Extrauterine growth and adipocytokines in appropriate-for-gestational-age preterm infants.

BACKGROUND: Extra-uterine growth retardation in preterm infants is associated with an increased risk for cardiometabolic diseases later in life. Adipocytokines are also associated with the development of cardiometabolic diseases. We examined the relationship between extra-uterine growth and serum concentrations of adipocytokines and metabolic hormones in preterm infants. METHODS: Serum concentrations of leptin, adiponectin, insulin, IL-6, TNF-α, C-peptide, GIP, GLP-1 and glucagon were measured in 38 appropriate-for-gestational-age preterm infants at birth, and at 33 and 38 weeks of postmenstrual age using a Bio-Plex 200TM suspension array system. RESULTS: Serum concentrations of leptin were not correlated with body weight at any time point. However, serum concentrations of adiponectin were correlated with body weight at all time points. Serum concentrations of IL-6 were decreased from birth to 33 and 38 weeks. Serum concentrations of TNF-α were not changed. Serum concentrations of C-peptide, GIP and glucagon increased from birth to 33 weeks, and decreased from 33 to 38 weeks. Serum concentrations of insulin and GLP-1 were not changed. CONCLUSION: Changes in serum concentrations of leptin and adiponectin showed unique profiles, thereby suggesting maldevelopment of white adipose tissue. This may affect the future development of adipose tissue and lead to increased risk for cardio-metabolic disorders. This article is protected by copyright. All rights reserved.

Dynamics of a deformable active particle under shear flow.

The motion of a deformable active particle in linear shear flow is explored theoretically. Based on symmetry considerations, we propose coupled nonlinear dynamical equations for the particle position, velocity, deformation, and rotation. In our model, both, passive rotations induced by the shear flow as well as active spinning motions, are taken into account. Our equations reduce to known models in the two limits of vanishing shear flow and vanishing particle deformability. For varied shear rate and particle propulsion speed, we solve the equations numerically in two spatial dimensions and obtain a manifold of different dynamical modes including active straight motion, periodic motions, motions on undulated cycloids, winding motions, as well as quasi-periodic and chaotic motions induced at high shear rates. The types of motion are distinguished by different characteristics in the real-space trajectories and in the dynamical behavior of the particle orientation and its deformation. Our predictions can be verified in experiments on self-propelled droplets exposed to a linear shear flow.

Physical biomarkers for human hematopoietic stem and progenitor cells.

Adhesion of hematopoietic stem and progenitor cells (HSPCs) to the bone marrow niche plays critical roles in the maintenance of the most primitive HSPCs. The interactions of HSPC-niche interactions are clinically relevant in acute myeloid leukemia (AML), because (i) leukemia-initiating cells adhered to the marrow niche are protected from the cytotoxic effect by chemotherapy and (ii) mobilization of HSPCs from healthy donors' bone marrow is crucial for the effective stem cell transplantation. However, although many clinical agents have been developed for the HSPC mobilization, the effects caused by the extrinsic molecular cues were traditionally evaluated based on phenomenological observations. This review highlights the recent interdisciplinary challenges of hematologists, biophysicists and cell biologists towards the design of defined in vitro niche models and the development of physical biomarkers for quantitative indexing of differential effects of clinical agents on human HSPCs.

Maxwell stress in fluid mixtures.

We examine the structure of Maxwell stress in binary fluid mixtures under an external electric field and discuss its consequence. In particular, we show that, in immiscible blends, it is intimately related to the statistics of domain structure. This leads to a compact formula, which may be useful in the investigation of electrorheological effects in such systems. The stress tensor calculated in a phase separated fluid under a steady electric field is in a good agreement with recent experiments.

Effect of body mass index-z score on adverse levels of cardiovascular disease risk factors.

BACKGROUND: Cardiovascular disease (CVD) risk factors are associated with body mass index z-score (BMISD) and/or insulin resistance (IR). However, the correlation between adverse levels of these risk factors and BMISD, and the effect of IR on these associations are not fully understood in children. The aim of this study was to evaluate the association between adverse levels of CVD risk factors and BMISD, and the effect of IR on these associations in schoolchildren. METHODS: Conventional CVD risk factors, C-reactive protein (CRP), uric acid (UA) and adiponectin were determined in 757 boys and 494 girls aged between 7 and 12 years. IR was assessed by the homeostasis model approximation index. RESULTS: BMISD were linearly associated with relative risks having adverse levels of all factors, except for glucose and low-density lipoprotein cholesterol (LDL-C) in boys, and except for glucose, LDL-C and adiponectin in girls (P < 0.01-0.001). These associations were weakened after adjustment for IR, but still significant in cases of UA and CRP in boys and UA, high-density lipoprotein cholesterol and CRP in girls (P < 0.01-0.001). CONCLUSION: The relative risk of having adverse levels of most CVD risk factors in school children increased across the entire range of BMISD. IR contributed to most of these relative risks, but BMISD itself also contributed to these relative risks. To prevent future development of CVD, it might be important for schoolchildren to maintain BMISD within normal range. However, in cases of hyper LDL-cholesterolemia, we should consider causes other than BMISD.

Early weight changes after birth and serum high-molecular-weight adiponectin level in preterm infants.

BACKGROUND: Extra-uterine growth retardation (EUGR) is associated with an increased risk for cardiometabolic diseases later in life. The aim of the present study was to examine the relationship between early weight change after birth in preterm infants and adiponectin (adn) multimeric complexes. METHODS: Subjects included 28 preterm infants born between weeks 24 and 33 of gestation. Serum adn multimeric complexes and the anthropometric parameters were measured in preterm infants at birth and at corrected term. RESULTS: Bodyweight (BW) decreased during the first week of life, with birthweight restored at approximately 19 days after birth. Nineteen of the subjects had EUGR at corrected term. Total (T)-adn, high-molecular-weight (H)-adn, and the ratio of H-adn to T-adn (H/T-adn) were significantly elevated at corrected term than at birth. Postmenstrual age, birthweight, birth length and lowest BW after birth were positively correlated with H-adn and H/T-adn. Weight reduction after birth was negatively correlated with H-adn. Age to restore birthweight was negatively correlated with T-adn, H-adn and H/T-adn. Stepwise multiple regression analysis indicated age to restore birthweight as the major predictor of T-adn and H-adn. DISCUSSION: Early weight changes after birth may alter serum adn level in preterm infants at corrected term. The appropriate nutritional support in the early postnatal period could reduce the prevalence of EUGR and the future risk for cardiometabolic diseases.

IL-17A produced by gammadelta T cells plays a critical role in innate immunity against listeria monocytogenes infection in the liver.

IL-17A is originally identified as a proinflammatory cytokine that induces neutrophils. Although IL-17A production by CD4(+) Th17 T cells is well documented, it is not clear whether IL-17A is produced and participates in the innate immune response against infections. In the present report, we demonstrate that IL-17A is expressed in the liver of mice infected with Listeria monocytogenes from an early stage of infection. IL-17A is important in protective immunity at an early stage of listerial infection in the liver because IL-17A-deficient mice showed aggravation of the protective response. The major IL-17A-producing cells at the early stage were TCR gammadelta T cells expressing TCR Vgamma4 or Vgamma6. Interestingly, TCR gammadelta T cells expressing both IFN-gamma and IL-17A were hardly detected, indicating that the IL-17A-producing TCR gammadelta T cells are distinct from IFN-gamma-producing gammadelta T cells, similar to the distinction between Th17 and Th1 in CD4(+) T cells. All the results suggest that IL-17A is a newly discovered effector molecule produced by TCR gammadelta T cells, which is important in innate immunity in the liver.

Linear viscoelasticity of a single semiflexible polymer with internal friction.

The linear viscoelastic behaviors of single semiflexible chains with internal friction are studied based on the wormlike-chain model. It is shown that the frequency dependence of the complex compliance in the high frequency limit is the same as that of the Voigt model. This asymptotic behavior appears also for the Rouse model with internal friction. We derive the characteristic times for both the high frequency limit and the low frequency limit and compare the results with those obtained by Khatri et al.

Deformable self-propelled particles with a global coupling.

We have proposed a model of deformable self-propelled particles in which the time-evolution equations are given in terms of the center-of-mass velocity and a nematic order parameter representing the motion-induced deformation [T. Ohta and T. Ohkuma, Phys. Rev. Lett. 102, 154101 (2009)]. We investigate its many-body problem applying a global orientational coupling. Depending on the strength of the interaction, the self-propelled particles exhibit various kinds of collective dynamics and chaotic behavior: a ballistic procession state, a scattered state, a coherently phase synchronized state, two types of in-phase synchronized state, and an anomalously diffusive state. The phase reduction method for the weak coupling regime reveals the bifurcations between the secular collective motions. The phase boundary among the chaos regime and the synchronized regimes is determined by the linear stability analysis of the synchronized states.

The ratio of high-molecular weight adiponectin and total adiponectin differs in preterm and term infants.

Adiponectin consists of three subspecies (high-, middle- and low-molecular weight adiponectin). Among these, high-molecular weight adiponectin (H-adn) is suggested to be an active form of this protein. To assess the relationship between H-adn and postnatal growth in preterm infants (PIs), serum H-adn and total adiponectin (T-adn) were measured in 46 PIs at birth and at corrected term, and 26 term infants (TI) at birth. T-adn and H-adn concentrations, and the ratio of H-adn to T-adn (H/T-adn) were significantly greater in TI and PI at corrected term than in PI at birth (p < 0.001). T-adn and H-adn concentrations in PI at corrected term were similar to those in TI, but H/T-adn in PI at corrected term was less than that in TI (p < 0.02). Stepwise multiple regression analysis revealed that the factors contributing to H/T-adn and serum concentrations of T- and H-adn in PI at corrected term were different from those in TI. These data suggest that quality of early postnatal growth in PIs is different from that in normally developed TI. Postnatal growth accompanying adipose tissue similar to TI may be important for PI to prevent future development of cardiovascular disease.

Importance of murine Vdelta1gammadelta T cells expressing interferon-gamma and interleukin-17A in innate protection against Listeria monocytogenes infection.

Murine gammadelta T cells participate in the innate immune response against infection by an intracellular pathogen Listeria monocytogenes. Vdelta1+gammadelta T cells coexpressing Vgamma6 are a major gammadelta T-cell subpopulation induced at an early stage of L. monocytogenes infection in the livers of infected mice. To investigate the protective role of the Vgamma6/Vdelta1+gammadelta T cells against L. monocytogenes infection, Vdelta1 gene-deficient (Vdelta1-/-) mice were analysed because these mice selectively lacked a Vgamma6/Vdelta1+gammadelta T-cell subpopulation in the L. monocytogenes-infected liver. The Vdelta1-/- mice showed increased bacterial burden in the liver and spleen, and decreased survival rate at an early stage of L. monocytogenes infection when compared to wild-type mice. Histological examination showed abscess-like lesions and unorganized distribution of macrophages in the liver of the Vdelta1-/- mice but not in the wild-type mice after L. monocytogenes infection. The Vgamma6/Vdelta1+gammadelta T cells produced interferon-gamma and interleukin-17A. All the results suggest that murine Vgamma6/Vdelta1+gammadelta T cells control the innate protective response against L. monocytogenes infection through production of the proinflammatory cytokines interferon-gamma and interleukin-17A in the infected liver.

Anti-adult T-cell leukemia effects of brown algae fucoxanthin and its deacetylated product, fucoxanthinol.

Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by human T-cell leukemia virus type 1 (HTLV-1) infection and remains incurable. Carotenoids are a family of natural pigments and have several biological functions. Among carotenoids, fucoxanthin is known to have antitumorigenic activity, but the precise mechanism of action is not elucidated. We evaluated the anti-ATL effects of fucoxanthin and its metabolite, fucoxanthinol. Both carotenoids inhibited cell viability of HTLV-1-infected T-cell lines and ATL cells, and fucoxanthinol was approximately twice more potent than fucoxanthin. In contrast, other carotenoids, beta-carotene and astaxanthin, had mild inhibitory effects on HTLV-1-infected T-cell lines. Importantly, uninfected cell lines and normal peripheral blood mononuclear cells were resistant to fucoxanthin and fucoxanthinol. Both carotenoids induced cell cycle arrest during G(1) phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and inducing the expression of GADD45alpha, and induced apoptosis by reducing the expression of Bcl-2, XIAP, cIAP2 and survivin. The induced apoptosis was associated with activation of caspase-3, -8 and -9. Fucoxanthin and fucoxanthinol also suppressed IkappaBalpha phosphorylation and JunD expression, resulting in inactivation of nuclear factor-kappaB and activator protein-1. Mice with severe combined immunodeficiency harboring tumors induced by inoculation of HTLV-1-infected T cells responded to treatment with fucoxanthinol with suppression of tumor growth, showed extensive tissue distribution of fucoxanthinol, and the presence of therapeutically effective serum concentrations of fucoxanthinol. Our preclinical data suggest that fucoxanthin and fucoxanthinol could be potentially useful therapeutic agents for patients with ATL.

Probing nonequilibrium fluctuations through linear response.

Linear response analysis in the nonequilibrium steady state (Gaussian regime) provides two independent fluctuation-response relations. One, in the form of the symmetric matrix, manifests the departure from the equilibrium formula through the quantity so-called irreversible circulation. The other, in the antisymmetric form, connects the asymmetries in the fluctuation and the response function. These formulas represent characteristic features of fluctuations far from equilibrium, which have no counterparts in thermal equilibrium.

Simple Physical Model Unravels Influences of Chemokine on Shape Deformation and Migration of Human Hematopoietic Stem Cells.

We studied the dynamic behavior of human hematopoietic stem cells (HSC) on the in vitro model of bone marrow surfaces in the absence and presence of chemokine (SDF1α). The deformation and migration of cells were investigated by varying the chemokine concentration and surface density of ligand molecules. Since HSC used in this study were primary cells extracted from the human umbilical cord blood, it is not possible to introduce molecular reporter systems before or during the live cell imaging. To account for the experimental observations, we propose a simple and general theoretical model for cell crawling. In contrast to other theoretical models reported previously, our model focuses on the nonlinear coupling between shape deformation and translational motion and is free from any molecular-level process. Therefore, it is ideally suited for the comparison with our experimental results. We have demonstrated that the results in the absence of SDF1α were well recapitulated by the linear model, while the nonlinear model is necessary to reproduce the elongated migration observed in the presence of SDF1α. The combination of the simple theoretical model and the label-free, live cell observations of human primary cells opens a large potential to numerically identify the differential effects of extrinsic factors such as chemokines, growth factors, and clinical drugs on dynamic phenotypes of primary cells.

Guidance for Pediatric Familial Hypercholesterolemia 2017.

This paper describes consensus statement by Joint Working Group by Japan Pediatric Society and Japan Atherosclerosis Society for Making Guidance of Pediatric Familial Hypercholesterolemia (FH) in order to improve prognosis of FH.FH is a common genetic disease caused by mutations in genes related to low density lipoprotein (LDL) receptor pathway. Because patients with FH have high LDL cholesterol (LDL-C) levels from the birth, atherosclerosis begins and develops during childhood which determines the prognosis. Therefore, in order to reduce their lifetime risk for cardiovascular disease, patients with FH need to be diagnosed as early as possible and appropriate treatment should be started.Diagnosis of pediatric heterozygous FH patients is made by LDL-C ≥140 mg/dL, and family history of FH or premature CAD. When the diagnosis is made, they need to improve their lifestyle including diet and exercise which sometimes are not enough to reduce LDL-C levels. For pediatric FH aged ≥10 years, pharmacotherapy needs to be considered if the LDL-C level is persistently above 180 mg/dL. Statins are the first line drugs starting from the lowest dose and are increased if necessary. The target LDL-C level should ideally be ＜140 mg/dL. Assessment of atherosclerosis is mainly performed by noninvasive methods such as ultrasound.For homozygous FH patients, the diagnosis is made by existence of skin xanthomas or tendon xanthomas from infancy, and untreated LDL-C levels are approximately twice those of heterozygous FH parents. The responsiveness to pharmacotherapy should be ascertained promptly and if the effect of treatment is not enough, LDL apheresis needs to be immediately initiated.

Efficacy and Safety of Pitavastatin in Children and Adolescents with Familial Hypercholesterolemia in Japan and Europe.

AIM: Children with Familial Hypercholesterolemia (FH) are widely prescribed statins, and it has been suggested that the effects of statins differ among ethnicities. We compared the efficacy and safety of pitavastatin in children and adolescents with FH in clinical trials conducted in Japan and Europe. METHODS: Low-density lipoprotein cholesterol (LDL-C) reductions, adjusted for confounding factors, and safety were compared between the studies in Japan and Europe. In the Japanese study, 14 males with heterozygous FH, aged 11.8±1.6 years, were randomized to 52-week double-blind treatment with 1 or 2 mg/day pitavastatin. In the European study, 106 children and adolescents with high risk hyperlipidemia (103 heterozygous FH), aged 10.6±2.9 years, were randomized to 12-week double-blind treatment with 1, 2 or 4 mg/day pitavastatin or placebo; 84 of these patients and 29 new patients participated in a 52-week open-label extension study. RESULTS: Age, body weight and baseline LDL-C were identified as factors influencing LDL-C reduction. There were no significant differences in the adjusted mean percentage reduction in LDL-C in Japanese and European children by pitavastatin (24.5% and 23.6%, respectively at 1 mg/day and 33.5% and 30.8%, respectively at 2 mg/day). Pitavastatin was well tolerated without any difference in the frequency or nature of adverse events between the treatment groups, or between the studies. CONCLUSION: There were no significant differences between the efficacy or safety of pitavastatin in Japanese and European children and adolescents with FH, suggesting no relevant ethnic differences in the safety or efficacy of pitavastatin.

Relationship between lipid abnormalities and insulin resistance in Japanese school children.

OBJECTIVE: Dyslipidemia and insulin resistance (IR) are risk factors for coronary heart disease (CHD) in adults. To help prevent the development of CHD, it may be useful to understand the relationship between lipid abnormalities and IR during childhood. METHODS AND RESULTS: IR was assessed by the homeostasis model approximation index. We studied 1175 Japanese school children (642 boys and 533 girls), aged between 7 and 12 years. Obesity was defined by the body mass index standard deviation score (BMISD) (obese: BMISD > or = 2.0). BMISD was most significantly associated with IR in nonobese children (P=0.000). Associations of IR with lipid-related parameters were affected by BMISD. After being corrected by BMISD, in nonobese children, log triglycerides (TG), apoB and low-density lipoprotein (LDL) size in boys and log TG, LDL size, and high-density lipoprotein (HDL) cholesterol in girls were still significantly associated with IR (P=0.000 to 0.017). In obese children, all parameters except for LDL cholesterol in boys and LDL size in girls were significantly associated with IR (P=0.000 to 0.030). Multiple regression analysis showed that log TG and LDL size in nonobese children, log TG in obese boys and LDL size in obese girls were independently associated with IR. Children with IIb and IV hyperlipidemia had significantly higher IR than those with normolipidemia and IIa, even after correcting for BMISD and age. CONCLUSIONS: Our results suggest that in addition to controlling body weight, it may be important for school children to characterize lipid phenotypes to prevent progression to CHD and/or type 2 diabetes and to identify subjects who are at high risk for these disorders.

External forcing and feedback control of nonlinear dissipative waves.

The dynamics of traveling waves in a nonlinear dissipative system are studied analytically and numerically. Spatiotemporal forcing and feedback forcing are applied to the traveling waves in a phase-separated system undergoing chemical reactions. The stability of the traveling waves and interesting, unexpected behavior, including the reversal of the propagation direction are analyzed in one dimension. The phase dynamical approach is applied to gain a theoretical understanding of the dynamics.

Turing patterns in three dimensions.

We investigate three-dimensional Turing patterns in two-component reaction diffusion systems. The FitzHugh-Nagumo equation, the Brusselator, and the Gray-Scott model are solved numerically in three dimensions. Several interconnected structures of domains as well as lamellar, hexagonal, and spherical domains are obtained as stable motionless equilibrium patterns. The relative stability of these structures is studied analytically based on the reduction approximation. The relation with the microphase-separated structures in block copolymers is also discussed.

Serum C-reactive protein and its relation to cardiovascular risk factors and adipocytokines in Japanese children.

BACKGROUND: C-Reactive protein (CRP) is an independent risk factor for atherosclerotic coronary heart diseases (ACHD) in adults. To help prevent ACHD, it may be useful to understand risk factors during childhood. OBJECTIVE: The objective of this study was to investigate serum CRP and its relation to other risk factors for ACHD and adipocytokines (adiponectin, IL-6, and TNF-alpha) in Japanese children. METHODS: CRP, conventional risk factors for ACHD, and adipocytokines were determined in 568 children (340 boys and 228 girls, aged 7-10 yr). Serum concentrations of adipocytokines were measured by sandwich ELISA. RESULTS: Children with high CRP concentrations (highest tertile) had higher body mass index (BMI) sd scores, insulin, insulin resistance, uric acid, and adipocytokines and had more atherogenic lipoprotein profiles than other children. However, after being corrected by BMI sd, only high-density lipoprotein cholesterol, apolipoprotein A-I, IL-6, and TNF-alpha for boys and high-density lipoprotein cholesterol, apolipoprotein B, uric acid, IL-6, and TNF-alpha for girls were significantly correlated with CRP. IL-6 was the strongest predictive variable for CRP and accounted for 26.2 and 27.7% of the variability in serum concentrations of CRP in boys and girls, respectively. Serum concentrations of IL-6 were partly dependent on BMI sd and TNF-alpha in both boys and girls. CONCLUSION: Although serum concentrations of CRP are partly regulated by adipocytokines and conventional risk factors for ACHD, high CRP levels were associated with atherogenic profiles of cardiovascular risk factors in children. Our findings suggest that it may be important to control body weight to prevent an increase in serum CRP in children.