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Thousands of confirmed and candidate exoplanets have been identified in recent years. Consequently, theoretical research on the formation and dynamical evolution of planetary systems has seen a boost, and the processes of planet-planet scattering, secular evolution, and interaction between planets and gas/debris disks have been well-studied. Almost all of this work has focused on the formation and evolution of isolated planetary systems, and neglect the effect of external influences, such as the gravitational interaction with neighbouring stars. Most stars, however, form in clustered environments that either quickly disperse, or evolve into open clusters. Under these conditions, young planetary systems experience frequent close encounters with other stars, at least during the first 1-10 Myr, which affects planets orbiting at any period range, as well as their debris structures., Comment: Proceedings of Cosmic-Lab: Star Clusters as Cosmic Laboratories for Astrophysics, Dynamics, and Fundamental Physics - MODEST16

Although vitamin D has been implicated in cardiovascular protection, few studies have addressed the role of vitamin D receptor (VDR) in atherosclerosis. Here we investigate the effect of inactivation of the VDR signaling on atherogenesis and the antiatherosclerotic mechanism of vitamin D. Low density lipoprotein receptor (LDLR)(-/-)/VDR(-/-) mice exhibited site-specific accelerated atherogenesis, accompanied by increases in adhesion molecules and proinflammatory cytokines in the aorta and cholesterol influx in macrophages. Macrophages showed marked renin up-regulation in the absence of VDR, and inhibition of renin by aliskiren reduced atherosclerosis in LDLR(-/-)/VDR(-/-) mice, suggesting that the renin-angiotensin system (RAS) promotes atherosclerosis in the absence of VDR. LDLR(-/-) mice receiving LDLR(-/-)/VDR(-/-) BMT developed larger lesions than LDLR(-/-) BMT controls. Moreover, LDLR(-/-) mice receiving Rag-1(-/-)/VDR(-/-) BMT, which were unable to generate functional T and B lymphocytes, still had more severe atherosclerosis than Rag-1(-/-) BMT controls, suggesting a critical role of macrophage VDR signaling in atherosclerotic suppression. Aliskiren treatment eliminated the difference in lesions between Rag-1(-/-)/VDR(-/-) BMT and Rag-1(-/-) BMT recipients, indicating that local RAS activation in macrophages contributes to the enhanced atherogenesis seen in Rag-1(-/-)/VDR(-/-) BMT mice. Taken together, these observations provide evidence that macrophage VDR signaling, in part by suppressing the local RAS, inhibits atherosclerosis in mice.

Myocardial ischemia induces cardiomyocyte injury and death, resulting in impairment of cardiac function. The adult cardiomyocytes possess a limited capacity of protection in myocardial ischemia, and nonmyocytic cells can be activated to support myocardial protection. We recently demonstrated that hepatic cells were able to upregulate genes encoding secreted proteins and were mobilized to the circulatory system, potentially contributing to myocardial protection against ischemic injury. In this investigation, we tested the potential mechanisms by which hepatic cells were mobilized in experimental myocardial ischemia. Following the induction of myocardial ischemia, hepatic cells, including hepatocytes and biliary epithelial cells, were mobilized to the circulatory system with a peak population 1.9 ± 0.4% at day 5. The cytokine IL-6 was upregulated in the ischemic myocardium as well as the serum. IL-6 promoted leukocyte retention in the liver as demonstrated by an increase in liver-retained leukocytes in myocardial ischemia in wild type mice, reduced leukocytes in IL-6−/− mice, and restoration of leukocyte retention in response to IL-6 administration to IL-6−/− mice. Liver-retained leukocytes exhibited upregulation of MMP-2, which in turn mediated hepatic cell mobilization by degrading extracellular matrix. These observations suggest that IL-6-stimulated leukocytes mediate the mobilization of hepatic cells via releasing MMP-2 in myocardial ischemia.

Aim To evaluate spasticity under controlled velocities and torques in children with cerebral palsy (CP) using a manual spasticity evaluator. Method The study involved 10 children with spastic CP (six males, four females; mean age 10y 1mo, SD 2y 9mo, range 7–16y; one with quadriplegia, six with right hemiplegia, three with left hemiplegia; Gross Motor Function Classification System levels I [n=2], II [n=3], III [n=2], IV [n=2], and V [n=1]; Manual Ability Classification System levels II [n=5], III [n=4], and V [n=1]) and 10 typically developing participants (four males, six females; mean age 10y 3mo, SD 2y 7mo, range 7–15y). Spasticity and catch angle were evaluated using joint position, resistance torque, and torque rate at velocities of 90°, 180°, and 270° per second, controlled using real-time audio-visual feedback. Biomechanically, elbow range of motion (ROM), stiffness, and energy loss were determined during slow movement (30°/s) and under controlled terminal torque. Results Compared with typically developing children, children with CP showed higher reflex-mediated torque (p

Cardiomyocyte injury occurs in myocardial ischemia, resulting in impairment of cardiac function. As the endogenous protective function of adult cardiomyocytes is limited, nonmyocytic cells may be activated to protect myocardium from ischemic injury. In this investigation, we demonstrated in a mouse model of myocardial ischemia that the liver was able to respond to myocardial ischemia to upregulate a number of genes encoding secreted proteins, mobilize its cells, and release cell contents into the circulatory system. These naturally occurring mechanisms suggested a possible cardioprotective role for myocardial ischemia-conditioned liver cells and inspired us to develop cardioprotective therapies based on these mechanisms. We demonstrated that administration of liver cell extract derived from myocardial ischemic mice, but not sham control mice, resulted in a significant reduction in acute myocardial infarction as well as the density of TUNEL+ cells in ischemic myocardium compared to administration of PBS at 2, 6, 12, and 24 hrs. These observations suggest that liver cells may respond to myocardial ischemia to express cardioprotective factors, which may be identified and used for alleviating myocardial infarction.

Objectives: To analyse rates of avoidable hospitalisations in Aboriginal and nonAboriginal residents of the Northern Territory, 1998–99 to 2005–06, and to consider the implications for primary care interventions. Design and setting: Retrospective descriptive analysis of inpatient discharge data from NT public hospitals. Main outcome measures: Avoidable hospitalisations by age, sex, Aboriginality and condition, with annual time trends. Results: Between 1998–99 and 2005–06, Aboriginal people in the NT had an avoidable hospitalisation rate of 11 090 per 100 000 population, nearly four times higher than the Australian rate of 2848 per 100 000. The rate for non-Aboriginal NT residents was 2779 per 100 000. During this period, the average annual increase in avoidable hospitalisations was 11.6% (95% CI, 11.0%–12.1%) in the NT Aboriginal population and 3.9% (95% CI, 3.3%–4.5%) in the non-Aboriginal population. The greatest increase occurred in those aged 45 years, and was primarily attributable to diabetes complications. Conclusions: The significantly higher rates of avoidable hospitalisations in NT Aboriginal people reflect the emerging epidemic of chronic disease in this population, highlight barriers to Aboriginal people accessing effective primary care, and emphasise

Spasticity, contracture, and muscle weakness are commonly observed poststroke in muscles crossing the ankle. However, it is not clear how biomechanical properties of the Achilles tendon change poststroke, which may affect functions of the impaired muscles directly. Biomechanical properties of the Achilles tendon, including the length and cross-sectional area, in the impaired and unimpaired sides of 10 hemiparetic stroke survivors were evaluated using ultrasonography. Elongation of the Achilles tendon during controlled isometric ramp-and-hold and ramping up then down contractions was determined using a block-matching method. Biomechanical changes in stiffness, Young's modulus, and hysteresis of the Achilles tendon poststroke were investigated by comparing the impaired and unimpaired sides of the 10 patients. The impaired side showed increased tendon length (6%; P = 0.04), decreased stiffness (43%; P < 0.001), decreased Young's modulus (38%; P = 0.005), and increased mechanical hysteresis (1.9 times higher; P < 0.001) compared with the unimpaired side, suggesting Achilles tendon adaptations to muscle spasticity, contracture, and/or disuse poststroke. In vivo quantitative characterizations of the tendon biomechanical properties may help us better understand changes of the calf muscle-tendon unit as a whole and facilitate development of more effective treatments.

Previously, we showed that vitamin D receptor gene knockout leads to hyperreninemia independent of calcium metabolism; however, the contribution of parathyroid hormone to renin upregulation remained unclear. Here we separated the role of vitamin D and parathyroid hormone in the regulation of renin expression in vivo by generating transgenic mice that overexpressed the human vitamin D receptor in renin-producing cells using the 4.1 kb Ren-1c gene promoter. Targeting of human vitamin D receptor to the juxtaglomerular cells of the mice was confirmed by immunohistochemistry. Renal renin mRNA levels and plasma renin activity were decreased in these transgenic mice by about 50% and 30%, respectively, with no significant change in blood pressure, calcium, or parathyroid hormone levels. Moreover using vitamin D receptor knockout mice, we found that expression of the human receptor in their juxtaglomerular cells reduced renin expression in these mice without affecting calcium or parathyroid hormone status. Our study shows that suppression of renin expression by 1,25-dihydroxyvitamin D in vivo is independent of parathyroid hormone and calcium.

Arterial smooth muscle cells (SMCs) are present in the elastic lamina-containing media, suggesting that the elastic laminae may regulate the development of SMCs. Here, we investigated the role of elastic laminae in regulating the formation of SM alpha actin filaments in mouse CD34+ bone marrow cells and the role of a protein tyrosine phosphatase, SH2 domain-containing protein tyrosine phosphatase (SHP)-1, in the mediation of this process. Mouse CD34+ bone marrow cells were isolated by magnetic separation and used for assessing the influence of elastic laminae and collagen matrix on the formation of SM alpha actin filaments. CD34+ cells with transgenic SHP-1 knockout or siRNA-mediated SHP-1 knockdown were used to assess the role of SHP-1 in mediating the formation of SM alpha actin filaments. In cell culture tests, elastic laminae, but not collagen matrix, stimulated the formation of SM alpha actin filaments in CD34+ cells. The phosphatase SHP-1 mediated the stimulatory effect of elastic laminae. The interaction of CD34+ cells with elastic laminae, but not with collagen matrix, induced activation of SHP-1. The suppression of SHP-1 by transgenic SHP-1 knockout or siRNA-mediated SHP-1 knockdown significantly reduced the formation of SM alpha actin filaments in CD34+ cells cultured on elastic laminae. The in vitro observations were confirmed by using an in vivo model of implantation of elastic lamina and collagen matrix scaffolds into the aorta. These observations suggest that elastic laminae stimulate the formation of SM alpha actin filaments in CD34+ bone marrow cells and SHP-1 mediates the stimulatory effect of elastic laminae.

Several partial models of cochlear subparts are available. However, a complete 3D model of an intact cochlea based on actual histological sections has not been reported. Hence, the aim of this study was to develop a novel 3D model of the guinea pig cochlea and conduct post-processes on this reconstructed model. We used a combination of histochemical processing and the method of acquiring section data from the visible human project (VHP) to obtain a set of ideal raw images of cochlear sections. After semi-automatic registration and accurate manual segmentation with professional image processing software, one set of aligned data and six sets of segmented data were generated. Finally, the segmented structures were reconstructed by 3D Slicer (a professional imaging process and analysis tool). Further, post-processes including 3D visualization and a virtual endoscope were completed to improve visualization and simulate the course of the cochlear implant through the scala tympani. The 3D cochlea model contains the main six structures: (1) the inner wall, (2) modiolus and spiral lamina, (3) cochlea nerve and spiral ganglion, (4) spiral ligament and inferior wall of cochlear duct, (5) Reissner's membrane and (6) tectorial membrane. Based on the results, we concluded that ideal raw images of cochlear sections can be acquired by combining the processes of conventional histochemistry and photographing while slicing. After several vital image processing and analysis steps, this could further generate a vivid 3D model of the intact cochlea complete with internal details. This novel 3D model has great potential in teaching, basic medical research and in several clinical applications.

A series of reactor blends of linear and branched polyethylenes have been prepared, in the presence of modified methylaluminoxane, using a combination of 2,6-bis[1(2,6-dimethyphenylimino) pyridyl]-cobalt(II) dichloride (1), known as an active catalyst for producing linear polyethylene, and [1,4-bis(2,6-diidopropylphenyl)] acenaphthene diimine nickel(II) dibromide (2), which is active for the production of branched polyethylene. The polymerizations were performed at various levels of catalyst feed ratio at 10 bar. The linear correlation between catalyst activity and concentration of catalyst 2 suggested that the catalysts performed independently from each other. The weight-average molecular weights ((M) over bar (w)), crystalline structures, and phase structures of the blends were investigated, using a combination of gel permeation chromatography, differential scanning calorimetry, wide-angle X-ray diffraction, and small angle X-ray scattering techniques. It was found that the polymerization activities and MWs and crystallization rate of the polymers took decreasing tendency with the increase of the catalyst 2 ratios, while melting temperatures (T-m), crystalline temperatures (T,), and crystalline degrees took decreasing tendency. Long period was distinctly influenced by the amorphous component concentration.

Background Recent estimates of the global burden of rheumatic heart disease (RHD) have highlighted the paucity of reliable RHD mortality data from populations most affected by RHD. Methods and Results We investigated RHD mortality rates and trends for Indigenous and non‐Indigenous Australians in the Northern Territory (NT) for the period 1977–2005 and seminationally (NT plus 4 other states, covering 89% of Indigenous Australians) from 1997 to 2005 using vital statistics data. All analysis was undertaken by Indigenous status, sex, and age at death. In the NT, 90% of all deaths from RHD were among Indigenous persons; however, the Indigenous population makes up only 30.4% of the NT population. The death rate ratio (Indigenous compared with non‐Indigenous) was 54.80 in the NT and 12.74 in the other 4 states (estimated at the median age of 50 years). Non‐Indigenous death rates were low for all age groups except ≥65 years, indicating RHD deaths in the elderly non‐Indigenous population. Death rates decreased at a more rapid rate for non‐Indigenous than Indigenous persons in the NT between 1997 and 2005. Indigenous persons in other parts of Australia showed lower death rates than their NT counterparts, but the death rates for Indigenous persons in all states were still much higher than rates for non‐Indigenous Australians. Conclusions Indigenous Australians are much more likely to die from RHD than other Australians. Among the Indigenous population, RHD mortality is much higher in the NT than elsewhere in Australia, exceeding levels reported in many industrialized countries more than a century ago. With the paucity of data from high‐prevalence areas, these data contribute substantially to understanding the global burden of RHD mortality.

OBJECTIVE: To assess the integration of a smoking cessation intervention into routine tuberculosis (TB) services. METHOD: Consecutive TB patients registered from 1 March to 31 August 2010 were enrolled in an intervention for self-reported smoking to promote tobacco cessation during treatment for TB. Information on the harmful health effects of tobacco smoke and smoking and TB were provided to TB patients who self-reported as current smokers. Smoking status was reassessed at every follow-up visit during anti-tuberculosis treatment with reinforced health messages and advice to quit. RESULTS: Of 800 TB patients enrolled, 572 (71.5%) were male and 244 (30.5%) were current smokers. Females were more likely to be non-smokers (100% vs. 35.8%, P < 0.001). Of the 244 current smokers, 144 (59.0%) started smoking at

A mammalian organism possesses a hierarchy of naturally evolved protective mechanisms against ischemic myocardial injury at the molecular, cellular, and organ levels. These mechanisms comprise regional protective processes, including upregulation and secretion of paracrine cell-survival factors, inflammation, angiogenesis, fibrosis, and resident stem cell-based cardiomyocyte regeneration. There are also interactive protective processes between the injured heart, circulation, and selected remote organs, defined as trans-system protective mechanisms, including upregulation and secretion of endocrine cell-survival factors from the liver and adipose tissue as well as mobilization of bone marrow, splenic, and hepatic cells to the injury site to mediate myocardial protection and repair. The injured heart and activated remote organs exploit molecular and cellular processes, including signal transduction, gene expression, cell proliferation, differentiation, migration, mobilization, and/or extracellular matrix production, to establish protective mechanisms. Both regional and trans-system cardioprotective mechanisms are mediated by paracrine and endocrine messengers and act in coordination and synergy to maximize the protective effect, minimize myocardial infarction, and improve myocardial function, ensuring the survival and timely repair of the injured heart. The concept of the trans-system protective mechanisms may be generalized to other organ systems-injury in one organ may initiate regional as well as trans-system protective responses, thereby minimizing injury and ensuring the survival of the entire organism. Selected trans-system processes may serve as core protective mechanisms that can be exploited by selected organs in injury. These naturally evolved protective mechanisms are the foundation for developing protective strategies for myocardial infarction and injury-induced disorders in other organ systems.

Pulmonary fibrosis is a serious lung disorder that can lead to respiratory failure. Here we show that transgenic mice expressing active renin from the liver (RenTgMK) developed progressive pulmonary fibrosis leading to impaired pulmonary function. Histological analyses revealed a marked increase in extracellular matrix (ECM) deposition and decrease in alveolar size in the lungs of RenTgMK mice compared to wild-type (WT) littermates, accompanied with increased expression of ECM proteins and fibrogenic factors. The increase in lung fibrosis led to a substantial decrease in respiratory system compliance. Two-week treatment with aliskiren (renin inhibitor) or losartan (AT1 antagonist) ameliorated pulmonary ECM deposition, blocked the induction of ECM proteins and fibrogenic factors and improved respiratory compliance in RenTgMK mice, confirming a critical role of the renin-Ang II-AT1 cascade in promoting pulmonary fibrogenesis. However, when RenTgMK mice were treated with hydralazine (a smooth muscle relaxant), the blood pressure was normalized but the lung fibrotic abnormalities, fibrogenic gene induction and pulmonary elasticity were not corrected. Moreover, intratracheal instillation of lipopolysaccharide induced more severe lung injury in RenTgMK mice compared to WT littermates. These observations demonstrate that the renin-angiotensin system is a key mediator of lung fibrosis and its pro-fibrotic effect is independent of blood pressure.

This paper describes an educational package for use in tertiary level tissue engineering education. Current learning science principles and theory were employed in the design process of these educational tools. Each module started with a challenge statement designed to motivate students and consisted of laboratory exercises centered on the “How People Learn” framework. The preliminary assessment of these modules supports their potential value in teaching tissue engineering laboratory exercises.

Synthetic polymers, including polytetrafluoroethylene and Dacron, and biomatrix proteins, including collagen and fibrin, have been used for the construction of vascular substitutes. However, these materials induce inflammatory reactions, contributing to thrombosis, smooth muscle cell (SMC) proliferation, and neointima formation, processes leading to the failure of vascular substitutes. Thus, a pressing issue in vascular reconstruction is to construct vascular substitutes with surface materials that are inflammation-resistant. Here, we demonstrate that the vascular elastic laminae exhibit such a property. Aortic specimens from donor rats were treated with 0.1M NaOH for various times, resulting in elastic lamina-collagen matrix scaffolds with and without the basal lamina. Matrix scaffolds were implanted into the host aorta with three different surface materials, including the elastic lamina, basal lamina, and adventitial collagen, and observed for leukocyte adhesion, endothelial migration, cell proliferation, and neointimal formation on these surfaces. It was found that the elastic lamina was associated with significantly lower leukocyte adhesion, BrdU incorporation, and neointima formation than the basal lamina and adventitial collagen, while the migration of endothelial cells was comparable on all three surfaces. The adventitial collagen matrix was associated with leukocyte infiltration from blood and subsequent SMC migration from the host aorta, whereas the elastic laminae were resistant to such processes. The morphology of the implanted elastic laminae appeared normal at all times. These observations suggest that the vascular elastic laminae exhibit inflammation-resistant properties and inhibit SMC mitogenic activities compared with collagen-containing matrices and may be considered a potential surface material for vascular reconstruction.

Purpose: We conducted a Phase II clinical trial with randomized patients to determine whether autologous formalin-fixed tumor vaccine (AFTV) protects against postsurgical recurrence of hepatocellular carcinoma (HCC). Experimental Design: Forty-one patients with HCC who had undergone curative resection were randomly allocated to the vaccine treatment (n = 19) or no adjuvant control group (n = 22). Three intradermal vaccinations were administered at 2-week intervals beginning 4–6 weeks after hepatic resection. A delayed-type hypersensitivity test was performed before and after vaccination. Primary and secondary end points are recurrence-free survival and overall survival, respectively. Observation continued until the majority of surviving patients had lived >12 months after the curative resection. Results: In a median follow-up of 15 months, the risk of recurrence in vaccinated patients was reduced by 81% (95% confidence interval, 33–95%; P = 0.003). Vaccination significantly prolonged the time to first recurrence (P = 0.003) and improved recurrence-free survival (P = 0.003) and overall survival rates (P = 0.01). AFTV played a significant role in preventing recurrence in patients with small tumors. Adverse effects were limited to grade 1 or 2 skin toxicities such as erythema, dry desquamation, and pruritus. Conclusions: AFTV therapy is a safe, feasible, and effective treatment for preventing postoperational recurrence of HCC. Patients with low tumor burdens benefit from the treatment. This treatment should be advanced to a large-scale randomized trial.

Motivated by physiological flows in capillaries, venules and the pleural space, the pressure-driven flow of a Newtonian fluid in a two-dimensional wavy-walled channel is investigated theoretically. The sinusoidal wavy shape is due to the configuration of underlying cells, their nuclei and intercellular junctions or clefts. The walls are lined with a thin poroelastic layer that models the glycocalyx coating of the cell surface. The upper and lower wavy walls are offset axially by the phase angle Φ ,w here Φ =0 (π )y ields an antisymmetric (symmetric) channel. Biphasic theory is employed fo rt he poroelastic layer and the flow is solved by a lubrication approximation using a small parameter, δ � 1, where δ is the channel width/wavelength ratio. The velocity fields in the core and layer are determined as perturbation expansions in δ 2 and finite-Reynolds-number effects occur at O(δ 2 )a ssuming δ 2 Re � 1. When the hydraulic resistivity, α ,t he ratio of the channel width to the Darcy permeability, is sufficiently large and Φ is near enough to π ,t he flow develops a trapped recirculation eddy within the glycocalyx layer near the widest part of the channel. This can be of significance to transport through the cellular boundary, since that location corresponds to intercellular clefts through which important fluid and solute exchange occurs. Increasing |Φ − π| diminishes the recirculation region. Increasing the Reynolds number moves the recirculation slightly upstream. Both layer velocity and wall shear stresses decrease as α increases and support the appearance of flow recirculation. Further, the wavy geometry allows a portion of the flow to enter and exit the layer, which provides a mechanism for convective transport between these two regions that otherwise have only diffusive interactions. The relevant P´ eclet number is Pe = V ∗ n b/D where D is molecular diffusivity and V ∗

Mechanical stretch has been shown to induce the degradation of alpha-actin filaments in smooth muscle cells (SMC) of experimental vein grafts. Here, we investigate the possible role of ERK1/2 and p38 MAPK in regulating this process using an ex vivo venous culture model that simulates an experimental vein graft. An exposure of a vein to arterial pressure induced a significant increase in the medial circumferential strain, which induced rapid alpha-actin filament disruption, followed by degradation. The percentage of SMC alpha-actin filament coverage was reduced significantly under arterial pressure (91 +/- 1%, 43 +/- 13%, 51 +/- 5%, 28 +/- 3%, and 19 +/- 5% at 1, 6, 12, 24, and 48 h, respectively), whereas it did not change significantly in specimens under venous pressure at theses times. The degradation of SMC alpha-actin filaments paralleled an increase in the relative activity of caspase 3 (3.0 +/- 0.7- and 1.7 +/- 0.4-fold increase relative to the control level at 6 and 12 h, respectively) and a decrease in SMC density (from the control level of 1,368 +/- 66 cells/mm(2) at time 0 to 1,205 +/- 90, 783 +/- 129, 845 +/- 61, 637 +/- 55, and 432 +/- 125 cells/mm(2) at 1, 6, 12, 24, and 48 h of exposure to arterial pressure, respectively). Treatment with a p38 MAPK inhibitor (SB-203580) significantly reduced the stretch-induced activation of caspase 3 at 6 h (from 3.0 +/- 0.7- to 2.2 +/- 0.3-fold) in conjunction with a significant rescue of alpha-actin filament degradation (from 43 +/- 13% to 69 +/- 15%) at the same time. Treatment with an inhibitor for the ERK1/2 activator (PD-98059), however, did not induce a significant change in the activity of caspase 3 or the percentage of SMC alpha-actin filament coverage. These results suggest that p38 MAPK and caspase 3 may mediate stretch-dependent degradation of alpha-actin filaments in vascular SMCs.

Vein graft is commonly used to replace malfunctioned arteries. However, intimal hyperplasia (IH) and re-stenosis often occur after surgery leading to serious clinical problems. A multi-physics computational model with tube wall growth and fluid–structure interactions and an iterative mixed method using finite volume, generalized finite difference and finite elements are introduced to simulate focal intimal hyperplasia and blood flow in rat abdominal artery with a vein graft. Physical parameters and physiological geometries from in vivo experimental data are used in model development and verifications. Our results indicate that the mismatches in geometry and mechanical properties between the host artery and the vein graft cause considerable disturbance in flow shear stress, eddy flow, tube wall deformation, and tensile stress/strain distributions. Focal intimal hyperplasia and re-stenosis process are closely related to eddy flow and low and oscillating shear stresses. A constitutive growth function which governs the IH growth is quantified based on experimental data and computational simulations. Further investigation of effects of other factors such as tensile stress and various cell interactions is needed to fully understand IH growth and re-stenosis process.

The proliferation of vascular cells contributes to the formation of neointima and hypertrophy of the blood vessel wall. Here we show that mechanical stretch possibly regulates the proliferation of vascular cells via the mediation of cell death in a rat vein graft model. The wall of vein grafts is subject to a suddenly increased mechanical stretch due to exposure to arterial blood pressure. Such a stretch induces rapid cell death with a reduction in cell density by approximately 60% within the first day after surgery. The initial cell death was followed by an increase in the percentage of proliferating cells, as shown by a BrdU incorporation assay (1.55 +/- 1.27%, 8.48 +/- 2.27%, 11.93 +/- 2.36%, 6.36 +/- 1.77%, and 5.60 +/- 1.46% at days 1, 5, 10, 20, and 30, respectively). When mechanical stretch was reduced by restraining the vein graft using a polytetrafluoroethylene sheath, the percentage of proliferating cells reduced significantly (0.76 +/- 0.76%, 1.70 +/- 0.46%, 1.29 +/- 0.56%, 0.99 +/- 0.83%, and 0.47+/-0.52% at days 1, 5, 10, 20, and 30, respectively). A further reduction in cell density, induced by local administration of a cell death inducer ceramide to experimental vein grafts (without sheath), enhanced subsequent cell proliferation. In contrast, a prevention of cell death, induced by local administration of a cell death inhibitor tetrapeptide-aldehyde DEVD-CHO to experimental vein grafts (without sheath), significantly reduced subsequent cell proliferation. These results suggest that mechanical stretch induces cell death, which possibly mediates subsequent cell proliferation in the present model.

Tea oil camellia (Camellia oleifera) is an important oil-producing plant which is widely distributed in the Dabie Mountain of Anhui province in China. Anthracnose (Colletotrichum gloeosporioides) is a common and serious disease which often cause flower and fruit drop in tea oil, leading to 50% or more loss in yields. Different Camellia varieties vary in their resistance to anthracnose. There are few studies on the physiological mechanisms of resistance to anthracnose. In this paper, eight different varieties of Camellia in China were selected for measurement of the content of four polyphenols, flavonoids, phenylalanine ammonia lyase and polyphenol oxidase. Among the polyphenols, catechol and salicylic acid content were related to anthracnose resistance, with the content of the resistant varieties been nearly five to ten times higher than that of the more susceptible varieties. Flavonoid content was also significantly higher in resistant varieties than in susceptible varieties. Activities of the defense-related enzymes phenylalanine ammonia lyase and polyphenol oxidase did not differ between different cultivars. However, enzyme activity of resistant cultivars improved markedly after pathogen inoculation, while those of susceptible cultivars did not change. This study broadens the understanding of the mechanisms of disease resistance in Camellia.Keywords: Anthracnose, Camellia oleifera, phenylalanine ammonia lyase, polyphenol oxidase.

Smooth muscle cell (SMC) migration from the media to the intima of blood vessels contributes to neointimal formation and atherogenesis. Here, the authors demonstrate how blood shear stress regulates vascular SMC migration in the encapsulating tissue of a micro-cylinder implanted in the center of the rat vena cava with the micro-cylinder perpendicular to blood flow, in this model, the micro-cylinder was exposed to a laminar flow with a known shear stress field in the leading region and a vortex flow in the trailing region. After surgery, the micro-cylinder was encapsulated by a thrombus-like tissue within one day, followed by SMC migration from the vena cava to the encapsulating tissue from day 3 to 20. SMC migration was time-dependent with a peak migration speed at day 5. At each given time (excluding day 1), blood shear stress exerts an inhibitory effect on SMC migration with significantly suppressed SMC migration in the laminar flow region than in the stagnation, separation, and vortex flow regions. SMCs were relatively parallel to the shear stress direction in high shear stress regions, whereas perpendicular to the shear stress direction in low shear stress regions. These results suggest that blood shear stress plays a role in regulating SMC migration and orientation in this model.

Leukocytes interact with endothelial cells and contribute to the development of vascular diseases such as thrombosis and atherosclerosis. These processes are possibly influenced by mechanical factors. This study focused on the role of mechanical stretch in the activation of monocytes and granulocytes in experimental vein grafts. Two models were created by using rats: a nonengineered vein graft with increased tensile stress, which was created by grafting a jugular vein into the abdominal aorta, and an engineered vein graft with reduced tensile stress, which was created by restricting the vein graft into a cylindrical sheath constructed by using fixative-treated intestinal tissue. The density of activated monocytes and granulocytes, which attached to the endothelium, and the distribution of the intercellular adhesion molecule (ICAM)-1 in endothelial cells were examined using immunohistological assays. It was found that, in nonengineered vein grafts, the density of activated monocytes and granulocytes increased significantly compared to that in normal jugular veins at day 1, 5, 10 and 20. At each observation time, the cell density in the proximal region of the nonengineered vein grafts was significantly higher than that in the middle and distal regions, and the cell density in the distal region was significantly higher than that in the middle region. These changes were associated with ICAM-1 clustering at day 1 and 5 and focal ICAM-1 un-regulation at day 10 and 20. In engineered vein grafts, the density of activated monocytes and granulocytes decreased significantly compared to that in nonengineered vein grafts at all observation times, although it was significantly higher than that in normal jugular veins. At each observation time, the cell density in the proximal and distal regions was significantly higher than that in the middle region, but no significant difference was found between the proximal and distal regions. ICAM-1 clustering along endothelial cell borders was found at day 1 and 5, but no apparent focal ICAM-1 up-regulation was found at day 10 and 20. These results suggested that mechanical stretch due to exposure to increased tensile stress contributed to the activation of monocytes and granulocytes in experimental vein grafts, and this event could be partially prevented by reducing tensile stress using a biomechanical engineering approach.

The present study focused on the role of blood flow in the formation of focal intimal hyperplasia in vein grafts, as well as the development of an engineering approach that can be used to eliminate disturbed blood flow and prevent blood flow-related focal intimal hyperplasia. A rat vein graft model was constructed by interposing a jugular vein into the abdominal aorta with end-to-end anastomoses. Locally disturbed flow was identified by analyzing particle streak-lines in methyl salicylate-cleared and perfused vein grafts in vitro with a physiological Reynolds number. At day 10, 20, and 30 after surgery, focal intimal hyperplasia of the vein grafts was examined using a histological approach and the density of alpha-actin positive cells was determined using immunohistological and fluorescent approaches. Results showed that apparent eddy blood flow formed at the proximal, but not at the distal, end of the vein grafts due to graft-host diameter mismatch and local geometric distortions, and was associated with apparent focal intimal hyperplasia. The thickness of the alpha-actin positive layers of the proximal vein grafts was significantly higher than that of the distal grafts (192 +/- 27 vs. 94 +/- 18 microm, 278 +/- 55 vs. 124 +/- 20 microm, and 288 +/- 24 vs. 131 +/- 23 microm for day 10, 20. and 30, respectively). The density of the alpha-actin positive cells, however, was similar between the proximal and the distal regions (3569 +/- 361 vs. 3285 +/- 343 cells/mm2, 5540 +/- 650 vs. 5376 + 887 cells/mm2, and 5465 +/- 791 vs. 5278 +/- 524 cells/mm2 for day 10, 20, and 30, respectively). When eddy blood flow was eliminated by matching the graft-host diameters using a tissue engineering approach, the average thickness of the alpha-actin positive layers of the proximal (71 +/- 15, 86 +/- 16, and 85 +/- 14 microm for day 10, 20, and 30, respectively) and the distal vein grafts (68 +/- 13, 80 +/- 14, and 79 +/- 13 microm for day 10, 20, and 30, respectively) was reduced significantly. The density of the alpha-actin positive cells was also reduced significantly in the proximal (2946 +/- 359, 3261 +/- 295, 3472 +/- 599 cells/mm2 for day 10, 20, and 30, respectively) and in the distal regions (3151 +/- 511, 3466 +/- 687, 3593 +/- 688 cells/mm2 for day 10, 20, and 30, respectively). The thickness of the alpha-actin positive layers and the density of the alpha-actin positive cells were not significantly different between the proximal and distal regions of the engineered vein grafts at each observation time. These results suggest that eddy flow may develop in vein grafts and may facilitate the formation of focal intimal hyperplasia, and the vascular tissue engineering approach developed in this study may be used to prevent blood flow-related focal intimal hyperplasia in vein grafts.

Mechanical tensile stress in vein grafts increases suddenly under the influence of arterial blood pressure. In this study, we examined the influence of increased tensile stress on the organization of the smooth muscle cells (SMCs) in the neointima and media of the rat vein grafts. An autogenous jugular vein was grafted into the abdominal aorta of the rat, and changes in the organization of the vein graft SMCs were studied by observing the distribution of SMC actin filaments and nuclei at 3 min and 1, 5, 10, and 30 days after surgery. In a normal jugular vein, the average wall circumferential tensile stress was ~ 3 kPa at an internal pressure of 3 mm Hg. The SMCs, that contained long, slender actin filamentous bundles, were oriented mainly in the circumferential direction of the vessel, and constituted a 2- to 3-cell-thick medial layer underneath the endothelium. In a vein graft, the wall circumferential tensile stress suddenly increased by ~ 140 times compared with the control level. In response to this suddenly increased stress, the SMC layer was stretched into a structure with scattered pores and disrupted SMC actin filamentous bundles within 3 min. This initial change was followed by a rapid reduction in the density of the SMC nuclei and actin filaments within 1 day and progressive SMC proliferation, that was associated with medial thickening and a change in the SMC orientation from 5 to 30 days. Further studies showed that a local inflation of normal jugular veins to 120 mm Hg for 3 min induced a similar change as found in the vein grafts, whereas the organization of the SMCs was not significantly changed in vein-vein grafts, that did not experience a change in tensile stress. These results suggested that increased tensile stress contributed to the initial damage of the SMCs and played a role in the regulation of medial SMC remodeling in vein grafts. © 1998 Biomedical Engineering Society.

Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia. Such processes are present in not only the heart, but also remote organs. In this investigation, we demonstrated a cardioprotective process involving FGF21 from the liver and adipose tissue. In response to myocardial ischemia/reperfusion injury in the mouse, FGF21 was upregulated and released from the hepatic cells and adipocytes into the circulation and interacted with FGFR1 in cardiomyocytes under the mediation of the cell membrane protein β-Klotho, inducing FGFR1 phosphorylation. This action caused phosphorylation of the signaling molecules PI3K p85, Akt1 and BAD, thereby reducing caspase 3 activity, cell death and myocardial infarction in association with improvement of myocardial function. These observations suggest that FGF21 is upregulated and released from the liver and adipose tissue in myocardial injury, contributing to myocardial protection by the mediation of the FGFR1/β-Klotho–PI3K–Akt1–BAD signaling network.

Myocardial ischemia activates innate cardioprotective mechanisms, including expression of growth factors, activation of cardiac resident stem cells and mobilization of bone marrow cells to the ischemic myocardium, which alleviate ischemic injury and promote cardiomyocyte regeneration. This review addresses a newly recognized cardioprotective mechanism involving the liver. Myocardial ischemia induces liver responses, including mobilization of hepatic cells to the circulatory system and upregulation of hepatic secretory proteins, such as fibroblast growth factor 21 (FGF21) and trefoil factor 3 (TFF3). The mobilized hepatic cells either engraft to the ischemic myocardium or disintegrate in the circulatory system, facilitating delivery of the hepatic secretory proteins. These proteins contribute to myocardial protection, alleviating myocardial infarction. These investigations provide new information for understanding the innate cardioprotective mechanisms and developing therapeutic strategies for myocardial infarction.