burned patients. Conclusions:,Increased TPO levels may enhance platelet activation during burn injury and sepsis, potentially participating in the pathogenesis of multi-organ failure in these diseases. [source]


Independent association of matrix metalloproteinase-10, cardiovascular risk factors and subclinical atherosclerosis

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2007
J. ORBE
Summary.,Objectives: Circulating levels of matrix metalloproteinase (MMP)-10 are related to inflammation in asymptomatic subjects with cardiovascular risk factors. Whether MMP-10 is associated with the severity of atherosclerosis remains to be determined. This study examines the relationship of systemic MMP-10 levels with atherosclerotic risk factors and subclinical atherosclerosis. Methods and results: Circulating levels of MMP-1, -9 and -10, and markers of inflammation [fibrinogen, interleukin-6, von Willebrand factor, and high-sensitivity C-reactive protein (hs-CRP)] were measured in 400 subjects (mean age 54.3 years, 77.7% men) with cardiovascular risk factors but free from clinical cardiovascular disease. Subclinical atherosclerosis was evaluated by both the mean carotid intima-media thickness (IMT) and the presence of atherosclerotic plaques with the use of B-mode ultrasound in all subjects. MMP-10 levels were positively correlated with fibrinogen (r = 0.24, P < 0.001), hs-CRP (r = 0.14, P < 0.01) and carotid IMT (r = 0.17, P < 0.01). The association between MMP-10 and IMT remained significant in multiple regression analysis (P < 0.02) when controlling for traditional atherosclerotic risk factors and inflammatory markers. Such an association was not observed for MMP-1 and -9. Subjects in the highest MMP-10 tertile had significantly higher carotid IMT (adjusted odds ratio 6.3, 95% confidence interval 1.3,31.4, P = 0.024). In addition, MMP-10 levels were significantly higher in patients with carotid plaques (n = 78) than in those with no plaques after adjusting for age and sex (P < 0.01). Conclusion: Higher serum MMP-10 levels were associated with inflammatory markers, increased carotid IMT and atherosclerotic plaques in asymptomatic subjects. Circulating MMP-10 may be useful to identify subclinical atherosclerosis in subjects free from cardiovascular disease. [source]


Clinical Pharmacokinetics of the PDT Photosensitizers Porfimer Sodium (Photofrin), 2-[1-Hexyloxyethyl]-2-Devinyl Pyropheophorbide-a (Photochlor) and 5-ALA-Induced Protoporphyrin IX

LASERS IN SURGERY AND MEDICINE, Issue 5 2006
David A. Bellnier PhD
Abstract Background and Objectives Photodynamic therapy (PDT) uses a photosensitizer activated by light, in an oxygen-rich environment, to destroy malignant tumors. Clinical trials of PDT at Roswell Park Cancer Institute (RPCI) use the photosensitizers Photofrin, Photochlor, and 5-ALA-induced protoporphyrin IX (PpIX). In some studies the concentrations of photosensitizer in blood, and occasionally in tumor tissue, were obtained. Pharmacokinetic (PK) data from these individual studies were pooled and analyzed. This is the first published review to compare head-to-head the PK of Photofrin and Photochlor. Study Design/Materials and Methods Blood and tissue specimens were obtained from patients undergoing PDT at RPCI. Concentrations of Photofrin, Photochlor, and PpIX were measured using fluorescence analysis. A non-linear mixed effects modeling approach was used to analyze the PK data for Photochlor (up to 4 days post-infusion; two-compartment model) and a simpler multipatient-data-pooling approach was used to model PK data for both Photofrin and Photochlor (at least 150 days post-infusion; three-compartment models). Physiological parameters were standardized to correspond to a standard (70 kg; 1.818 m2 surface area) man to facilitate comparisons between Photofrin and Photochlor. Results Serum concentration-time profiles obtained for Photofrin and Photochlor showed long circulating half-lives, where both sensitizers could be found more than 3 months after intravenous infusion; however, estimated plasma clearances (standard man) were markedly smaller for Photofrin (25.8 ml/hour) than for Photochlor (84.2 ml/hour). Volumes of distribution of the central compartment (standard man) for both Photofrin and Photochlor were about the size (3.14 L, 4.29 L, respectively) of plasma volume, implying that both photosensitizers are almost 100% bound to serum components. Circulating levels of PpIX were generally quite low, falling below the level of instrument sensitivity within a few days after topical application of 5-ALA. Conclusion We have modeled the PK of Photochlor and Photofrin. PK parameter estimates may, in part, explain the relatively long skin photosensitivity attributed to Photofrin but not Photochlor. Due to the potential impact and limited experimental PK data in the PDT field further clinical studies of photosensitizer kinetics in tumor and normal tissues are warranted. Lasers Surg. Med. © 2006 Wiley-Liss, Inc. [source]


Circulating levels of brain-derived neurotrophic factor correlate with disease severity in the intrinsic type of atopic dermatitis

ALLERGY, Issue 12 2006
U. Raap
Background:, Recent studies have shed light on the complex regulation of genetic, environmental, immunologic and pharmacologic factors, which contribute to the development of atopic dermatitis (AD). However, it is still unclear to which extent neuroimmune mediators have a role in AD. Aims of the study:, To assess peripheral neurotrophin levels and their correlation with scoring atopic dermatitis (SCORAD) scores in both the intrinsic and extrinsic types of AD compared with patients with psoriasis and nonatopic healthy subjects. Methods:, Levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were assessed in peripheral blood with enzyme-linked immunosorbent assay. Based on IgE-mediated sensitization, AD was divided into the extrinsic and intrinsic type. Severity of AD was assessed with SCORAD score and with psoriasis area and severity index (PASI) in patients with psoriasis. Results:, Brain-derived neurotrophic factor and NGF were detectable in all the subjects studied. However, the levels of both neurotrophins were significantly higher in patients with extrinsic and intrinsic types of AD compared with patients with psoriasis and nonatopic healthy subjects (NGF: P < 0.001, BDNF: P < 0.001). NGF and BDNF levels were similar in the intrinsic and extrinsic type of AD. There was a significant correlation between BDNF and SCORAD score only in patients with the intrinsic type of AD (r = 0.57, P < 0.05). Conclusions:, This study shows for the first time that NGF and BDNF are increased in both, the extrinsic type and the intrinsic type of AD. This finding points to a similar pathophysiologic background implicating a neuroimmune network in both variants of this chronic inflammatory skin disease. Future studies are needed to show the direct mechanisms of neurotrophin action in chronic inflammatory skin. [source]


Circulating levels of KL-6 in acute respiratory distress syndrome sepsis or traumatic brain injury in critically ill children

PEDIATRIC PULMONOLOGY, Issue 8 2006
George Briassoulis MD
Abstract KL-6 is a high molecular weight glycoprotein that is expressed on the apical borders of normal secretary alveolar epithelial cells. The aim of our study was to elucidate the potential role of circulating levels of KL-6, related to C-reacting protein (CRP), disease severity (PRISM, TISS), length of stay (LOS) or mechanical ventilation (LOMV), and outcome, in children with acute respiratory distress syndrome (ARDS), sepsis, or traumatic brain injury (TBI). KL-6 concentrations were monitored using solid phase sandwich enzyme-linked immunosorbent assay in plasma of nine patients with ARDS and compared to nine patients with TBI, nine with sepsis, and nine ventilated patients with cancer of matched illness severity on days 1, 3, 5, 7, and 10. Initial respiratory/ventilatory parameters (oxygenation index, plateau pressures) were recorded for ARDS patients. Patients with ARDS had higher early plasma levels of KL-6 (956,±,400 U/ml), as compared to patients with TBI (169,±,9 U/ml), sepsis (282,±,81 U/ml), and ventilated controls (255,±,40 U/ml). Significant correlations were demonstrated between plasma KL-6 concentration and oxygenation index, PaO2: FiO2 ratio, LOS and LOMV, but not with CRP or PRISM. Only in patients with ARDS, plasma KL-6 levels were higher in non-survivors than survivors (P,<,0.03). Plasma KL-6 levels have possible prognostic significance and may provide a useful marker for ARDS in critically ill children. Pediatr Pulmonol. 2006; 41: 790,795. © 2006 Wiley-Liss, Inc. [source]


Circulating adhesion molecules in sera of asthmatic children

PEDIATRIC PULMONOLOGY, Issue 4 2002
Ren-Bin Tang MD
Abstract Infiltration of cells into the lung in asthma is regulated by several expressions of cell adhesion molecules (CAMs) on cells present in the airways, and may play a role in the pathogenesis of bronchial asthma. We sought to evaluate the role of serum concentrations of the soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) in the control of disease activity in acute asthma. Circulating levels of sICAM-1, sVCAM-1, and sE-selectin in sera from 15 normal control subjects and from 20 allergic asthmatic children with acute exacerbations who had returned to stable condition were determined by using commercially available enzyme-linked immunosorbent assay kits. The mean concentration of serum sICAM-1 levels was significantly higher during an acute exacerbation of asthmatic children than in those with stable asthma (19.41,±,10.65 ng/mL vs. 13.46,±,5.44 ng/mL; P,<,0.001) or in control subjects (9.83,±,2.02 ng/mL; P,<,0.001). For sVCAM-1 and sE-selectin, the mean serum concentration of sVCAM-1 was slightly higher in children during an acute exacerbation asthma than when stable. However, the differences did not reach statistical significance. The mean serum concentrations of sVCAM-1 and sE-selectin in acute asthma or stable asthma were significiantly higher than in control subjects. This study provides further evidence that serum concentrations of sICAM-1, sVCAM-1, and sE-selectin are increased in acute asthma. These findings further confirm that leukocyte endothelial adhesion plays a role in inflammmatory airway disease. Pediatr Pulmonol. 2002; 33:249,254. © 2002 Wiley-Liss, Inc. [source]


Sustained and therapeutic levels of human factor IX in hemophilia B mice implanted with microcapsules: key role of encapsulated cells

THE JOURNAL OF GENE MEDICINE, Issue 3 2006
Jianping Wen
Abstract Background A gene therapy delivery system based on microcapsules enclosing recombinant cells engineered to secrete a therapeutic protein was explored in this study. In order to prevent immune rejection of the delivered cells, they were enclosed in non-antigenic biocompatible alginate microcapsules prior to being implanted intraperitoneally into mice. We have shown that encapsulated C2C12 myoblasts can temporarily deliver therapeutic levels of factor IX (FIX) in mice, but the C2C12 myoblasts elicited an immune response to FIX. In this study we report the use of mouse fetal G8 myoblasts secreting hFIX in hemophilia mice. Methods Mouse G8 myoblasts were transduced with MFG-FIX vector. A pool of recombinant G8 myoblasts secreting ,1500 ng hFIX/106 cells/24 h in vitro were enclosed in biocompatible alginate microcapsules and implanted intraperitoneally into immunocompetent C57BL/6 and hemophilic mice. Results Circulating levels of hFIX in treated mice reached ,400 ng/ml for at least 120 days (end of experiment). Interestingly, mice treated with encapsulated G8 myoblasts did not develop anti-hFIX antibodies. Activated partial thromboplastin time (APTT) of plasmas obtained from treated hemophilic mice was reduced from 107 to 82 sec on day 60 post-treatment, and whole blood clotting time (WBCT) was also corrected from 7,9 min before treatment to 3,5 min following microcapsule implantation. Further, mice were protected against bleeding following major trauma. Thus, the FIX delivery in vivo was biologically active. Conclusions Our findings suggest that the type of cells encapsulated play a key role in the generation of immune responses against the transgene. Further, a judicious selection of encapsulated cells is critical for achieving sustained gene expression. Our findings support the feasibility of encapsulated G8 myoblasts as a gene therapy approach for hemophilia B. Copyright © 2005 John Wiley & Sons, Ltd. [source]


Genetic and plasma variation of insulin-like growth factor binding proteins in relation to prostate cancer incidence and survival

THE PROSTATE, Issue 12 2009
Mattias Johansson
Abstract BACKGROUND Binding proteins regulate bioavailability of insulin-like growth factor-I (IGF-I) in the circulation and affect apoptosis of tumor cells in the prostate. We analyzed genetic variation within genes coding for IGF binding proteins in relation to prostate cancer incidence and survival. We also investigated if circulating IGFBP3 affects prostate cancer-specific survival. MATERIALS AND METHODS Eleven haplotype tagging SNPs and two single SNPs in the IGFBP1, IGFBP3, and IGFALS genes were genotyped within the CAncer Prostate in Sweden (CAPS) study including 2,774 cases and 1,736 controls. Plasma samples for analyses of total- and intact IGFBP3 levels were available for 1,521 cases and 909 controls. Complete follow-up of vital status was achieved by linkage to the Swedish Cause of Death Register. RESULTS We found no clear association between the genetic variants and prostate cancer incidence or survival. The rare allele of the IGFBP3 SNP rs2854744 was associated with elevated plasma levels of total IGFBP3 (Ptrend,=,9,×,10,8), but not intact IGFBP3 (Ptrend,=,0.16). Elevated levels of total- (Ptrend,=,0.03) and intact IGFBP3 (Ptrend,=,6,×,10,14) were associated with increased risk of prostate cancer specific death. Treatment and tumor characteristics accounted for the association with total IGFBP3, whereas the association with intact IGFBP3 was attenuated, but still statistically significant in adjusted analysis (Ptrend-adjusted,=,0.0004). Elevated intact IGFBP3 was also significantly associated with increased risk of prostate cancer-specific death among patients who were chemically or surgically castrated (Ptrend-adjusted,=,0.0003), and among patients who had not been treated (Ptrend-adjusted,=,0.02). CONCLUSIONS Circulating levels of intact IGFBP3 measured after diagnosis is associated with increased risk of prostate cancer-specific death. Prostate 69:1281,1291, 2009. © 2009 Wiley-Liss, Inc. [source]


Dietary effects on insulin and glucagon plasma levels in rainbow trout (Oncorhynchus mykiss) and gilthead sea bream (Sparus aurata)

AQUACULTURE NUTRITION, Issue 2 2009
P. ROJAS
Abstract The effects of dietary amino acid profile (based on muscle (M) or whole body composition (WB) and the balance between indispensable (IAA) and dispensable amino acids (DAA) in the diet, on plasma levels of insulin and glucagon, were analysed in rainbow trout and gilthead sea bream. Plasma insulin values (baseline and 6 h postfeeding) were higher in trout than in sea bream, but the relative postfeeding increase was more pronounced in sea bream. Within the same dietary amino acid profile, diets with lower IAA/DAA, had a lower effect on the postfeeding secretion of insulin in both species. Circulating levels of glucagon (baseline and postfeeding relative increases) were higher in sea bream. In trout, diets with WB amino acid profile had a greater secretory effect on postfeeding glucagon than did diets with M profile, while gilthead sea bream showed an inverse response to circulating glucagon with respect to diet. Muscle insulin and insulin growth factor-I binding parameters were not affected by the dietary regimen. The postfeeding glucagon response depends on both the dietary AA profile and the fish species, while that of insulin seems to be more uniform, and is affected in a similar way regardless of the species. [source]


Transgenic disruption of glucocorticoid signaling in mature osteoblasts and osteocytes attenuates K/BxN mouse serum,induced arthritis in vivo

ARTHRITIS & RHEUMATISM, Issue 7 2009
Frank Buttgereit
Objective Endogenous glucocorticoids (GCs) modulate numerous biologic systems involved in the initiation and maintenance of arthritis. Bone cells play a critical role in the progression of arthritis, and some of the effects of GCs on inflammation may be mediated via these cells. The aim of this study was to investigate the impact of osteoblast-targeted disruption of GC signaling on joint inflammation, cartilage damage, and bone metabolism in the K/BxN mouse serum transfer model of autoimmune arthritis. Methods Intracellular GC signaling was disrupted in osteoblasts through transgenic overexpression of 11,-hydroxysteroid dehydrogenase type 2 under the control of a type I collagen promoter. Arthritis was induced in 5-week-old male transgenic mice and their wild-type (WT) littermates, and paw swelling was assessed daily until the mice were killed. The mice were examined by histology, histomorphometry, and microfocal computed tomography, and serum was analyzed for cytokines, adrenocorticotropic hormone, and corticosterone. Results Acute arthritis developed in both transgenic and WT mice treated with K/BxN mouse serum. However, the arthritis and local inflammatory activity were significantly attenuated in transgenic mice, as judged by clinical and histologic indices of inflammation and cartilage damage. Bone turnover and bone volume remained unchanged in arthritic transgenic mice, while WT mice exhibited stimulated bone resorption, suppressed osteoblast activity, and significantly reduced bone volume, compatible with the known effects of active inflammation on bone. Circulating levels of proinflammatory cytokines tended to be lower in arthritic transgenic mice than in control transgenic mice. Conclusion Disruption of GC signaling in osteoblasts significantly attenuates K/BxN mouse serum,induced autoimmune arthritis in mice. These data suggest that osteoblasts modulate the immune-mediated inflammatory response via a GC-dependent pathway. [source]


Mechanism of action of vitamin C in sepsis: Ascorbate modulates redox signaling in endothelium

BIOFACTORS, Issue 1 2009
John X. Wilson
Abstract Circulating levels of vitamin C (ascorbate) are low in patients with sepsis. Parenteral administration of ascorbate raises plasma and tissue concentrations of the vitamin and may decrease morbidity. In animal models of sepsis, intravenous ascorbate injection increases survival and protects several microvascular functions, namely, capillary blood flow, microvascular permeability barrier, and arteriolar responsiveness to vasoconstrictors and vasodilators. The effects of parenteral ascorbate on microvascular function are both rapid and persistent. Ascorbate quickly accumulates in microvascular endothelial cells, scavenges reactive oxygen species, and acts through tetrahydrobiopterin to stimulate nitric oxide production by endothelial nitric oxide synthase. A major reason for the long duration of the improvement in microvascular function is that cells retain high levels of ascorbate, which alter redox-sensitive signaling pathways to diminish septic induction of NADPH oxidase and inducible nitric oxide synthase. These observations are consistent with the hypothesis that microvascular function in sepsis may be improved by parenteral administration of ascorbate as an adjuvant therapy. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source]


Circulating levels and clinical significance of soluble CD86 in myeloma patients

BRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2006
B. D. Hock
Summary Circulating soluble CD86 (sCD86) levels are elevated in a number of leukaemias and are an independent prognostic factor in acute myeloid leukaemia. We investigated the clinical significance of circulating sCD86 in 299 patients from the UK Medical Research Council myeloma VIth trial, where patients received ABCM [adriamycin, carmustine (BCNU), cyclophosphamide, melphalan] either alone or with prednisolone (ABCM + P). Serum levels of sCD86 were significantly elevated (P = 0·0001) in myeloma patients and using the median normal donor level (0·621 ng/ml) as a cut-off point, 70% of patients had elevated levels (range = 0·015,15·87 ng/ml, median = 1·1 ng/ml). In univariate analysis elevated sCD86 levels were associated with significantly shorter (P < 0·001) survival (median = 22 vs. 51 months) and event-free survival (median = 14 vs. 31 months) in ABCM + P but not ABCM patients. Multivariate analysis demonstrated that sCD86 was a significant, independent prognostic marker of both overall [risk ratio (RR) = 2·04, P = 0·0006] and event-free (RR = 1·95, P = 0·0004) survival in ABCM + P patients. In conclusion, this study demonstrated that sCD86 levels are a significant independent prognostic marker in at least some myeloma treatment groups and its biological role and prognostic value should be further investigated. [source]


Adipocytokines and the metabolic syndrome among older persons with and without obesity: the InCHIANTI study

CLINICAL ENDOCRINOLOGY, Issue 1 2010
Sari Stenholm
Summary Objectives, Adipose tissue-derived inflammation may contribute to metabolic alterations and eventually to the metabolic syndrome (MetS). The purpose of this study was to: (1) examine the role of adipocytokines in the association between obesity and the MetS and (2) to determine whether the association is different in obese and non-obese persons. Design, Cross-sectional population-based InCHIANTI study. Subjects, A total of 944 community-dwelling adults aged 65 years and older living in Tuscany, Italy. Measurements, Obesity was defined as body mass index ,30 kg/m2 and MetS as ,3 of the ATP-III criteria. Circulating levels of C-reactive protein, interleukin (IL)-6, IL-1 receptor antagonist (IL-1ra), IL-18, tumour necrosis factor (TNF)-, R1, adiponectin, resistin and leptin were measured. Additionally, insulin resistance was determined using the homeostasis model assessment (HOMA-IR). Results, The prevalence of the MetS was 32%. Both overall and abdominal obesity were significantly associated with the MetS after adjusting for inflammatory cytokines, adipokines and lifestyle factors. After adjusting for multiple confounders and HOMA-IR, IL-1ra, TNF-, R1 and adiponectin (P < 0·05) remained significantly associated with the MetS. Having multiple cytokines in the highest tertile increased the likelihood of having the MetS in both obese (P for trend 0·002) and non-obese persons (P for trend 0·001) independent of insulin resistance. Conclusions, Non-obese and obese individuals who develop an intense pro-inflammatory state may be more prone to develop the MetS than those with lower levels of inflammation. [source]


Growth hormone and insulin-like growth factor 1 levels and their relation to survival in children with bacterial sepsis and septic shock

JOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 4 2004
N Önenli-Mungan
Objectives: Despite improved supportive care, the mortality of sepsis and septic shock is still high. Multiple changes in the neuroendocrine systems, at least in part, are responsible for the high morbidity and mortality. A reduced circulating level of insulin-like growth factor and an elevated level of growth hormone are the reported characteristic findings early in the course of sepsis and septic shock in adults. The aim of this study was to evaluate the changes of growth hormone/insulin-like growth factor 1 axis in sepsis and septic shock and investigate the relationship between these hormones and survival. Methods: Fifty-one children with sepsis (S), 21 children with septic shock (SS) and 30 healthy, age- and sex-matched children (C) were enrolled in this study. Growth hormone, insulin-like growth factor 1 and cortisol levels of the sepsis and septic shock groups were obtained before administration of any inotropic agent. Results: Growth hormone levels were 32.3 ± 1.5 µIU/mL (range 4,56), 15.9 ± 0.6 µIU/mL (range 11,28) and 55.7 ± 2.7 µIU/mL (range 20,70) in S, C and SS groups, respectively. The difference between the growth hormone levels of the S and C groups, S and SS groups, and C and SS groups were significant (P < 0.001). Non-survivors (54.7 ± 1.6 µIU/mL) had significantly higher growth hormone levels than survivors (29.4 ± 1.5 µIU/mL) (P < 0.001). Insulin-like growth factor 1 levels were 38.1 ± 2.1 ng/mL (range 19,100), 122.9 ± 9.6 ng/mL (range 48,250) and 22.2 ± 1.9 ng/mL (range 10,46) in the S, C and SS groups, respectively, and the difference between the insulin-like growth factor 1 levels of the S and C, S and SS, and C and SS groups were significant (P < 0.001). Non-survivors (8.8 ± 1.1 µg/dL) had significantly lower cortisol levels than survivors (40.9 ± 2.1 µg/dL) (P < 0.001). We detected a significant difference between the levels of cortisol in non-survivors (19.7 ± 1.8 µg/dL) and survivors (33.9 ± 0.9 µg/dL) (P < 0.01). Conclusions: There were elevated levels of growth hormone with decreased levels of insulin-like growth factor 1 in children during sepsis and septic shock compared to healthy subjects. In addition, there were even higher levels of growth hormone and lower levels of insulin-like growth factor 1 in non-survivors than in survivors. We think that both growth hormone and insulin-like growth factor 1 may have potential prognostic value to serve as a marker in bacterial sepsis and septic shock in children. As there is insufficient data in the paediatric age group, more studies including large numbers of patients and additionally evaluating cytokines and insulin-like growth factor binding proteins are needed. [source]


Cover Picture , Mol.

MOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 12 2008
Nutr.
Selected topics of issue 12 are: Procyanidin effects on oesophageal adenocarcinoma cells strongly depend on flavan-3-ol degree of polymerization Daily Intake of thiamine correlates with the circulating level of endothelial progenitor cells and the endothelial function in patients with type II diabetes Fungal siderophores function as protective agents of LDL oxidation and are promising anti-atherosclerotic metabolites in functional food Identification of four IgE-reactive proteins in raspberry (Rubus ideaeus L.) [source]


Nutritional Effect of Dialysis Therapy

ARTIFICIAL ORGANS, Issue 3 2003
Tsutomu Sanaka
Abstract: The prognosis of patients with end-stage renal disease has been improved by the recent remarkable advances in medical and engineering technology. However, there are still many unsolved problems in the clinical field. One of the problems is an intractable malnutrition characterized by clinical manifestations including hypoproteinemia and decrease in muscular volume, which is associated with deterioration in the quality of the patient's life. Malnutrition in hemodialysis patients involves abnormal energy metabolism and aberrant amino acid metabolism. In the most malnourished patients, immunodefense mechanisms and homeostasis are disrupted, greatly influencing the prognosis. Moreover, when the performance of dialyzer used is too high, the dialysis treatment might remove a necessary nutrient for the patient. There is also a possibility that the protein catabolism is accelerated when the biocompatibility is inferior. On the other hand, in malnutri-tion, the circulating level of insulin-like growth factor-1 (IGF-1) falls while the level of insulin-like growth factor binding protein-1 (IGFBP-1) is remarkably increased. It has been recognized that IGF-1 and IGFBP-1 are indicators reflecting the initiation of a malnutritional state in patients with chronic renal failure, although there are many indicators such as albumin, prealbumin, and anthropometric measurement for nutritional assessment. We have suggested that r-hGH and IGF-1 improve the malnutritional state by alleviating hypoproteinemia and abnormality of serum amino acid profile in uremic patients on hemodialysis. The serum IGF-1/IGFBP-1 ratio is useful not only as a nutritional parameter but also as a predicting index of responsiveness to r-hGH. It is necessary to examine the problem from various angles to improve malnutrition in the dialysis patient, while considering the above mentioned. [source]


The birth process initiates an acute phase reaction in the fetus-newborn infant

ACTA PAEDIATRICA, Issue 9 2000
G Marchini
Our goal was to investigate whether the normal birth process stimulated an acute phase response in healthy infants with physiological changes in the circulating levels of acute phase cytokines and acute phase proteins. We also monitored body temperature, body weight and behavioural state in order to investigate if clinical signs of acute phase reaction were present. We made cross-sectional measurements of interleukin-1,, interleukin-6, C-reactive protein, serum amyloid A, procalcitonin, prealbumin, body weight, body temperature and the duration of the sleeping period during the first four postnatal days. We found an increase in interleukin-6 (p < 0.001) during the first day, followed by an increase in C-reactive protein, serum amyloid A and procalcitonin on the second postnatal day (p < 0.01). The level of prealbumin fell after birth and reached its lowest value at 3 d of age (p < 0,001). Interleukin-l p remained unchanged. The duration of the sleeping period was longer during the first day (p < 0.01). There was an increase in body temperature during the first day (p < 0.01). Maximal weight loss was during the first 2 d. Conclusions: The normal birth process and extra-uterine adaptation stimulates an acute phase reaction in the newborn infant with a release of interleukin-6 and acute phase proteins and a depression of prealbumin. This reaction, as the body's first line inflammatory defence system, probably affects the infant's behaviour, nutritional state as well as the regulation of body temperature. [source]


The effects of acute and chronic exercise on the vasculature

ACTA PHYSIOLOGICA, Issue 4 2010
J. J. Whyte
Abstract Regular physical activity (endurance training, ET) has a strong positive link with cardiovascular health. The aim of this review is to draw together the current knowledge on gene expression in different cell types comprising the vessels of the circulatory system, with special emphasis on the endothelium, and how these gene products interact to influence vascular health. The effect beneficial effects of ET on the endothelium are believed to result from increased vascular shear stress during ET bouts. A number of mechanosensory mechanisms have been elucidated that may contribute to the effects of ET on vascular function, but there are questions regarding interactions among molecular pathways. For instance, increases in flow brought on by ET can reduce circulating levels of viscosity and haemostatic and inflammatory variables that may interact with increased shear stress, releasing vasoactive substances such as nitric oxide and prostacyclin, decreasing permeability to plasma lipoproteins as well as the adhesion of leucocytes. At this time the optimal rate-of-flow and rate-of-change in flow for determining whether anti-atherogenic or pro-atherogenic processes proceed remain unknown. In addition, the impact of haemodynamic variables differs with vessel size and tissue type in which arteries are located. While the hurdles to understanding the mechanism responsible for ET-induced alterations in vascular cell gene expression are significant, they in no way undermine the established benefits of regular physical activity to the cardiovascular system and to general overall health. This review summarizes current understanding of control of vascular cell gene expression by exercise and how these processes lead to improved cardiovascular health. [source]


Flow cytometric measurement of circulating endothelial cells: The effect of age and peripheral arterial disease on baseline levels of mature and progenitor populations

CYTOMETRY, Issue 2 2006
Rebecca Gusic Shaffer
Abstract Background: Age and cardiovascular disease status appear to alter numbers and function of circulating endothelial progenitor cells (EPCs). Despite no universal phenotypic definition, numerous studies have implicated progenitors with apparent endothelial potential in local responses to vascular injury and with cardiovascular disease in general. To further define the role of this lineage in peripheral artery disease (PAD), we developed a multiparameter flow cytometry assay to analyze multiple phenotypic definitions of progenitor cells (PCs), EPCs, and mature endothelial cells (ECs) and evaluate effects of age and PAD on baseline levels of each subset. Methods: Blood was collected from young healthy subjects (N = 9, mean age 33 ± 8 years), older healthy subjects (N = 13, mean age 66 ± 8 years), and older subjects with PAD (N = 15, mean age 69 ± 8 years). After ammonium chloride lysis, cells were stained and analyzed on a Becton-Dickinson LSR II with a 5-color antibody panel: FITC-anti-CD31, PE-anti-CD146, PE-anti-CD133, PerCP-Cy5.5-anti-CD3,-CD19,-CD33 (lineage panel), PE-Cy7-anti-CD34, and APC-anti-VEGF-R2. Viability was assessed by propidium iodide exclusion, and only viable, low to medium side scatter lineage-negative singlets were analyzed. In some studies, cells were sorted for morphological studies. Subsets were defined as indicated later. Results: Our results, using a comprehensive flow cytometric panel, indicate that CD133+, CD34+, and CD133+/CD34+ PCs are elevated in younger healthy individuals compared to older individuals, both healthy and with PAD. However, the number of EPCs and mature ECs did not significantly differ among the three groups. Assessment of endothelial colony forming units and dual acLDL-lectin staining supported the flow cytometric findings. Conclusions: We describe a comprehensive flow cytometric method to detect circulating mature and progenitor endothelial populations confirmed by conventional morphological and functional assays. Our findings suggest that aging may influence circulating levels of PCs, but not EPCs or ECs; PAD had no effect on baseline levels of any populations investigated. This study provides the basis for evaluating the potential effects of acute stress and therapeutic intervention on circulating progenitor and endothelial populations as a biomarker for cardiovascular status. © 2005 International Society for Analytical Cytology [source]


Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drug

DIABETES OBESITY & METABOLISM, Issue 2 2007
Iskandar Idris
Exploiting the incretin effect to develop new glucose-lowering treatments has become the focus of intense research. One successful approach has been the development of oral inhibitors of dipeptidyl peptidase-IV (DPP-IV). These drugs reversibly block DPP-IV-mediated inactivation of incretin hormones, for example, glucagon-like peptide 1 (GLP-1) and also other peptides that have alanine or proline as the penultimate N-terminal amino acid. DPP-IV inhibitors, therefore, increase circulating levels and prolong the biological activity of endogenous GLP-1, but whether this is sufficient to fully explain the substantial reduction in haemoglobin A1c (HbA1c) and associated metabolic profile remains open to further investigation. DPP-IV inhibitors such as vildagliptin and sitagliptin have been shown to be highly effective antihyperglycaemic agents that augment insulin secretion and reduce glucagon secretion via glucose-dependent mechanisms. This review summarizes the major clinical trials with DPP-IV inhibitors as monotherapy and as add-on therapy in patients with type 2 diabetes. The magnitude of HbA1c reduction with DPP-IV inhibitors depends upon the pretreatment HbA1c values, but there seems to be no change in body weight, and very low rates of hypoglycaemia and gastrointestinal disturbance with these agents. DPP-IV inhibitors represent a major new class of oral antidiabetic drug and their metabolic profile offers a number of unique clinical advantages for the management of type 2 diabetes. [source]


Circulating insulin antibodies: influence of continuous subcutaneous or intraperitoneal insulin infusion, and impact on glucose control

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 6 2009
R. P. Radermecker
Abstract The purification of animal insulin preparations and the use of human recombinant insulin have markedly reduced the incidence, but not completely suppressed, the development of anti-insulin antibodies (IAs). Advances in technologies concerning the mode of delivery of insulin, i.e. continuous subcutaneous insulin infusion (CSII), continuous peritoneal insulin infusion (CPII) and more recently inhaled insulin administration, appear to significantly increase circulating levels of immunoglobulin G (IgG) anti-IAs in diabetic patients. However, the increase is usually moderate and mostly transient as compared to previous observations with poorly purified animal insulin preparations. The clinical impact of these circulating anti-IAs remains unclear. Nevertheless, several studies have suggested that antibodies could retard insulin action, leading to a worsening of postprandial hyperglycaemia and/or serve as a carrier, thus leading to unexpected hypoglycaemia. CPII may be associated with more marked and sustained increase in IAs levels, possibly related to the use of an unstable insulin and the formation of immunogenic aggregates of insulin. The possible clinical consequences of these high levels of IAs remain to be evaluated because a low-glucose morning syndrome or severe insulin resistance with ketone bodies production have been reported in some cases. In conclusion, even if CSII and CPII may promote the development of circulating IAs, this increase does not lead to immunological insulin resistance, compared to that previously described with animal non-purified insulin preparations, and seems to have only marginal influence on blood glucose control or complications in most diabetic patients. Copyright © 2009 John Wiley & Sons, Ltd. [source]


The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2009
Swapnil N. Rajpathak
Abstract This review addresses the possible role of the insulin-like growth factor (IGF)-axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF-I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin-like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre-diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross-sectionally with altered circulating levels of IGF-I and its binding proteins (IGFBPs). Administration of recombinant human IGF-I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF-I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic ,-cell mass and function. There is considerable inter-individual heterogeneity in endogenous levels of IGF-I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association. Copyright © 2009 John Wiley & Sons, Ltd. [source]