Niveles séricos de IGF-1 e IGFBP-3 en pacientes con esófago de Barrett y adenocarcinoma de esófago. Estudio longitudinal

BackgroundBarrett's esophagus (BE) is an entity with a known histological progression to malignancy. The insulin-like growth factor (IGF) system is involved in the carcinogenesis through obesity-related mechanisms that include IGF and it has been associated with several types of cancer.ObjectivesTo evaluate the serological levels of IGF-1 and IGFBP-3 in patients with BE and esophageal adenocarcinoma.Patients and methodsProspective study of patients with BE and esophageal adenocarcinoma who underwent upper endoscopy between September 2012 and December 2015. A baseline determination of IGF-1 and IGFBP-3 was performed. We included a control group of patients without BE.ResultsOne hundred sixteen patients were included: 36 controls, 62 with BE (42 without dysplasia and 20 with dysplasia) and 18 with adenocarcinoma. IGF-1 and IGF-1/IGFBP-3 molar ratio showed a progression to high levels in BE and adenocarcinoma than in controls (IGF-1: 135.55 ± 66.07 ng/ml, 148.33 ± 81.5 ng/ml, 108.19 ± 46.69 ng/ml, respectively; P = .049) (molar ratio: 0.23 ± 0.91, 0.29 ± 0.11, 0.19 ± 0.06, respectively; P = .001), without differences between the histological types of BE. Fifty-four out of the 65 patients with BE were followed up (median of 58.50 months, range 12–113) and 11 of them (20.4%) presented progression to low-grade dysplasia (n = 8) or high-grade dysplasia/adenocarcinoma (n = 3), without differences in the IGF system compared with patients without progression.ConclusionsPatients with BE and esophageal adenocarcinoma have changes in the IGF system although the serological levels of IGF-1 and IGFBP-3 do not correlate with histological progression of BE.     

Association between the ratio of insulin-like growth factor-I to insulin-like growth factor binding protein-3 and inflammation in incident automated peritoneal dialysis patients

BackgroundThe insulin-like growth factor (IGF) system is known to be associated with inflammation in various populations. However, the association between the IGF system and inflammation has not previously been investigated in automated peritoneal dialysis (APD) patients. Therefore, the aim of this study was to investigate whether the IGF system correlates with inflammation in APD patients.MethodsWe prospectively determined IGF-I activity, the ratio of serum IGF-I concentrations to those of IGF binding protein-3 (IGFBP-3), and inflammatory markers at initiation of APD and after 6 months of follow-up in 21 incident APD patients.ResultsThe mean age was 55.2 ± 13.1 years, and 11 patients (52.3%) were male. Continuous cyclic PD (CCPD) was performed in 11 patients, and nocturnal intermittent PD (NIPD) in 10 patients. The mean value of IGF-I/IGFBP-3 was 0.21 ± 0.13. At baseline, IGF-I/IGFBP-3 was negatively correlated with high-sensitivity C-reactive protein (hs-CRP) (r = ? 0.27, P = 0.032) and interleukin-6 (IL-6) (r = ? 0.19, P = 0.046) concentrations. After 6 months, IGF-I/IGFBP-3 (P = 0.048) had decreased significantly, while the hs-CRP (P = 0.036) increased significantly in the CCPD group. However, there were no significant changes in IGF-I/IGFBP-3 (P = 0.59) and hs-CRP (P = 0.14) during 6 months in the NIPD group. Furthermore, compared with the NIPD group, IGF-I/IGFBP-3 (P = 0.041) decreased greater, whereas hs-CRP (P = 0.048) concentrations increased greater in the CCPD group.ConclusionsThe IGF system was significantly associated with inflammatory markers in incident APD patients, and different APD modalities modulate the IGF system and inflammation.     

Pharmacodynamic hormonal effects of anamorelin,a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers

ObjectiveActivation of ghrelin receptors stimulates GH secretion and appetite, increasing lean body mass and body weight. However, clinical use of ghrelin is limited because it has a short half-life and must be administered parenterally. Anamorelin is a novel, orally active, non-peptidic ghrelin mimetic and growth hormone secretagogue. Our objective was to evaluate its hormonal effects in healthy subjects.DesignA double-blind, randomized, placebo-controlled study evaluated the short-term effects of anamorelin on GH, insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), prolactin, ACTH, LH, FSH, TSH, cortisol, insulin and glucose. Normal healthy volunteers (n = 32) recruited from the general population were administered escalating doses of anamorelin (25, 50, and 75 mg daily) vs. placebo.ResultsAnamorelin significantly increased GH levels at all doses (p ? 0.01). Effects on the somatotropic axis were maintained, as evidenced by sustained increases in IGF-1 and IGFBP-3 compared to placebo following 5–6 days of treatment. Negligible effects on other anterior pituitary hormone profiles and on fasting glucose were noted and all mean hormone levels remained within normal range. Some degree of insulin resistance as assessed by HOMA-IR was evident after treatment with 75 mg dose but not with the 25 or the 50 mg doses. Significant dose-related increases in body weight were recorded. Changes in body weight directly correlated with changes in IGF-1 levels. Anamorelin was well tolerated.ConclusionsAnamorelin increases GH, IGF-1, IGFBP-3 and body weight with good tolerability and selectivity, without affecting other anterior pituitary axes or fasting glucose levels.     

Relationships of insulin-like growth factor-1, its binding proteins,and cardiometabolic risk in hypertensive perimenopausal women

PurposeDuring the transition from premenopause to postmenopause, many women experience weight gain and central fat deposition; therefore, we hypothesized that circulating growth factors can play a role in the pathogenesis of hypertension, metabolic syndrome, and subclinical organ damage in perimenopausal women.Basic ProceduresThe study included 192 women aged 40 to 60 years; 152 had newly diagnosed essential hypertension that had never been treated, and 40 were normotensive age-matched controls. For all subjects, 24-h ambulatory blood pressure monitoring (ABPM), echocardiographic examination with assessment of left ventricular mass (LVM) and systolic and diastolic functions (GE Vivid 7.0, General Electric Vingmed Ultrasound, Horten, Norway), carotid ultrasound with measurement of intima-media thickness, and carotid-femoral pulse wave velocity (PWV) measurement (SphygmoCor, AtCor Medical, Sydney, Australia) were performed. Serum levels of insulin-like growth factor 1 (IGF-1), insulin-like growth factor-binding protein 2 (IGFBP-2), and insulin-like growth factor-binding protein 3 (IGFBP-3) were measured using an immunochemical assay.Main FindingsHypertensive women had significantly lower IGFBP-2 levels than did normotensive controls (162.9 ± 83.7 vs. 273.1 ± 103.0 μg/L, p < 0.001); the groups did not differ regarding IGF and IGFBP-3 concentrations. After adjusting the covariates, multivariate analysis showed that IGFBP2 was significantly negatively correlated with 24-h systolic blood pressure (β = − 0.31, p = 0.02). The adjusted odds ratio for hypertension per standard deviation decrease in IGFBP-2 was 3.43 (95% confidence interval [CI] 1.65–7.13). IGFBP-2 showed a negative correlation with the number of metabolic syndrome components. Independent of body composition, IGFBP-2 was significantly related to left ventricular relative wall thickness and the ratio of mitral inflow velocities as parameter of diastolic function.Principal ConclusionsIn perimenopausal women, decreased IGFBP-2 levels may play a role in blood pressure regulation and the development of subclinical left ventricular diastolic dysfunction. Whether IGFBP-2 is a marker or a mediator of cardiovascular disease in this population merits further investigation.     

Biomarkers of airway and systemic inflammation in obese asthmatic paediatric patients

BackgroundIt is thought that airway inflammation is more common in obese asthmatic patients because inflammation is harder to control and does not respond well to glucocorticoid treatment.ObjectiveThis study's aim was to investigate the effect of obesity on airway and systemic inflammation in children with asthma and to identify the biomarkers that play a role in this inflammation.MethodsThe study included patients aged 6–16 years who were diagnosed with asthma in the paediatric allergy outpatient clinic of Bagcilar Training and Research Hospital in Turkey. Complete blood count parameters were compared between three groups: obese asthmatic (n = 43), obese non-asthmatic (n = 45), and non-obese non-asthmatic (control group, n = 30). Levels of high-sensitive CRP (hs-CRP), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), and matrix metalloproteinase-9 (MMP-9), and 25(OH)-vitamin D were compared between the groups.ResultsNo statistically significant differences were observed in 25(OH)-vitamin D, NGAL, OPN, hs-CRP, and MMP-9 levels between groups. There was a statistically significant negative correlation between FEV1/FVC and NGAL and MMP-9.ConclusionThis is the first study to investigate levels of hs-CRP, NGAL, OPN, MMP-9, and 25(OH)-vitamin D in obese asthmatic children. Larger studies with sputum and BAL examinations are required to determine the potential of biomarkers for identifying inflammation in obese asthmatic children.     

The relationship between hs-CRP and asthma control test in asthmatic patients

BackgroundHigh sensitive C-reactive protein (hs-CRP) has been shown to be associated with asthma in recent studies. However, the relationship between hs-CRP and the control of asthma has not been clearly identified yet.ObjectiveTo investigate the association of hs-CRP with asthma control test (ACT), which reveals the degree of asthma control, and to compare hs-CRP in adults with mild and moderate asthma in chronic, stable asthmatic patients.MethodsThirty patients with physician-diagnosed asthma (11 mild, 19 moderate), and 30 healthy patients were enrolled in the study. In addition to medical history and physical examination, asthma was assessed according to GINA guideline. Respiratory function tests (RFT) and ACT were performed. The serum hs-CRP levels of all cases patients were measured.ResultsThe levels of hs-CRP in asthmatic patients were significantly higher than those in the control cases (p = 0.002). The serum hs-CRP levels in the moderate asthmatics were significantly higher than those in the mild asthmatic ones (p = 0.04). When asthmatic cases were divided into two groups according to ACTs; the levels of hs-CRP in the groups of ACT ≤ 20 (uncontrolled groups) were significantly higher than the groups of ACT ≥ 20 (controlled groups) (p = 0.02). The hs-CRP levels showed significant correlations with ACT (p = 0.00, r = ?0.91) and asthma severity (p = 0.04, r = 038) in asthmatic patients.ConclusionIn conclusion it was shown that hs-CRP is related with asthma severity and ACT, and hs-CRP is a potential sensitive marker which reveals the severity and the control of asthma.     

GLP-1 infusion reduces IGFBP-1 serum level in humans

ObjectiveGlucagon-like peptide-1 (GLP-1) and the insulin-like growth factor (IGF) system are important factors in metabolic regulation and cellular growth. Interactions between the systems exist but these are vaguely explored and only in vitro, where GLP-1 has been reported to stimulate IGF-binding protein 1 (IGFBP-1). This study, therefore, aimed to elucidate the effects of GLP-1 on IGF-I and the IGFBPs, which regulate IGF-I bioactivity.DesignWe investigated the effects of a 2-hour intravenous GLP-1 infusion on the IGF system in 12 overnight fasted healthy humans, using a randomized, double-blinded, cross-over study design. Serum samples were assessed for immunoreactive levels of IGF-I, IGFBP-1 and -2 as well as for bioactive IGF-I, which was determined by a cell-based IGF-I kinase receptor activation assay.ResultsGLP-1 infusion markedly increased insulin levels (p < 0.0001), reduced IGFBP-1 levels (p = 0.02), and tended to increase IGF-I bioactivity (p = 0.06). There were no significant changes in IGFBP-2 or immunoreactive IGF-I levels.ConclusionIn this short-term study, GLP-1 reduced IGFBP-1 levels in vivo and tended to increase IGF-I bioactivity. The IGFBP-1 outcome is opposite to the in vitro situation, hereby demonstrating that in vivo the ability of GLP-1 to stimulate insulin and hereby suppress IGFBP-1 outweighs any direct stimulatory effects of GLP-1 on IGFBP-1.     

Elevated level of serum osteopontin in school-age children with asthma

BackgroundThe role of osteopontin (OPN) has not been elucidated in childhood asthma.ObjectiveOur purpose was to investigate whether OPN levels change due to allergic inflammation in pre-school and school-age children.MethodsIn this prospective, cross-sectional study, 42 healthy children and a total of 51 children with asthma were recruited. OPN levels and its association with clinical and laboratory parameters were investigated in the study population. The asthma group were divided into two groups with respect to age, ≤5-years (n = 23) and >5-years (n = 28), and labelled Asthma Group 1 and Asthma Group 2, respectively. OPN levels were compared between subgroups.ResultsSerum OPN levels were significantly higher in the asthma group when compared to the control group (p = 0.004). OPN levels were similar in Asthma Group 1 and control groups, whereas it was found to be higher in Asthma Group 2 (p > 0.025, p = 0.001, respectively). In the >5-years age asthmatic group, OPN levels of the patients with allergic rhinitis (n = 15) were higher than those of the patients (n = 13) without allergic rhinitis (p = 0.021).ConclusionThe study underscores the relationship between childhood asthma and OPN as the first study in the literature. In this study we found that OPN, which plays a role in Th2 mediated inflammation, may also play a role in childhood asthma. The fact that OPN levels do not increase in preschool-age children with asthma might be due to the transient wheezing in this group.     

Associations of IGF-1 gene variants and milk protein intake with IGF-I concentrations in infants at age 6 months — Results from a randomized clinical trial

ObjectiveThe interplay of genetic and nutritional regulation of the insulin-like growth factor-I axis in children is unclear. Therefore, potential gene–nutrient effects on serum levels of the IGF-I axis in a formula feeding trial were studied.DesignEuropean multicenter randomized clinical trial of 1090 term, formula-fed infants assigned to receive cow's milk-based infant and follow-on formulae with lower (LP: 1.25 and 1.6 g/100 mL) or higher (HP: 2.05 and 3.2 g/100 mL) protein contents for the first 12 months of life; a comparison group of 588 breastfed infants (BF) was included. Eight single nucleotide polymorphisms (SNPs) of the IGF-1-(rs6214, rs1520220, rs978458, rs7136446, rs10735380, rs2195239, rs35767, and rs35766) and two of the IGFBP-3-(rs1496495, rs6670) gene were analyzed. Serum levels of total and free IGF-I, IGFBP-3 and the molar ratio IGF-1/IGFBP-3 at age 6 months were regressed on determined SNPs and feeding groups in 501 infants.ResultsIGF-1-SNPs rs1520220, rs978458, and rs2195239 significantly increased total-IGF-I and molar-ratio IGF-I/IGFBP-3 by ~ 1.3 ng/mL and ~ 1.3 per allele, respectively; compared to LP infants concentration and molar-ratio were increased in HP by ~ 1.3 ng/mL and ~ 1.3 and decreased in BF infants by ~ 0.6 ng/mL and ~ 0.6, respectively. IGFBP-3 was only affected by the BF group with ~ 450 ng/mL lower levels than the LP group. No gene-feeding-group interaction was detected for any SNP, even without correction for multiple testing.ConclusionsVariants of the IGF-1-gene play an important role in regulating serum levels of the IGF-I axis but there is no gene-protein-interaction. The predominant nutritional regulation of IGF-I and IGFBP-3 gives further evidence that higher protein intake contributes to metabolic programming of growth.     

Interstitial fluid contains higher in vitro IGF bioactivity than serum: A study utilizing the suction blister technique

ContextCirculating insulin-like growth factors (IGFs) are bound in complexes which affect their tissue-accessibility. Interstitial fluid is in close proximity to target cells, but the IGF-system is not well-described herein.ObjectiveTo perform a thorough comparison of the IGF-system in suction blister fluid (SBF) vs. in serum, with emphasis on bioactive IGF levels.DesignEight hour study including samples collected in the fasting state (20 h) and after a meal.SettingClinical research facility.ParticipantsSix healthy males (age 37.0 ± 8.8 years, BMI 22.5 ± 1.4 kg/m²) (mean ± SD).Main outcome measureSerum and SBF concentrations of bioactive IGF (determined in vitro by specific IGF-I receptor (IGF-IR) phosphorylation assay), immunoreactive IGF and IGF binding protein (IGFBP) levels, Western ligand blotting (WLB) of IGFBPs and IGFBP-3 Western immunoblotting (WiB).ResultsThe ability of SBF to phosphorylate the IGF-IR in vitro was 41 ± 27% higher than that of serum (P = 0.007 by repeated measures ANOVA). By contrast, immunoreactive IGF and IGFBP-concentrations were approximately 50% lower in SBF than in serum (all P ≤ 0.002). A marked difference in the composition of IGFBPs between serum and SBF was observed, including 3-fold elevated amounts of IGFBP-3 fragments in SBF (P < 0.001). For both IGF-I, IGF-II and IGFBP-2, the effect of food intake differed between serum and SBF (all P ≤ 0.03).ConclusionDespite lower concentrations, the in vitro IGF bioactivity was higher in SBF than in serum. This may relate to an increased enzymatic IGFBP-degradation and an altered IGFBP-composition in SBF, making more IGF-I and -II accessible to the IGF-IR. The impact of food intake on the IGF system differs between serum and interstitial fluid.     

A comparative study of insulin resistance for Saudi and Caucasian subjects across a range of glycaemic categories

AimSaudi and Caucasian subjects, matched for adiposity, and of differing glycaemic status were compared using several insulin sensitivity indices and to also to assess insulin, glucose and insulin-like growth factor binding protein-1 (IGFBP-1) responses to intravenous glucose.MethodsSubjects with normal glucose tolerance (NGT; n = 24), impaired fasting glucose (IFG; n = 12), impaired glucose tolerance (IGT; n = 12), and type 2 diabetes (DM; n = 13) were recruited from Saudi (n = 33) and Caucasian (n = 28) populations. All had specimens taken in the context of a standard oral glucose tolerance test at their first visit and had the insulin sensitivity parameter (Si) determined by frequently-sampled intravenous glucose tolerance test (FSIVGTT) at a second visit.ResultsSaudis in the NGT and pooled glucose intolerance categories had significantly higher diastolic blood pressure (p < 0.001, p < 0.05 respectively) and HbA1c (p < 0.01, p < 0.05 respectively) compared to Caucasians. Caucasians in the NGT category had significantly higher Si, fasting and 2 h IGFBP-1 (p < 0.01, p < 0.05 and p < 0.01 respectively) compared to Saudis. Two hours following oral or intravenous glucose serum IGFBP-1 decreased to 44% (p < 0.001) and 50% (p < 0.05) of baseline levels respectively.ConclusionsOur data suggest that adult Saudis with normal glucose tolerance appear to be more insulin resistant than Caucasians matched for adiposity. In normal individuals at 2 h the IGFBP-1 level will be about half the baseline level regardless of the route of glucose administration.     

QTLs influencing IGF-1 levels in a LOU/CxFischer 344 F2 rat population. Tracks towards the metabolic theory of Ageing

ObjectiveSince a reduction of the insulin/IGF-1 signaling cascade extends life span in many species and IGF-1 signaling might partly mediate the effects of caloric restriction (CR), an experimental intervention for increasing longevity, the purpose of the present study was to use quantitative trait loci (QTL) analysis, an unbiased genetic approach, to identify particular regions of the genome influencing plasma IGF-1 levels in an F2 intercross between F344 and LOU/C rats; the latter being an inbred strain of Wistar origin, considered as a model of healthy aging since it resists to age (and diet)-induced obesity.DesignF1 hybrids were obtained by crossbreeding LOU/C with F344 rats, and then F1 were bred inter se to obtain the F2 population, of which 93 males and 94 females were studied. Total plasma IGF-1 levels were determined by radioimmunoassay. A genome scan of the F2 population was made with 100 microsatellite markers) selected for their polymorphism between LOU/C and F344 strains (and by covering evenly the whole genome.ResultsBy simple interval mapping sex-dependent QTLs were found on chromosome 17 in males and on chromosome 18 in females. By multiple interval mapping, additional QTLs were found on chromosomes 1, 4, 5, 6, 12, 15 and 19 in males and on chromosomes 3, 5, 6, 12 and 17 in females. Only the markers D1Rat196 and D12Mgh5 were found in both males and females. The majority of QTLs corresponded to metabolic syndrome (cardiac function: n = 45 (30%), obesity/diabetes: n = 22 (15%), inflammation: n = 19 (13%) and only a limited number to body weight: n = 13 (9%), proliferation (n = 10 (7%) or ossification: n = 7 (5%). Ninety-six candidate genes were located on the different QTLs. A significant proportion of these genes are connected to IGF-1 production and receptor pathways (n = 18) or metabolic syndrome (n = 11).ConclusionsSubsequent studies are necessary to determine whether the genetic networks underscored are also involved in age-associated obesity, diabetes and inflammation as well as cardiovascular impairments.     

Plasma profiling by a protein array approach identifies IGFBP-1 as a novel biomarker of abdominal aortic aneurysm

ObjectiveCytokines are important mediators of immune-inflammatory responses implicated in abdominal aortic aneurysm (AAA) pathogenesis. Our objective was to investigate the cytokine expression profile in plasma of AAA patients.MethodsCytokine protein expression was measured in plasma of 5 large AAA patients (aortic size >50 mm) and 5 controls (aortic size <30 mm) using a 20-cytokine antibody-based protein array. IGFBP-1 plasma concentrations were analyzed by ELISA. IGFBP-1 protein levels were analyzed in AAA thrombus by immunohistochemistry and Western blot. Platelet aggregation was assessed by conventional optical aggregometry.ResultsSeveral proteins including MIP-3alpha (CCL20), Eotaxin-2 and IGFBP-1 were increased in AAA patients compared to controls. Among them, IGFBP-1 concentrations were significantly higher in large AAA patients vs control subjects. These data were validated in plasma of patients with large AAA (n = 30) compared to matched controls (n = 30) [834(469–1628) vs 497(204–893) pg/ml, p < 0.01]. Furthermore, the potential association of IGFBP-1 with AAA size was analyzed in a second independent group of subjects [large AAA (n = 59), small AAA patients (aortic size = 30–50 mm, n = 54) and controls (n = 30)]. Interestingly, IGFBP-1 levels correlated with AAA size (r = 0.4, p < 0.001), which remained significant after adjusting for traditional risk factors. IGFBP-1 was localized in the luminal part of AAA thrombus and IGFBP-1 levels were increased in AAA thrombus conditioned media compared to media layer and healthy media. Interestingly, IGFBP-1 abrogated the potentiation of ADP-induced platelet aggregation triggered by IGF-1.ConclusionsIGFBP-1 has been identified by a protein array approach as a potential novel biomarker of AAA. The biological role of IGFBP-1 in AAA pathogenesis could be related to the modulation on the effect of IGF-1 on platelet aggregation.     

Relación entre la expresión de IL-2 e IL-4 y sus polimorfismos y los riesgos de padecer infección por Mycoplasma pneumoniae y asma en niños

IntroductionAsthma is an inflammatory disorder of the airways and the symptoms of asthma could be exacerbated by Mycoplasma pneumoniae infection. Interleukin-2 and interleukin-4 have been implicated in immune and inflammatory reactions. We examined the associations of IL2 and IL4 polymorphisms and expression with the risks of asthma and M. pneumoniae infection in children.Methods392 asthmatic children and 849 controls were recruited into the study. Eight polymorphisms in IL2 and IL4 were genotyped with Sequenom MassARRAY platform. M. pneumoniae infection and copy number was determined with fluorescence PCR. IL-2 and IL-4 serum expression levels were determined by using ELISA.ResultsWe found a significant association of IL2 rs6534349 polymorphism with increased asthma risk (heterozygotes, P = .029; homozygous variants; P = .013) and of IL4 rs2227284 polymorphism with reduced asthma risk (heterozygotes, P = .026; homozygous variants; P = .001). Besides, the association of other polymorphisms, except rs2070874 polymorphism, became apparent when the asthmatic children were grouped according to GINA classification of asthma control and severity. In addition, IL-2 and IL-4 serum expression levels were significantly higher in M. pneumoniae negative (P = .038) and positive (P = .011) subjects respectively. This observation holds true among asthmatic patients (P = .016 for IL-2 and P = .042 for IL-4), but only the IL-4 observation remained correct among non-asthmatic controls (P = .032). We also observed that the rs6534349 GG genotype was significantly associated with increased odds of getting high load M. pneumoniae infection (P = .0376).ConclusionsIL2 and IL4 could be important biomarkers for estimating the risks of asthma and M. pneumoniae infection in children.     

Associations between a fetal imprinted gene allele score and late pregnancy maternal glucose concentrations

AimWe hypothesised that some of the genetic risk for gestational diabetes (GDM) is due to the fetal genome affecting maternal glucose concentrations. Previously, we found associations between fetal IGF2 gene variants and maternal glucose concentrations in late pregnancy.MethodsIn the present study, we tested associations between SNP alleles from 15 fetal imprinted genes and maternal glucose concentrations in late pregnancy in the Cambridge Baby Growth and Wellbeing cohorts (1160 DNA trios).ResultsFour fetal SNP alleles with the strongest univariate associations: paternally-transmitted IGF2 rs10770125 (P-value = 2 × 10^–4) and INS rs2585 (P-value = 7 × 10^–4), and maternally-transmitted KCNQ1(OT1) rs231841 (P-value = 1 × 10^–3) and KCNQ1(OT1) rs7929804 (P-value = 4 × 10^–3), were used to construct a composite fetal imprinted gene allele score which was associated with maternal glucose concentrations (P-value = 4.3 × 10^–6, n = 981, r² = 2.0%) and GDM prevalence (odds ratio per allele 1.44 (1.15, 1.80), P-value = 1 × 10^–3, n = 89 cases and 899 controls). Meta-analysis of the associations including data from 1367 Hyperglycaemia and Adverse Pregnancy Outcome Study participants confirmed the paternally-transmitted fetal IGF2/INS SNP associations (rs10770125, P-value = 3.2 × 10^–8, rs2585, P-value = 3.6 × 10^–5) and the composite fetal imprinted gene allele score association (P-value = 1.3 × 10^–8), but not the maternally-transmitted fetal KCNQ1(OT1) associations (rs231841, P-value = 0.4; rs7929804, P-value = 0.2).ConclusionThis study suggests that polymorphic variation in fetal imprinted genes, particularly in the IGF2/INS region, contribute a small but significant part to the risk of raised late pregnancy maternal glucose concentrations.     

Effect of milk proteins on linear growth and IGF variables in overweight adolescents

ObjectiveMilk may stimulate growth acting via insulin-like growth factor-I (IGF-I) secretion but the effect in adolescents is less examined. This study investigates the effect of milk proteins on linear growth, IGF-I, IGF binding protein-3 (IGFBP-3) and IGF-I/IGFBP-3 ratio in overweight adolescents.DesignThe trial included 193 overweight adolescents aged 12–15 years. They were randomized to drink 1 L/day of: skimmed milk, whey, casein or water for 12 weeks; all milk-based drinks contained 35 g protein/L. A subgroup of 32 adolescents was examined 12 weeks before they were randomized into the groups and started the intervention (pre-test control group). Examinations included anthropometry, diet registration and blood samples which were analyzed for IGF-I and IGFBP-3 by chemiluminescence methods. The effects of milk-based drinks on linear growth, IGF-I, IGFBP-3 and IGF-I availability, calculated as the IGF-I/IGFBP-3 ratio, were compared with baseline, the pre-test control group and water.ResultsIGF-I increased with skimmed milk (P = 0.015) and tended to increase with casein (P = 0.075) compared to the pre-test control group. IGFBP-3 but not IGF-I increased with skimmed milk (P = 0.006) and casein (P = 0.001) compared to water. There was no difference in height or height Z-score for any of the milk-based test drink groups compared to water or compared to the pre-test control group. However, height Z-score decreased within the whey group.ConclusionsSkimmed milk and casein may have a stimulating effect on the IGF-I system whereas there was no positive effect on height in overweight adolescents during this 12 week intervention.     

Interleukin-33 in children with asthma: A systematic review and meta-analysis

BackgroundPrevious studies have shown that serum interleukin 33 serving as an “alarmin” is increased in children with asthma. The objective of this study was to assess the validity of serum IL33 test for early diagnosis of childhood asthma.MethodsA literature search was performed in June 2016 using PubMed, Embase, the Cochrane Library and other Chinese Medical Databases to identify studies. The search terms used were “cytokine”, “interleukin-33“, “asthma” and “children”. The meta-analysis was performed using Review Manager 5.3 software. Random-effects model was used to estimate the standardized mean differences (SMDs) with 95% confidence intervals (CIs).ResultsA total of eight studies were included into this meta-analysis, involving 330 asthmatic children and 248 healthy children. The meta-analysis results revealed that the serum IL33 level was higher in asthmatic children compared to that in healthy children (SMD = 1.29, 95%CI = 0.53–2.05, P = 0.0009), with significant heterogeneity across studies (I² = 94% and P < 0.00001).ConclusionsThe meta-analysis showed that serum IL33 is a helpful biomarker for early diagnosis of childhood asthma. However, owing to lack of enough data, the increased serum concentration of IL33 cannot be an indicator for the asthma severity.     

Relationship between exhaled leukotriene and 8-isoprostane levels and asthma severity,asthma control level,and asthma control test score

ObjectiveExhaled breath condensate (EBC) is a completely non-invasive method for the collection of airway secretions to measure intense inflammation in the airways of asthmatics. It has been shown that the childhood asthma control test (c-ACT) is a good tool for use in the evaluation of asthmatics. Whether the c-ACT score and asthma control level correlate with the airway inflammation is not well known. We aimed to evaluate the relationship between exhaled cysteinyl leukotrienes (Cys-LTs) and 8-isoprostane levels and asthma severity, asthma control level and c-ACT score in asthmatic children.MethodsThirty asthmatic children were evaluated with c-ACT score and pulmonary function tests. Asthma severity and asthma control level were assessed according to GINA. EBC was collected and Cys-LTs and 8-isoprostane concentrations were determined using a specific immunoassay kit.ResultsExhaled 8-isoprostane level in patients with moderate persistent asthma [114 (55–146) pg/ml] was higher than in the mild persistent group [52 (21–91) pg/ml] (p = 0.05, Mann–Whitney U [MWU]). EBC 8-isoprostane in children with 1–4 asthma exacerbations/year [52 (16–80) pg/ml] was significantly lower than in children with >4 asthma exacerbations/year [114 (57–129) pg/ml] (p < 0.05, MWU). No significant relation was determined between exhaled 8-isoprostane and Cys-LTs levels and c-ACT score and asthma control level. Exhaled 8-isoprostane correlated negatively with bronchodilator response (p = 0.015, r = −0.45).ConclusionsExhaled 8-isoprostane, as an oxidative stress specifier, was found to be increased in relation with asthma exacerbation frequency and oxidative stress increases with the severity of asthma. In contrast to asthma severity level, c-ACT score and asthma control level may not reflect airway inflammation.     

Leptin and resistin in overweight patients with and without asthma

BackgroundExcess body mass increases the risk of development of asthmatic symptoms and their severity and decreases the treatment effectiveness. One of the hypotheses explaining the link between the two diseases concerns the adipokines, hormones produced by adipose tissue with a proinflammatory character. The aim of this study was to compare the levels of the adipokines (leptin and resistin) between overweight asthmatic patients, asthmatic patients with normal weight and overweight patients without asthma.Methods80 peripheral blood samples were collected from patients and blood serum extracted. Three groups were selected: overweight asthmatic patients (BMI ≥ 25), overweight patients without asthma and asthmatic patients with normal weight (BMI < 25). Waist circumference of the patients was measured (cut-off points were 80 cm for women and over 94 cm for men) and a skin prick test performed. Comparison of adipokine concentration between the 3 groups was made and association between these concentrations and the measurements was performed.ResultsAlthough the concentrations of both adipokines were slightly higher for overweight asthmatic patients compared to overweight healthy patients, these differences were not significant. A significant association was found between leptin concentration and both BMI (p < 0.01) and waist circumference (p < 0.01). A difference for this cytokine was also found between asthmatic and non-asthmatic female patients (p < 0.05).ConclusionsAs expected overweight patients with BMI ≥ 25 and patients with increased waist circumference showed higher leptin levels. We suggest that the studied cytokines, with a stronger indication for leptin, can elicit asthmatic inflammation in obese phenotype of asthma that affects more frequently women.