The influence of anisotropy on brain injury prediction.

Traumatic Brain Injury (TBI) occurs when a mechanical insult produces damage to the brain and disrupts its normal function. Numerical head models are often used as tools to analyze TBIs and to measure injury based on mechanical parameters. However, the reliability of such models depends on the incorporation of an appropriate level of structural detail and accurate representation of the material behavior. Since recent studies have shown that several brain regions are characterized by a marked anisotropy, constitutive equations should account for the orientation-dependence within the brain. Nevertheless, in most of the current models brain tissue is considered as completely isotropic. To study the influence of the anisotropy on the mechanical response of the brain, a head model that incorporates the orientation of neural fibers is used and compared with a fully isotropic model. A simulation of a concussive impact based on a sport accident illustrates that significantly lowered strains in the axonal direction as well as increased maximum principal strains are detected for anisotropic regions of the brain. Thus, the orientation-dependence strongly affects the response of the brain tissue. When anisotropy of the whole brain is taken into account, deformation spreads out and white matter is particularly affected. The introduction of local axonal orientations and fiber distribution into the material model is crucial to reliably address the strains occurring during an impact and should be considered in numerical head models for potentially more accurate predictions of brain injury.

Glutathione S-transferase M1-null genotype as risk factor for SOS in oxaliplatin-treated patients with metastatic colorectal cancer.

BACKGROUND: Oxaliplatin is used as a neo-adjuvant therapy in hepatic colorectal carcinoma metastasis. This treatment has significant side effects, as oxaliplatin is toxic to the sinusoidal endothelial cells and can induce sinusoidal obstruction syndrome (SOS), which is related to decreased overall survival. Glutathione has an important role in the defence system, catalysed by glutathione S-transferase (GST), including two non-enzyme producing polymorphisms (GSTM1-null and GSTT1-null). We hypothesise that patients with a non-enzyme producing polymorphism have a higher risk of developing toxic injury owing to oxaliplatin. METHODS: In the nontumour-bearing liver, the presence of SOS was studied histopathologically. The genotype was determined by a semi-nested PCR. RESULTS: Thirty-two of the 55 (58%) patients showed SOS lesions, consisting of 27% mild, 22% moderate and 9% severe lesions. The GSTM1-null genotype was present in 25 of the 55 (46%). Multivariate analysis showed that the GSTM1-null genotype significantly correlated with the presence of (moderate-severe) SOS (P=0.026). CONCLUSION: The GSTM1-null genotype is an independent risk factor for SOS. This finding allows us, in association with other risk factors, to conceive a potential risk profile predicting whether the patient is at risk of developing SOS, before starting oxaliplatin, and subsequently might result in adjustment of treatment.

Multi-scale mechanics of traumatic brain injury: predicting axonal strains from head loads.

The length scales involved in the development of diffuse axonal injury typically range from the head level (i.e., mechanical loading) to the cellular level. The parts of the brain that are vulnerable to this type of injury are mainly the brainstem and the corpus callosum, which are regions with highly anisotropically oriented axons. Within these parts, discrete axonal injuries occur mainly where the axons have to deviate from their main course due to the presence of an inclusion. The aim of this study is to predict axonal strains as a result of a mechanical load at the macroscopic head level. For this, a multi-scale finite element approach is adopted, in which a macro-level head model and a micro-level critical volume element are coupled. The results show that the axonal strains cannot be trivially correlated to the tissue strain without taking into account the axonal orientations, which indicates that the heterogeneities at the cellular level play an important role in brain injury and reliable predictions thereof. In addition to the multi-scale approach, it is shown that a novel anisotropic equivalent strain measure can be used to assess these micro-scale effects from head-level simulations only.

A tissue-level anisotropic criterion for brain injury based on microstructural axonal deformation.

Different length scales from micrometers to several decimeters play an important role in diffuse axonal injury. The kinematics at the head level result in local impairments at the cellular level. Finite element methods can be used for predicting brain injury caused by a mechanical loading of the head. Because of its oriented microstructure, the sensitivity of brain tissue to a mechanical load can be expected to be orientation dependent. However, the criteria for injury that are currently used at the tissue level in finite element head models are isotropic and therefore do not consider this orientation dependence, which might inhibit a reliable assessment of injury. In this study, an anisotropic brain injury criterion is developed that is able to describe the effects of the oriented microstructure based on micromechanical simulations. The effects of both the main axonal direction and of local deviations from this direction are accounted for. With the anisotropic criterion for brain injury, computational head models will be able to account for aspects of diffuse axonal injury at the cellular level and can therefore more reliably predict injury.

Micromechanics of diffuse axonal injury: influence of axonal orientation and anisotropy.

Multiple length scales are involved in the development of traumatic brain injury, where the global mechanics of the head level are responsible for local physiological impairment of brain cells. In this study, a relation between the mechanical state at the tissue level and the cellular level is established. A model has been developed that is based on pathological observations of local axonal injury. The model contains axons surrounding an obstacle (e.g., a blood vessel or a brain soma). The axons, which are described by an anisotropic fiber-reinforced material model, have several physically different orientations. The results of the simulations reveal axonal strains being higher than the applied maximum principal tissue strain. For anisotropic brain tissue with a relatively stiff inclusion, the relative logarithmic strain increase is above 60%. Furthermore, it is concluded that individual axons oriented away from the main axonal direction at a specific site can be subjected to even higher axonal strains in a stress-driven process, e.g., invoked by inertial forces in the brain. These axons can have a logarithmic strain of about 2.5 times the maximum logarithmic strain of the axons in the main axonal direction over the complete range of loading directions. The results indicate that cellular level heterogeneities have an important influence on the axonal strain, leading to an orientation and location-dependent sensitivity of the tissue to mechanical loads. Therefore, these effects should be accounted for in injury assessments relying on finite element head models.

Enhanced pulmonary leptin expression in patients with severe COPD and asymptomatic smokers.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory reaction of the lungs involving activation of epithelial cells. Leptin is a pleiotropic cytokine important in the regulation of immune responses via its functional receptor Ob-Rb. This study was undertaken to test the hypothesis that severe COPD is associated with increased leptin expression in epithelial cells. METHODS: Immunohistochemistry for leptin was performed on peripheral lung specimens from 20 patients with COPD (GOLD stage 4), 14 asymptomatic ex-smokers and 13 never smokers. Leptin and Ob-Rb mRNA expression were determined by rtPCR in cultured primary bronchial epithelial cells and primary type II pneumocytes. NCI-H292 and A549 cell lines were used to study functional activation of leptin signalling. RESULTS: Leptin immunoreactivity in lung tissue was observed in bronchial epithelial cells, type II pneumocytes, macrophages (tissue/alveolar) and interstitial lymphocytic infiltrates. rtPCR analysis confirmed pulmonary leptin and Ob-Rb mRNA expression in primary bronchial epithelial cells and pneumocytes. Leptin-expressing bronchial epithelial cells and alveolar macrophages were markedly higher in patients with severe COPD and ex-smokers than in never smokers (p<0.02). Exposure of cultured primary bronchial epithelial cells to smoke resulted in increased expression of both leptin and Ob-Rb (p<0.05). Leptin induced phosphorylation of STAT3 in both NCI-H292 and A549 cells. CONCLUSIONS: Leptin expression is increased in bronchial epithelial cells and alveolar macrophages of ex-smokers with or without severe COPD compared with never smokers. A functional leptin signalling pathway is present in lung epithelial cells.

The rocker bone: a new kind of mineralised tissue?

In some Ophidiiform fishes, the anterior part of the swimbladder is thickened into a hard structure called the "rocker bone", which is thought to play a role in sound production. Although this structure has been described as cartilage or bone, its nature is still unknown. We have made a thorough analysis of the rocker bone in Ophidion barbatum and compared it with both classical bone and cartilage. The rocker bone appears to be a new example of mineralisation. It consists of (1) a ground substance mainly composed of proteoglycans (mucopolysaccharide acid) and fibres and (2) a matrix containing small mineralised spherules composed of a bioapatite and fibrils. These spherules are embedded in mineralised cement of a similar composition to the spherules themselves. The rocker bone grows via the apposition of new apatite spherules at its periphery. These spherules are first secreted by the innermost fibroblast layer of the capsule contained in the rocker bone and then grow extracellularly. Blood vessels, which represent the only means of transport for matrix and mineral material, are numerous. They enter the rocker bone via the hyle and ramify towards the capsule. We propose to call this new kind of mineralised tissue constituting the rocker bone "frigolite" (the Belgian name for styrofoam) in reference to the presence of spherules of different sizes and the peculiarity of the rocker bone in presenting a smooth surface when fractured.

Biomechanics of traumatic brain injury: influences of the morphologic heterogeneities of the cerebral cortex.

Traumatic brain injury (TBI) can be caused by accidents and often leads to permanent health issues or even death. Brain injury criteria are used for assessing the probability of TBI, if a certain mechanical load is applied. The currently used injury criteria in the automotive industry are based on global head kinematics. New methods, based on finite element modeling, use brain injury criteria at lower scale levels, e.g., tissue-based injury criteria. However, most current computational head models lack the anatomical details of the cerebrum. To investigate the influence of the morphologic heterogeneities of the cerebral cortex, a numerical model of a representative part of the cerebral cortex with a detailed geometry has been developed. Several different geometries containing gyri and sulci have been developed for this model. Also, a homogeneous geometry has been made to analyze the relative importance of the heterogeneities. The loading conditions are based on a computational head model simulation. The results of this model indicate that the heterogeneities have an influence on the equivalent stress. The maximum equivalent stress in the heterogeneous models is increased by a factor of about 1.3-1.9 with respect to the homogeneous model, whereas the mean equivalent stress is increased by at most 10%. This implies that tissue-based injury criteria may not be accurately applied to most computational head models used nowadays, which do not account for sulci and gyri.

Nanoblock coupling effect in iodine intercalated [Bi(0.82)CaO(2)](2)[CoO(2)](1.69) layered cobaltite.

We report on the structural, microstructural, and electronic properties of iodine intercalated [Bi0.82CaO2]2[CoO2]1.69 misfit cobaltite. We first prove through a detailed and careful structural study that the block layer structure can be modified in the desired way. Iodine enters the material between the [BiO] double layers, and the c-cell parameter of the pristine compound is elongated by 3.6 Angstrom. On the basis of this result, we point out the coupling between the block-layer structure and the transport properties. Additionally, we provide in-depth commentary and discussion of some extra results, clarifying some doping effects in the quasi-2D studied phase. Finally, we also propose some expressions that might be useful to material scientists for the tuning of the properties of such compounds.

Differences in local versus systemic TNFalpha production in COPD: inhibitory effect of hyaluronan on LPS induced blood cell TNFalpha release.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by both airway inflammation and systemic changes. To elucidate the relationship between local and systemic inflammation, tumour necrosis factor alpha (TNFalpha) production by sputum cells and blood cells of patients with COPD and controls was compared and the effect of the extracellular matrix compound hyaluronan (HA) on TNFalpha release was studied. METHODS: Four study groups were included: 10 steroid free COPD patients, 8 steroid treated patients, 10 healthy smokers, and 11 healthy non-smokers. Sputum cells and blood were incubated for 24 hours with or without lipopolysaccharide (LPS) in the absence or presence of HA (122 kDa or HMW fragment). TNFalpha was measured by ELISA. RESULTS: Sputum cells produced spontaneously high levels of TNFalpha but were unresponsive to LPS. Sputum cells from COPD patients (both steroid free and steroid treated) produced significantly less TNFalpha than cells from healthy non-smoking subjects (p=0.017 and p=0.001, respectively). In contrast, blood cells produced TNFalpha only in response to LPS. No differences were observed in TNFalpha production by blood cells between the patient groups and the control groups. HA (both fragments) partially blocked LPS (1 ng/ml) induced TNFalpha release by blood cells from all study groups, whereas TNFalpha production by sputum cells was not influenced by HA. CONCLUSION: These data indicate a difference between local and systemic TNFalpha production. Sputum cells of patients with COPD produced less TNFalpha than controls, which could contribute to impaired local defence. An inhibitory effect of HA on TNFalpha release in blood cells was observed which was similar in both patients and controls.

In vivo behaviour of hydroxyapatite coatings on titanium implants: a quantitative study in the rabbit.

The aim of this study was to evaluate quantitatively the behaviour of in vivo hydroxyapatite coated implants (HA) in the rabbit over time, and to compare the results with observations made on titanium plasma spray implants (TPS). Results were analysed according to the percentage of bone contact. Eighteen HA cylindrical implants (3.25 x 8 mm) and 6 TPS cylindrical implants from Steri-Oss were placed in the epiphysis of the femur in 24 white rabbits. Each rabbit received one implant. Three rabbits with one HA implant (n = 3) and 1 rabbit with one TPS implant (n = 1) were sacrificed after implantation periods of 2, 4, 6, 8, 10 and 12 months. Implants were cut along the long axis and prepared for histological and histomorphometrical evaluations. Measurements of coating thickness and percentage of bone contact were performed with scanning electron microscopy analysis on the sides of the implant, in 3 different types of bone, namely cortical, trabecular and marrow. In cortical bone, dense bone was apposed to the HA implants: from 92.3 +/- 5.5% at 2 months to 89.6 +/- 6.5% at 1 year, with no significant regression of HA thickness (P = 0.37). TPS coating showed less bone contact, but thickness was stable (P = 0.46). In trabecular zone, where bone contact was less pronounced, a significant regression of HA coatings thickness (P < 0.05) was observed. Nevertheless TPS coatings were stable (P = 0.81). Histomorphometrical results demonstrated that a highly significant regression (P < 0.0001) of HA thickness was observed in the marrow area, where the bone-to-implant contact never exceeded 7.6% from 2 to 12 months. TPS coating did not reveal any sign of resorption (P = 0.88), despite a rare bone contact. Histological analysis revealed inflammatory and giant cells, principally in the marrow area in contact with HA coating, but always in restrictive numbers. We conclude that bone contact protected the HA coating from resorption.