Numerical assessment on the effective mechanical stimuli for matrix-associated metabolism in chondrocyte-seeded constructs

The self-regeneration capacity of articular cartilage is limited, due to its avascular and aneural nature. Loaded explants and cell cultures demonstrated that chondrocyte metabolism can be regulated via physiologic loading. However, the explicit ranges of mechanical stimuli that correspond to favourable metabolic response associated with extracellular matrix (ECM) synthesis are elusive. Unsystematic protocols lacking this knowledge produce inconsistent results. This study aims to determine the intrinsic ranges of physical stimuli that increase ECM synthesis and simultaneously inhibit nitric oxide (NO) production in chondrocyte-agarose constructs, by numerically re-evaluating the experiments performed by Tsuang et al. (2008). Twelve loading patterns were simulated with poro-elastic finite element models in ABAQUS. Pressure on solid matrix, von Mises stress, maximum principle stress and pore pressure were selected as intrinsic mechanical stimuli. Their development rates and magnitudes at the steady state of cyclic loading were calculated with MATLAB at the construct level. Concurrent increase in glycosaminoglycan and collagen was observed at 2300 Pa pressure and 40 Pa/s pressure rate. Between 0-1500 Pa and 0-40 Pa/s, NO production was consistently positive with respect to controls, whereas ECM synthesis was negative in the same range. A linear correlation was found between pressure rate and NO production (R = 0.77). Stress states identified in this study are generic and could be used to develop predictive algorithms for matrix production in agarose-chondrocyte constructs of arbitrary shape, size and agarose concentration. They could also be helpful to increase the efficacy of loading protocols for avascular tissue engineering. Copyright (c) 2010 John Wiley \& Sons, Ltd.

Copeptin concentration in cord blood in infants with early-onset sepsis, chorioamnionitis and perinatal asphyxia

Background Vasopressin is one of the most important physiological stress and shock hormones. Copeptin, a stable vasopressin precursor, is a promising sepsis marker in adults. In contrast, its involvement in neonatal diseases remains unknown. The aim of this study was to establish copeptin concentrations in neonates of different stress states such as sepsis, chorioamnionitis and asphyxia. Methods Copeptin cord blood concentration was determined using the BRAHMS kryptor assay. Neonates with early-onset sepsis (EOS, n = 30), chorioamnionitis (n = 33) and asphyxia (n = 25) were compared to a control group of preterm and term (n = 155) neonates. Results Median copeptin concentration in cord blood was 36 pmol/l ranging from undetectable to 5498 pmol/l (IQR 7 - 419). Copeptin cord blood concentrations were non-normally distributed and increased with gestational age (p < 0.0001). Neonates born after vaginal compared to cesarean delivery had elevated copeptin levels (p < 0.0001). Copeptin correlated strongly with umbilical artery pH (Spearman's Rho -0.50, p < 0.0001), umbilical artery base excess (Rho -0.67, p < 0.0001) and with lactate at NICU admission (Rho 0.54, p < 0.0001). No difference was found when comparing copeptin cord blood concentrations between neonates with EOS and controls (multivariate p = 0.30). The highest copeptin concentrations were found in neonates with asphyxia (median 993 pmol/l). Receiver-operating-characteristic curve analysis showed that copeptin cord blood concentrations were strongly associated with asphyxia: the area under the curve resulted at 0.91 (95%-CI 0.87-0.96, p < 0.0001). A cut-off of 400 pmol/l had a sensitivity of 92% and a specifity of 82% for asphyxia as defined in this study. Conclusions Copeptin concentrations were strongly related to factors associated with perinatal stress such as birth acidosis, asphyxia and vaginal delivery. In contrast, copeptin appears to be unsuitable for the diagnosis of EOS.

A generalized anisotropic quadric yield criterion and its application to bone tissue at multiple length scales

Nonlinear computational analysis of materials showing elasto-plasticity or damage relies on knowledge of their yield behavior and strengths under complex stress states. In this work, a generalized anisotropic quadric yield criterion is proposed that is homogeneous of degree one and takes a convex quadric shape with a smooth transition from ellipsoidal to cylindrical or conical surfaces. If in the case of material identification, the shape of the yield function is not known a priori, a minimization using the quadric criterion will result in the optimal shape among the convex quadrics. The convexity limits of the criterion and the transition points between the different shapes are identified. Several special cases of the criterion for distinct material symmetries such as isotropy, cubic symmetry, fabric-based orthotropy and general orthotropy are presented and discussed. The generality of the formulation is demonstrated by showing its degeneration to several classical yield surfaces like the von Mises, Drucker–Prager, Tsai–Wu, Liu, generalized Hill and classical Hill criteria under appropriate conditions. Applicability of the formulation for micromechanical analyses was shown by transformation of a criterion for porous cohesive-frictional materials by Maghous et al. In order to demonstrate the advantages of the generalized formulation, bone is chosen as an example material, since it features yield envelopes with different shapes depending on the considered length scale. A fabric- and density-based quadric criterion for the description of homogenized material behavior of trabecular bone is identified from uniaxial, multiaxial and torsional experimental data. Also, a fabric- and density-based Tsai–Wu yield criterion for homogenized trabecular bone from in silico data is converted to an equivalent quadric criterion by introduction of a transformation of the interaction parameters. Finally, a quadric yield criterion for lamellar bone at the microscale is identified from a nanoindentation study reported in the literature, thus demonstrating the applicability of the generalized formulation to the description of the yield envelope of bone at multiple length scales.

Specimen specific parameter identification of ovine lumbar intervertebral discs: On the influence of fibre-matrix and fibre-fibre shear interactions.

Numerical models of the intervertebral disc, which address mechanical questions commonly make use of the difference in water content between annulus and nucleus, and thus fluid and solid parts are separated. Despite this simplification, models remain complex due to the anisotropy and nonlinearity of the annulus and regional variations of the collagen fibre density. Additionally, it has been shown that cross-links make a large contribution to the stiffness of the annulus. Because of this complex composite structure, it is difficult to reproduce several sets of experimental data with one single set of material parameters. This study addresses the question to which extent the ultrastructure of the intervertebral disc should be modelled so that its moment-angle behaviour can be adequately described. Therefore, a hyperelastic constitutive law, based on continuum mechanical principles was derived, which does not only consider the anisotropy from the collagen fibres, but also interactions among the fibres and between the fibres and the ground substance. Eight ovine lumbar intervertebral discs were tested on a custom made spinal loading simulator in flexion/extension, lateral bending and axial rotation. Specimen-specific geometrical models were generated using CT images and T2 maps to distinguish between annulus fibrosus and nucleus pulposus. For the identification of the material parameters the annulus fibrosus was described with two scenarios: with and without fibre-matrix and fibre-fibre interactions. Both scenarios showed a similar behaviour on a load displacement level. Comparing model predictions to the experimental data, the mean RMS of all specimens and all load cases was 0.54±0.15° without the interaction and 0.54±0.19° when the fibre-matrix and fibre-fibre interactions were included. However, due to the increased stiffness when cross-links effects were included, this scenario showed more physiological stress-strain relations in uniaxial and biaxial stress states. Thus, the present study suggests that fibre-matrix and fibre-fibre interactions should be considered in the constitutive law when the model addresses questions concerning the stress field of the annulus fibrosus.

Nitric oxide mediates the blood pressure response to mental stress in humans

Nitric oxide (NO) regulates arterial pressure by modulating peripheral vascular tone and sympathetic vasoconstrictor outflow. NO synthesis is impaired in several major cardiovascular disease states. Loss of NO-induced vasodilator tone and restraint on sympathetic outflow could result in exaggerated pressor responses to mental stress.

Coronary artery disease, nitric oxide and oxidative stress: the "Yin-Yang" effect--a Chinese concept for a worldwide pandemic

Prevention of coronary artery disease (CAD) and reduction of its mortality and morbidity remains a major public health challenge throughout the "Western world". Recent evidence supports the concept that the impairment of endothelial function, a hallmark of insulin resistance states, is an upstream event in the pathophysiology of insulin resistance and its main corollaries: atherosclerosis and myocardial infarction. Atherosclerosis is currently thought to be the consequence of a subtle imbalance between pro- and anti-oxidants that produces favourable conditions for lesion progression towards acute thrombotic complications and clinical events. Over the last decade, a remarkable burst of evidence has accumulated, offering the new perspective that bioavailable nitric oxide (NO) plays a pivotal role throughout the CAD-spectrum, from its genesis to the outcome after acute events. Vascular NO is a critical modulator of coronary blood flow by inhibiting smooth muscle contraction and platelet aggregation. It also acts in angiogenesis and cytoprotection. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes development of major cardiovascular risk factors (insulin resistance, arterial hypertension and dyslipidaemia) in mice, and characterises CAD-prone insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction causes metabolic insulin resistance and characterises atherosclerosis, heart failure and cardiogenic shock in humans, suggesting a "Yin-Yang" effect of NO in the cardiovascular homeostasis. Here, we will present a concise overview of the evidence for this novel concept, providing the conceptual framework for developing a potential therapeutic strategy to prevent and treat CAD.

Stress and hemostasis: an update

Numerous naturalistic, experimental, and mechanistic studies strongly support the notion that-as part of fight-or-flight response-hemostatic responses to acute psychosocial stress result in net hypercoagulability, which would protect a healthy organism from bleeding in case of injury. Sociodemographic factors, mental states, and comorbidities are important modulators of the acute prothrombotic stress response. In patients with atherosclerosis, exaggerated and prolonged stress-hypercoagulability might accelerate coronary thrombus growth following plaque rupture. Against a background risk from acquired prothrombotic conditions and inherited thrombophilia, acute stress also might trigger venous thromboembolic events. Chronic stressors such as job strain, dementia caregiving, and posttraumatic stress disorder as well as psychological distress from depressive and anxiety symptoms elicit a chronic low-grade hypercoagulable state that is no longer viewed as physiological but might impair vascular health. Through activation of the sympathetic nervous system, higher order cognitive processes and corticolimbic brain areas shape the acute prothrombotic stress response. Hypothalamic-pituitary-adrenal axis and autonomic dysfunction, including vagal withdrawal, are important regulators of hemostatic activity with longer lasting stress. Randomized placebo-controlled trials suggest that several cardiovascular drugs attenuate the acute prothrombotic stress response. Behavioral interventions and psychotropic medications might mitigate chronic low-grade hypercoagulability in stressed individuals, but further studies are clearly needed. Restoring normal hemostatic function with biobehavioral interventions bears the potential to ultimately decrease the risk of thrombotic diseases.

Lattice NRQCD study of in-medium bottomonium states using Nf = 2+1, 48³ × 12 HotQCD configurations

The behavior of bottomonium state correlators at non-zero temperature, 140.4(β = 6.664) ≤ T ≤ 221(β = 7.280) (MeV), where the transition temperature is 154(9) (MeV), is studied, using lattice NRQCD on 48³ ×12 HotQCD HiSQ action configurations with light dynamical Nf = 2+1 (mu,s/ms = 0.05) staggered quarks. In order to understand finite temperature effects on quarkonium states, zero temperature behavior of bottomonium correlators is compared based on 32⁴ (β = 6.664,6.800 and 6.950) and 48³ ×64 (β = 7.280) lattices. We find that temperature effects on S-wave bottomoniumstates are small but P-wave bottomoniumstates show a noticeable temperature dependence above the transition temperature.

Search for strong production of supersymmetric particles in final states with missing transverse momentum and at least three b-jets at √s= 8 TeV proton-proton collisions with the ATLAS detector

This paper reports the results of a search for strong production of supersymmetric particles in 20.1 fb−1 of proton-proton collisions at a centre-of-mass energy of 8TeV using the ATLAS detector at the LHC. The search is performed separately in events with either zero or at least one high-pT lepton (electron or muon), large missing transverse momentum, high jet multiplicity and at least three jets identified as originated from the fragmentation of a b-quark. No excess is observed with respect to the Standard Model predictions. The results are interpreted in the context of several supersymmetric models involving gluinos and scalar top and bottom quarks, as well as a mSUGRA/CMSSM model. Gluino masses up to 1340 GeV are excluded, depending on the model, significantly extending the previous ATLAS limits.

The elusive S2 state, the S1/S2 splitting, and the excimer states of the benzene dimer

We observe the weak S 0 → S 2 transitions of the T-shaped benzene dimers (Bz)2 and (Bz-d 6)2 about 250 cm−1 and 220 cm−1 above their respective S 0 → S 1 electronic origins using two-color resonant two-photon ionization spectroscopy. Spin-component scaled (SCS) second-order approximate coupled-cluster (CC2) calculations predict that for the tipped T-shaped geometry, the S 0 → S 2 electronic oscillator strength f el (S 2) is ∼10 times smaller than f el (S 1) and the S 2 state lies ∼240 cm−1 above S 1, in excellent agreement with experiment. The S 0 → S 1 (ππ ∗) transition is mainly localized on the “stem” benzene, with a minor stem → cap charge-transfer contribution; the S 0 → S 2 transition is mainly localized on the “cap” benzene. The orbitals, electronic oscillator strengths f el (S 1) and f el (S 2), and transition frequencies depend strongly on the tipping angle ω between the two Bz moieties. The SCS-CC2 calculated S 1 and S 2 excitation energies at different T-shaped, stacked-parallel and parallel-displaced stationary points of the (Bz)2 ground-state surface allow to construct approximate S 1 and S 2 potential energy surfaces and reveal their relation to the “excimer” states at the stacked-parallel geometry. The f el (S 1) and f el (S 2) transition dipole moments at the C 2v -symmetric T-shape, parallel-displaced and stacked-parallel geometries are either zero or ∼10 times smaller than at the tipped T-shaped geometry. This unusual property of the S 0 → S 1 and S 0 → S 2 transition-dipole moment surfaces of (Bz)2 restricts its observation by electronic spectroscopy to the tipped and tilted T-shaped geometries; the other ground-state geometries are impossible or extremely difficult to observe. The S 0 → S 1/S 2 spectra of (Bz)2 are compared to those of imidazole ⋅ (Bz)2, which has a rigid triangular structure with a tilted (Bz)2 subunit. The S 0 → S 1/ S 2 transitions of imidazole-(benzene)2 lie at similar energies as those of (Bz)2, confirming our assignment of the (Bz)2 S 0 → S 2 transition.

Effects of stereotypic behaviour and chronic mild stress on judgement bias in laboratory mice

Cognitive processes are influenced by underlying affective states, and tests of cognitive bias have recently been developed to assess the valence of affective states in animals. These tests are based on the fact that individuals in a negative affective state interpret ambiguous stimuli more pessimistically than individuals in a more positive state. Using two strains of mice we explored whether unpredictable chronic mild stress (UCMS) can induce a negative judgement bias and whether variation in the expression of stereotypic behaviour is associated with variation in judgement bias. Sixteen female CD-1 and 16 female C57BL/6 mice were trained on a tactile conditional discrimination test with grade of sandpaper as a cue for differential food rewards. Once they had learned the discrimination, half of the mice were subjected to UCMS for three weeks to induce a negative affective state. Although UCMS induced a reduced preference for the higher value reward in the judgement bias test, it did not affect saccharine preference or hypothalamic–pituitary–adrenal (HPA) activity. However, UCMS affected responses to ambiguous (intermediate) cues in the judgement bias test. While control mice showed a graded response to ambiguous cues, UCMS mice of both strains did not discriminate between ambiguous cues and tended to show shorter latencies to the ambiguous cues and the negative reference cue. UCMS also increased bar-mouthing in CD-1, but not in C57BL/6 mice. Furthermore, mice with higher levels of stereotypic behaviour made more optimistic choices in the judgement bias test. However, no such relationship was found for stereotypic bar-mouthing, highlighting the importance of investigating different types of stereotypic behaviour separately.