Associations between anthropometric indicators in early life and low-grade inflammation, insulin resistance and lipid profile in adolescence.

BACKGROUND AND AIMS: The long-term relations between excessive adiposity in early childhood and unfavourable cardiometabolic profiles in later ages are not yet completely understood. We aimed to assess the associations between birth weight (BW) and BMI from 6 months to 6 years of age, with biomarkers indicative of low-grade inflammation, insulin resistance and lipid profiles in adolescence. METHODS AND RESULTS: Retrospective school-based study with 415 Portuguese adolescents (220 girls), mean age of 14.08 ± 1.6 years old. Anthropometric data from birth to 6 years old was extracted from individual child health book records. Actual weight and height were measured and BMI calculated. Participants were classified at each time point as normal weight or overweight according to WHO reference values. Biomarkers were obtained from venous blood samples. Linear regressions were used to explore the associations between the biomarkers and early life anthropometric indicators. From 2 years onwards, BMI associated positively with the inflammatory score and HOMA-IR in adolescence. Children who were overweight/obese from 2 to 6 years of age presented significantly higher inflammatory score and HOMA-IR later in adolescence. TC/HDL ratio was also positively associated with BMI from the age of 5 years onwards. The associations between BMI and cardiometabolic outcomes remained positive in adolescence, with overweight adolescents presenting a higher inflammatory score, HOMA-IR and TC/HDL than normal weight adolescents. CONCLUSION: A high BMI from an early age was consistently associated with worse inflammatory and lipid profiles and insulin resistance in adolescence. No associations were found between BW and the same studied outcomes.

Longitudinal association between ideal cardiovascular health status and muscular fitness in adolescents: The LabMed Physical Activity Study.

BACKGROUND AND AIMS: Muscular fitness is an emerging predictor for cardiovascular disease mortality. The ideal cardiovascular health metrics has been inversely related to a subsequent cardiometabolic health in adulthood. However, evidence regarding muscular fitness and ideal cardiovascular health in adolescents is scarce. This study aimed to examine the longitudinal association between ideal cardiovascular health index and muscular fitness. METHODS AND RESULTS: This study cohort consisted of 331 adolescents (183 girls) from the LabMed Physical Activity Study who were followed from 2011 to 2013. Ideal cardiovascular health, as defined by the American Heart Association, was determined as meeting ideal health factors (total cholesterol, blood pressure, and glucose) and behaviors (smoking status, body mass index, physical activity, and diet). Handgrip strength and standing long jump tests assessed muscular fitness and were transformed into standardized values according to age and sex. ANCOVA showed a significant association between the accumulation of ideal cardiovascular health metrics at baseline and muscular fitness indices at follow-up (F(4, 322) = 2.280, p = 0.04). In addition, the higher the number of ideal cardiovascular health metrics accumulated, the higher the likelihood of having a high muscular fitness over a two-year period (p for trend = 0.01), after adjustments for age, sex, pubertal stage and socioeconomic status and muscular fitness at baseline. CONCLUSION: The ideal cardiovascular health status during adolescence was associated with high muscular fitness levels over a two-year period.

Muscular fitness and metabolic and inflammatory biomarkers in adolescents: Results from LabMed Physical Activity Study.

This study aimed to evaluate the associations between muscular fitness and inflammatory biomarkers and to investigate the relationship between muscular fitness and selected clustered inflammatory biomarkers in adolescents. This is a cross-sectional analysis with 529 adolescents (267 girls) aged 12-18 years. Handgrip strength and standing long jump tests assessed MF. Continuous scores of clustered inflammatory biomarkers (sum of Z-scores of C-reactive protein [CRP], C3, C4, fibrinogen, and leptin); metabolic risk factor (MRF) score (sum of Z-scores of SBP, triglycerides, ratio total cholesterol [TC]/HDL, HOMA-IR, and waist circumference [WC]) were computed. Regression analyses showed an inverse association between muscular fitness score (ß=-.204; P<.021) and clustered score of inflammatory biomarkers, adjusted for age, sex, pubertal stage, socioeconomic status, adherence to the Mediterranean diet, cardiorespiratory fitness (CRF), MRF score, and body fat. Analysis of covariance showed that adolescents with an adverse inflammatory profile with low levels of muscular fitness exhibit the poorest MRF score (F3,525 =6.461; P<.001), adjusted for age, sex, pubertal stage, socioeconomic status, adherence to the Mediterranean diet, CRF, and body fatness. The inflammatory state seems to explain a significant part of the highest MRF score and in adolescents with high inflammatory status and low muscular strength.

Association between serum adiponectin levels and muscular fitness in Portuguese adolescents: LabMed Physical Activity Study.

BACKGROUND AND AIM: Paradoxically, recent investigations have showed that adiponectin levels are inversely associated with muscle strength. However, to date, there is a lack of knowledge on the relationship between muscular fitness (MF) and adiponectin levels in adolescents. We aimed to examine the independent associations between MF and adiponectin levels in adolescents, controlling for several potential confounders. METHODS AND RESULTS: This is a cross-sectional analysis with 529 Portuguese adolescents aged 12-18 years. A MF score was computed as the mean of the handgrip strength and standing long jump standardized values by age and gender. We measured fasting glucose, insulin, HDL-cholesterol, C-reactive protein and adiponectin. Linear regression analysis showed a significant inverse association between adiponectin (Z-score by age and sex) and MF score, after adjustments for age, sex, pubertal stage, socioeconomic status, adherence to the Mediterranean diet, body mass index, HOMA-IR, HDL-cholesterol, C-reactive protein and cardiorespiratory fitness (unstandardized ß = -0.176; p < 0.005). Analysis of covariance showed a significant difference between the Low MF/Non-overweight group and the High MF/Non-overweight Group (p < 0.05) and between the Low MF/Non-overweight and High MF/Overweight Group (p < 0.05) (F (5, 523) = 2.262, p = 0.047). CONCLUSION: Adiponectin circulating levels are inversely and independently associated with MF. In non-overweight adolescents, those with high levels of MF presented lower levels of adiponectin compared to those with Low MF. Likewise, overweight adolescents with High MF presented lower levels of serum adiponectin than non-overweight adolescents with Low MF.

Binding mode of Pyridoclax to myeloid cell leukemia-1 (Mcl-1) revealed by nuclear magnetic resonance spectroscopy, docking and molecular dynamics approaches.

Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family proteins. Its amplification is one of the most frequent genetic aberrations found in human cancers. Pyridoclax, a promising BH3 mimetic inhibitor, interacts directly with Mcl-1 and induces massive apoptosis at a concentration of 15 µM in combination with anti-Bcl-xL strategies in chemo-resistant ovarian cancer cell lines. In this study, a combined experimental and theoretical approach was used to investigate the binding mode of Pyridoclax to Mcl-1. The representative poses generated from dynamics simulations compared with NMR data revealed: (i) Pyridoclax bound to P1 and P2 pockets of Mcl-1 BH3 binding groove through its styryl and methyl groups establishing mainly hydrophobic contacts, (ii) one of the ending pyridines interacts through electrostatic interaction with K234 side chain, a negatively charged residue present only in this position in Mcl-1. Communicated by Ramaswamy H. Sarma.

S100 protein-annexin interactions: a model of the (Anx2-p11)(2) heterotetramer complex.

The (Anx2)(2)(p11)(2) heterotetramer has been implicated in endo- and exocytosis in vivo and in liposome aggregation in vitro. Here we report on the modelling of the heterotetramer complex using docking algorithms. Two types of models are generated-heterotetramer and heterooctamer. On the basis of the agreement between the calculated (X-ray) electron density and the observed projected density from cryo-electron micrographs on the one hand, and calculated energy criteria on the other hand, the heterotetramer models are proposed as the most probable, and one of them is selected as the best model. Analysis of this model at an atomic level suggests that the interaction between the Anx2 core and p11 has an electrostatic character, being stabilised primarily through charged residues.

Annexin A5 D226K structure and dynamics: identification of a molecular switch for the large-scale conformational change of domain III.

The domain III of annexin 5 undergoes a Ca(2+)- and a pH-dependent conformational transition of large amplitude. Modeling of the transition pathway by computer simulations suggested that the interactions between D226 and T229 in the IIID-IIIE loop on the one hand and the H-bond interactions between W187 and T224 on the other hand, are important in this process [Sopkova et al. (2000) Biochemistry 39, 14065-14074]. In agreement with the modeling, we demonstrate in this work that the D226K mutation behaves as a molecular switch of the pH- and Ca(2+)-mediated conformational transition. In contrast, the hydrogen bonds between W187 and T224 seem marginal.

[XYY male with right aortic arch and ligamentum arteriosum: a fortuitus association?]. / Síndroma 47 XYY com arco aórtico direito e ligamentum arteriosum: uma associação fortuita?

INTRODUCTION: The XYY male has characteristicaly tall stature, behavior problems and speech delay. There may may be an association with nephro-urologic malformations but cardiovascular anomalies are usually not present. CASE REPORT: It is reported a case of a boy with a 47 XYY karyotype with persistent respiratory distress and swallowing difficulties since two months old. On diagnosis workup the fiberoptic bronchoscopy showed a significant pulsatil tracheal obstruction at its right lateral wall and the magnetic resonance imaging of the mediastinum comproved the presence of a vascular ring (right aortic arch with left ligamentum arteriosum). The patient was submitted to surgery with improvment in the respiratory symptoms. DISCUSSION: The XYY male is a sex chromosomal abnormality that usually is not associated with cardiovascular malformations. A vascular ring presents with persistent respiratory distress and feeding difficulties; the begining and severity of the symptoms varies with the type of vascular ring. The main procedure to be requested is the fiberoptic bronchoscopy and the best image study is the magnetic resonance imaging of the mediastinum.

[Neonatal bronchoscopy: a retrospective analysis of 67 cases and a review of their indications]. / Broncoscopia no recém-nascido: análise retrospectiva de 67 casos e revisão das indicações.

The availability of newer, more sophisticated and versatile bronchoscopes has expanded the spectrum and scope of the indications for bronchoscopy in the newborn infant both for diagnostic and therapeutic purposes. The aim of this study was to carry out a retrospective analysis of the bronchoscopies performed on newborn infants, and to review the indications of this procedure in this age group. Sixty-three patients were submitted to 67 bronchoscopies in a period of 13 years, allowing the diagnosis of 45 anomalies and malformations of the tracheo-bronchial tree, and the performance of 24 bronchoalveolar lavages. In six cases, endoscopic removal of secretions helped to resolve resistant atelectasia, while in another case, with esophageal atresia, intra-operative definition of the fistula tract was possible through catheterisation of the fistula with the bronchoscope. The flexible bronchoscope was preferred for diagnosis by direct visualisation, and the rigid bronchoscope for some diagnostic and therapeutic procedures. Stridor, unexplained cyanosis, hemoptysis, persistent or recurrent pulmonary images, difficulties in the intubation or extubation, and persistent disturbances in ventilation are among the main indications for bronchoscopy in the newborn infant. Bronchoscopy also allows the performance of subsidiary techniques, such as bronchoalveolar lavage, biopsy and laser therapy.

7-Nitro-1H-indazole, an inhibitor of nitric oxide synthase.

The crystal structure of 7-nitro-1H-indazole, C(7)H(5)N(3)O(2), an inhibitor of nitric oxide synthase, shows the existence of an intramolecular hydrogen bond between an O atom of the nitro group and the NH group of the indazole ring. The crystal packing consists of intermolecular hydrogen bonding and indazole.indazole interactions.

YC-1, an activation inductor of soluble guanylyl cyclase.

The crystal structure of 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole, C(19)H(16)N(2)O(2), showed that the furan O and indazole N atoms lie on the same face of the molecule. The crystal packing consists of intermolecular hydrogen bonding, and indazole-indazole and indazole-phenyl interactions.

S100-annexin complexes: some insights from structural studies.

Several annexins have been shown to bind proteins that belong to the S100 calcium-binding protein family. The two best-characterized complexes are annexin II with p11 and annexin I with S100C, the former of which has been implicated in membrane fusion processes. We have solved the crystal structures of the complexes of p11 with annexin II N-terminus and of S100C with annexin I N-terminus. Using these structural results, as well as electron microscopy observations of liposome junctions formed in the presence of such complexes (Lambert et al., 1997 J Mol Biol 272, 42-55), we propose a computer generated model for the entire annexin II/p11 complex.

Oxidation of tetrahydro-beta-carboline by cytochrome P-450cam--determination and rationalisation of product distribution.

Cytochrome P-450cam oxidises 1,2,3,4-tetrahydro-beta-carboline, an indolic alkaloid. We report here measurements of the product distribution of this oxidation. To rationalise the experimental results, ab initio quantum-chemistry calculations of the product stabilities and molecular-dynamics calculations of the substrate-binding mode in the active site were performed. The calculations suggest that the product distribution is influenced by both the relative intrinsic gas-phase stabilities of the monohydroxy products and by conformational rearrangement of the active site on substrate binding.

Pathway for large-scale conformational change in annexin V.

Crystallographic studies have shown that the binding of calcium to domain III of annexin V is accompanied by a large conformational change involving surface exposure of Trp187. Here we examine this conformational transition using computer simulation. It is found that the burial of Trp187 is accompanied by a large increase in conformational strain, compensated by improved protein-protein interaction energies. A low energy pathway for the conformational change is determined using the conjugate peak refinement method [Fischer, S., and Karplus, M. (1992) Chem. Phys. Lett. 194, 252-261] with solvent effects taken into account using nonuniform charge scaling. The pathway obtained is complex, involving >300 dihedral angle transitions and the complete unwinding of one helix. Acidic residues play a key role in the conformational pathway, via a succession of direct hydrogen bonds with the indole ring of Trp187. This finding is discussed in the light of experimentally determined pH, calcium ion and mutational effects on the conformational transition.

Association of two 3D QSAR analyses. application to the study of partial agonist serotonin-3 ligands.

CATALYST and COMFA, two software packages for 3D QSAR studies, were associated to correlate the three-dimensional structures of 75 serotonin 5-HT3 ligands to their biological affinities. The conformational analysis and the influence of chemical function-based alignments (the basis of this association) on final results are discussed in this publication. These two analyses allow for precisely quantitating the weights of significant chemical groups or functions on the biological affinities.