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The heart is capable of activating protective mechanisms in response to ischemic injury to support myocardial survival and performance. These mechanisms have been recognized primarily in the ischemic heart, involving paracrine signaling processes. Here, we report a distant cardioprotective mechanism involving hepatic cell mobilization to the ischemic myocardium in response to experimental myocardial ischemia–reperfusion (MI-R) injury. A parabiotic mouse model was generated by surgical skin-union of two mice and used to induce bilateral MI-R injury with unilateral hepatectomy, establishing concurrent gain- and loss-of-hepatic cell mobilization conditions. Hepatic cells, identified based on the cell-specific expression of enhanced YFP, were found in the ischemic myocardium of parabiotic mice with intact liver (0.2 ± 0.1%, 1.1 ± 0.3%, 2.7 ± 0.6, and 0.7 ± 0.4% at 1, 3, 5, and 10 days, respectively, in reference to the total cell nuclei), but not significantly in the ischemic myocardium of parabiotic mice with hepatectomy (0 ± 0%, 0.1 ± 0.1%, 0.3 ± 0.2%, and 0.08 ± 0.08% at the same time points). The mobilized hepatic cells were able to express and release trefoil factor 3 (TFF3), a protein mitigating MI-R injury as demonstrated in TFF3−/− mice (myocardium infarcts 17.6 ± 2.3%, 20.7 ± 2.6%, and 15.3 ± 3.8% at 1, 5, and 10 days, respectively) in reference to wildtype mice (11.7 ± 1.9%, 13.8 ± 2.3%, and 11.0 ± 1.8% at the same time points). These observations suggest that MI-R injury can induce hepatic cell mobilization to support myocardial survival by releasing TFF3.

Selinexor is a selective inhibitor of nuclear export with anti-cancer properties. We performed a phase I study to determine the safety and maximum tolerated dose of selinexor when combined with high-dose dexamethasone, ifosfamide, carboplatin and etoposide (DICE) in relapsed/refractory T-cell lymphoma (TCL) and natural-killer/T-cell lymphoma (NKTL). Patients with relapsed/refractory TCL and NKTL were treated with standard dose ICE, dexamethasone 20 mg on days 3 to 7, and escalating doses of oral selinexor on days 3, 5 and 7 in a 3+3 design. Dose levels (DL) 1, 2 and 3 were 40, 60 and 80 mg, respectively. Eleven patients with a median age of 60 years were enrolled; six at DL1 and five at DL2. Patients had received a median of two (range, 1-4) prior lines of treatment and seven had primary refractory disease at entry into the study. Patients received a median of three cycles (range, 1-6) of selinexor-DICE. The most common grade 1 or 2 toxicities included nausea (64%), fatigue (55%), and anorexia (45%) and the most common grade 3 or 4 toxicities included thrombocytopenia (82%), anemia (82%), neutropenia (73%), and hyponatremia (73%). Two patients developed dose-limiting toxicities at DL2 and one at DL1. Five patients discontinued treatment for reasons other than disease progression or lack of response. Of the ten evaluable patients, the overall and complete response rates were 91% and 82%, respectively. The maximum tolerated dose of selinexor was 40 mg when combined with DICE. The combination showed promising complete response rates in patients with relapsed/refractory TCL and NKTL but was poorly tolerated. (clinicaltrials. gov identifier: NCT03212937).

Background: The COVID-19 vaccine for children and adolescents, who are indispensable populations to curb the pandemic, would protect this population against rare severe COVID-19 and infectious conditions. Here we aimed to assess the safety, tolerability and immunogenicity of a candidate COVID-19 vaccine, CoronaVac, containing inactivated SARS-CoV-2, in children and adolescents aged 3-17 years old. Methods: We did a randomised, double-blind, placebo-controlled phase 1/2 clinical trial of CoronaVac in healthy children and adolescents aged 3-17 years old in Zanhuang (Hebei, China). Vaccine (in 0 ·5ml aluminum hydroxide adjuvant) or placebo (adjuvant only) was given by intramuscular injection in two doses (day 0 and day 28). We conducted phase 1 trial in 71 participants with an age de-escalation in tree groups and dose-escalation in two blocks (1.5ug or 3ug per injection). Within each block, participants were randomly assigned (3:1) using block randomisation to receive CoronaVac or placebo. In phase 2, participants were randomly assigned (2:2:1) using block randomisation to receive either CoronaVac at 1.5ug or 3ug per dose, or placebo. The primary safety endpoint was adverse reactions within 28 days after each injection in all participants who received at least one dose. The primary immunogenicity endpoint was seroconversion rate at 28 days after the second injection and its GMT as the secondary endpoint. This study is ongoing and is registered with ClinicalTrials.gov (NCT04551547). Findings: Between October 31 and December 2, 2020, 72 participants were enrolled in phase 1, and between December 12 and December 30, 2020, 480 participants were enrolled in phase 2. 500 participants received at least one dose of vaccine or placebo (n=71 for phase 1 and n=479 for phase 2; safety population). In the combined safety profile of phase 1 and phase 2, any adverse reactions within 28 days after injection occurred in 56 (26%) of 219 participants in the 1·5ug group, 63 (29%) of 217 in the 3ug group and 27 (24%) of 114 in the placebo group, without significant difference. Most adverse reactions were mild and moderate in severity and injection site pain (73[13%]) of 550 participants was the most frequently reported event. As of March 12, 2021, only one serious adverse event has been reported, which was considered unrelated to vaccination. In phase 1, seroconversion after the second dose was observed in 27 of 27 participants (100·0% [95%CI 87·3-100·0]) in the 1·5ug groups and 26 of 26 participants (100·0% [86·8-100·0]) in the 3ug group, with the geometric mean titers of 55·0 (95%CI 38·9-77·9) and 117·4 (87·8-157·0). In phase 2, seroconversion was seen in 180 of 186 participants (96·8% [93·1-98·8]) in the 1·5ug group and 180 of 180 participants (100·0% [98·0-100·0]) in the 3ug group, with the geometric mean titers of 86·4 (73·9-101·0) and 142·2 (124·7-162·1). There were no detectable antibody responses in the placebo groups. Interpretation: CoronaVac was well tolerated and induced strong neutralising antibody responses in children and adolescents aged 3-17 years. The study has provided solid safety and immunogenicity data to support the further study and use of CoronaVac in children and adolescents. Trial Registration: NCT04551547 Funding Statement: Chinese National Key Research and Development Program and Beijing Science and Technology Program. Declaration of Interests: QG and XL are employees of Sinovac Life Sciences Co., Ltd. YS, WY and LW are employees of Sinovac Biotech Ltd. All other authors declare no competing interests. Ethics Approval Statement: The clinical trial protocol and informed consent form were approved by the Ethics Committee of Hebei CDC (IRB2020-005).

While abnormal muscle tone has been observed in people with stroke, how these changes in muscle tension affect sarcomere morphology remains unclear. The purpose of this study was to examine time-course changes in passive muscle fiber tension and sarcomeric adaptation to these changes post-ischemic stroke in a mouse model by using a novel in-vivo force microscope. Twenty-one mice were evenly divided into three groups based on the time point of testing: 3 days (D3), 10 days (D10), and 20 days (D20) following right middle cerebral artery ligation. At each testing time, the muscle length, width, and estimated volume of the isolated soleus muscle were recorded, subsequently followed by in-vivo muscle tension and sarcomere length measurement. The mass of the soleus muscle was measured at the end of testing to calculate muscle density. Two-way ANOVA with repeated measures was used to examine the differences in each of the dependent variable among the three time-point groups and between the two legs. The passive muscle stress of the impaired limbs in the D3 group (27.65 ± 8.37 kPa) was significantly lower than the less involved limbs (42.03 ± 18.61 kPa; p = 0.05) and the impaired limbs of the D10 (48.92 ± 14.73; p = 0.03) and D20 (53.28 ± 20.54 kPa; p = 0.01) groups. The soleus muscle density of the impaired limbs in the D3 group (0.69 ± 0.12 g/cm3) was significantly lower than the less involved limbs (0.80 ± 0.09 g/cm3; p = 0.04) and the impaired limbs of the D10 (0.87 ± 0.12 g/cm3; p = 0.02) and D20 (1.00 ± 0.14 g/cm3; p < 0.01) groups. The D3 group had a shorter sarcomere length (2.55 ± 0.26 μm) than the D10 (2.83 ± 0.20 μm; p = 0.03) and D20 group (2.81 ± 0.15 μm; p = 0.04). These results suggest that, while ischemic stroke may cause considerable changes in muscle tension and stress, sarcomere additions under increased mechanical loadings may be absent or disrupted post-stroke, which may contribute to muscle spasticity and/or joint contracture commonly observed in patients following stroke.

Cardioprotective engineering is an emerging bioengineering discipline aiming to develop engineering strategies to optimize cardioprotective actions against cardiac injuries and disorders. Although there exist innate cardioprotective mechanisms capable of supporting cardiomyocyte survival in response to an insult, not all these mechanisms are optimized in promptness and effectiveness, suggesting the necessity of cardioprotective engineering. Various cardioprotective strategies have been developed and used in experimental and clinical investigations; however, few of these strategies have exerted a significant clinical impact. There are two major challenges in cardioprotective engineering—understanding the innate cardioprotective mechanisms and developing engineering strategies for precise control of the types, levels, timing, and coordination of cardioprotective actions to facilitate recovery from injuries and disorders. Understanding the innate mechanisms is the foundation for developing cardioprotective engineering strategies. Here, ischemic myocardial injury is used as an example to demonstrate the concept of cardioprotective engineering.

In the paper, a net-shape power spinning process for manufacturing poly-V grooved aluminum pulley from tube billet is investigated through finite element (FE) simulation and forming experiment. The process includes two steps of axial upsetting to drum-shape the tube billet and radial spinning to form the grooved exterior shape of the pulley. The upsetting stage is beneficial for the forming of the middle tooth of the pulley. Firstly, the material characteristics of AL1100 are studied. After the establishment of an FE model under the software environment of DEFROM, the deformation characteristics of the upsetting stage are studied, and the effect laws of mandrel feed and friction on the outside drum-shaped surface of billet are evaluated. Based on the FE simulation results of upsetting stage, the primary loads, the flow of materials, and the stress and strain state of the billet in the spinning stage are studied. The influence laws of the feed radio of the rollers, the diameter of the rollers, the mandrel feed ratio, and the axial clearances between rollers and mandrel or back die on the spinning process are discussed by using orthogonal experiments under FE simulation. Two of the primary loads, namely the spinning force and the main torsion, are found to be most sensitive to the feed radio of the rollers. The chucking force, which is another primary load, is found to be most sensitive to the axial clearances. The formability is found to be most easily affected by the mandrel feed ratio. Furthermore, poly-V grooved aluminum pulleys of high performance are produced by forming experiments on power spinning lathe with the optimized process parameters. The net-shape spinning forming process could provide a new plastic forming method of aluminum pulley parts, and the method of orthogonal experiments may be of general significance to determine and optimize the process parameters in spinning forming.

Ischemic stroke causes brain infarction and neurological deficits. Along with these pathological changes, ischemic stroke also activates neuroprotective mechanisms that mitigate brain injury. It has long been recognized that the ischemic brain can upregulate neuroprotective genes to support neuronal survival. The present investigation demonstrated that, in addition to the ischemic brain, the liver was able to respond to ischemic stroke to upregulate genes encoding secreted neuroprotective proteins, including fibroblast growth factor 21 (FGF21), resistin-like molecule γ (RELMγ), and trefoil factor 3 (TFF3). These proteins access the ischemic brain via the circulation to protect ischemic neurons from injury. This report shows how these liver-derived neuroprotective genes were identified by transcriptomic analysis and neuroprotective protein screening.

Myocardial ischemia (MI) activates innate cardioprotective mechanisms, enhancing cardiomyocyte tolerance to ischemia. Here, we report a MI-activated liver-dependent mechanism for myocardial protection. In response to MI in the mouse, hepatocytes exhibited 6- to 19-fold upregulation of genes encoding secretory proteins, including α-1-acid glycoprotein (AGP)2, bone morphogenetic protein-binding endothelial regulator (BMPER), chemokine (C-X-C motif) ligand 13, fibroblast growth factor (FGF)21, neuregulin (NRG)4, proteoglycan 4, and trefoil factor (TFF)3. Five of these proteins, including AGP2, BMPER, FGF21, NRG4, and TFF3, were identified as cardioprotective proteins since administration of each protein significantly reduced the fraction of myocardial infarcts (37 ± 9%, 34 ± 7%, 32 ± 8%, 39 ± 6%, and 31 ± 7%, respectively, vs. 48 ± 7% for PBS at 24 h post-MI). The serum level of the five proteins elevated significantly in association with protein upregulation in hepatocytes post-MI. Suppression of a cardioprotective protein by small interfering (si)RNA-mediated gene silencing resulted in a significant increase in the fraction of myocardial infarcts, and suppression of all five cardioprotective proteins with siRNAs further intensified myocardial infarction. While administration of a single cardioprotective protein mitigated myocardial infarction, administration of all five proteins furthered the beneficial effect, reducing myocardial infarct fractions from PBS control values from 46 ± 6% (5 days), 41 ± 5% (10 days), and 34 ± 4% (30 days) to 35 ± 5%, 28 ± 5%, and 24 ± 4%, respectively. These observations suggest that the liver contributes to cardioprotection in MI by upregulating and releasing protective secretory proteins. These proteins may be used for the development of cardioprotective agents.

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.

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.

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.

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

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 ∗

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.

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.

We investigated the effect of locally altered blood pressure on the remodeling processes of the cells and extracellular matrices of the splenic and ileal arteries and used an indicial function approach to quantitatively analyze the relationship between the altered blood pressure and the remodeling processes. Blood pressure in these arteries was locally modulated by constricting the aorta at a location between the celiac and mesenteric bifurcations, resulting in a higher blood pressure at the splenic arteries then at the ileal arteries, After the pressure changes, the cross-sectional areas and the fractions of the cells and extracellular matrices of the splenic and ileal arteries were examined by electron microscopy at 2, 6, 10, 20, and 30 days. We found that both arteries remodeled, but the splenic arteries (higher blood pressure) remodeled more rapidly and to a larger degree than the ileal arteries (lower pressure compared with the splenic arteries) of the same animal. To verify whether an identical change in the blood pressure at the splenic and ileal arteries leads to the same remodeling process in these arteries, we created another model by constricting the aorta at a location between the mesenteric and renal bifurcations, resulting in hypertension of the same level at both splenic and ileal arteries. We found that the remodeling processes of the cells and matrices were almost identical in the arteries with similar changes in blood pressure. Thus we conclude that the remodeling processes of cells and matrices of the splenic and ileal arteries are dependent on the local blood pressure in aorta constriction-induced hypertension, and the indicial analysis is a useful approach in the description of the relationship between the blood pressure and the arterial remodeling processes.

Background Fibroblast growth factor receptor 4 (FGFR4) displays multiple biological activities, including mitogenic and angiogenic activity, and plays important roles in the etiology and progression of prostate cancer. Gly388Arg polymorphism in FGFR4 gene has been reported to be involved in prostate cancer incidence and aggressiveness in several studies. To derive a more precise estimation of the relationship, a meta-analysis was performed. Methods Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Results The Arg388 allele increased prostate cancer risk compared with Gly388 allele (OR = 1.17, 95% CI = 1.07-1.29). When stratified by race, there was a significantly increased prostate cancer risk in Asian and Caucasian populations. Moreover, prostate cancer patients with Arg/Arg genotype had a 1.34-fold increased risk of advanced prostate cancer (95% CI: 1.03-1.74) compared with those with Gly/Gly+Gly/Arg genotype. Conclusion This meta-analysis showed the evidence that FGFR4 Gly388Arg polymorphism was associated with an increased risk of prostate cancer development and progression, suggesting that FGFR4 Gly388Arg polymorphism could be a marker for prostate cancer development and progression.

Vitamin D inhibits renin expression and blocks the compensatory induction of renin associated with the use of renin-angiotensin system inhibitors. Here we test the therapeutic effects of two commonly used vitamin D analogs and their combination with losartan on the development of left ventricular hypertrophy. One-month-old male spontaneously hypertensive rats were treated with vehicle, losartan, paricalcitol, doxercalciferol, a combination of losartan and paricalcitol, or a combination of losartan and doxercalciferol for 2 months. Blood pressure was markedly reduced by losartan, but not by paricalcitol or doxercalciferol alone. Echocardiograpy demonstrated a 65 to 80% reduction in left ventricular wall thickness with losartan, paricalcitol, or doxercalciferol monotherapy and almost complete prevention of left ventricular hypertrophy with the combination therapies. Attenuation of cardiac and cardiomyocyte hypertrophy, and suppression of atrial and brain natriuretic peptides, were most marked in the combination therapy groups. These changes were well correlated with left ventricular gene and microRNA expression profiles in the different treatment groups. Renal and cardiac renin expression was markedly increased in losartan-treated animals, but nearly normalized with combination therapy. The same vitamin D analogs suppressed plasma renin activity in patients receiving chronic hemodialysis. These data demonstrate that vitamin D analogs have potent antihypertrophic activity in part via suppression of renin in the kidney and heart, and combination of these analogs with losartan achieves much better therapeutic effects because of the blockade of the compensatory renin increase.

Vascular thrombosis, intimal hyperplasia, and atherosclerosis are common disorders affecting a very large portion of the human population. A potential reduction in these disorders will elicit a significant impact. It has been shown that endothelial cells play a critical role in protecting blood vessels against the formation of thrombosis and atherosclerosis. Hence, a successful endothelial cell lining of arterial constructs will prevent intimal hyperplasia in reconstructed arteries. However, in practice endothelial cells often detach from reconstructed arteries due to weak adhesion strength, hindering the effectiveness of endothelial cell lining.Copyright © 2010 by ASME

Atherosclerosis is the leading cause of morbidity and mortality in the developed world. A common treatment option is arterial bypass surgery, which requires the use of a vascular graft. Autologous vein is the current gold standard for use as a vascular graft; however, donor site morbidity and inconsistent availability have provided an impetus to explore alternative graft sources.Copyright © 2010 by ASME

Rheological properties of blood vessels are expected to change in disease process if the structure of the vessel wall changes. This is illustrated in diabetes, which can be induced in rat by a single injection of Streptozocin. One of the rheological properties of the blood vessel is the stress-strain relationship. The nonlinear stress-strain relationship of arteries is best expressed as derivations of a strain-energy function. In this paper, the stress-strain relations are measured and the coefficients in the strain energy function of arteries are determined for diabetic and control rats. The meaning of these coefficients are explained. The influence of diabetes on the elastic property of the arteries is expressed by the changes of these coefficients. A point of departure of the present paper from all other blood vessel papers published so far is that all strains used here are referred to the zero-stress state of the arteries, whereas all other papers refer strains to the no-load state. The existence of a large difference between the zero-stress state and no-load state of arteries is one of our recent findings. We have explained that the use of zero-stress state as a basis of strain measurements reveals that the in vivo circumferential stress distribution is quite uniform in the vessel wall at the homeostatic condition. It also makes the strain energy function much more accurate than those in which the residual stress is ignored. Using these new results, the stress and strain distribution in normal and diabetic arteries are presented.

Zero-stress states of the main pulmonary arteries and aorta and small systemic arteries were determined in 22 nondiabetic and 29 streptozocin (STZ)-induced diabetic rats. The zero-stress state of each vessel was obtained by cutting the vessel transversely into a series of short rings, then cutting each ring radially, which caused the ring to spring open into a sector. Each sector can be characterized by its opening angle. The opening angle has strong regional dependence. In some regions of rat arteries, the opening angle can be greater than 360 degrees. Rats were studied 5, 10, 20, 30, and 40 days after an injection of 75 mg/kg body wt i.v. STZ. During diabetes development, the opening angles in general increased and reached a plateau in approximately 30 days. The maximum change of opening angle over normal lies in the range of 18-105 degrees, depending on location. The pulmonary arteries were affected by diabetes as much as the systemic arteries. The course of change of the opening angle during diabetogenesis was different from those of the serum glucose level and blood pressure. Blood pressure in carotid, external iliac, and pulmonary arteries did not change significantly in diabetogenesis. To clarify the physiological meaning of the opening angle, we measured the circumferential strain in the blood vessel wall in homeostatic condition and the residual strain at the no-load state, with both strains referred to the zero-stress state. We calculated the corresponding stresses in the vessel wall. The circumferential stress in the vessel wall was greatly increased by diabetes; great errors will result if the opening angle is ignored.

Objective: To present recent estimates of alcohol consumption and its impact on the health of people in the Northern Territory, and to draw comparisons with Australia as a whole. Design, setting and participants: Descriptive study of alcohol consumption in the NT population, based on sales data and self-report surveys, and alcohol-attributable deaths and hospitalisations among people in the NT in the 2004–05 and 2005–06 financial years using population alcohol-attributable fractions specific to the NT. Main outcome measures: Per capita consumption of pure alcohol, self-reported level of consumption, and age-standardised rates of death and hospitalisation attributable to alcohol. Results: Apparent per capita consumption of pure alcohol for both Aboriginal and nonAboriginal populations in the NT has been about 14 litres or more per year for many years, about 50% higher than for Australia as a whole. We estimated that there were 120 and 119 alcohol-attributable deaths in the NT in 2004–05 and 2005–06, respectively, at corresponding age-standardised rates of 7.2 and 7.8 per 10000 adult population. Alcohol-attributable deaths occur in the NT at about 3.5 times the rate they do in Australia generally; rates in nonAboriginal people were about double the national rate, while they were 9–10 times higher in Aboriginal people. There were 2319 and 2544 alcohol-attributable hospitalisations in the NT in 2004–05 and 2005–06, respectively, at corresponding rates of 146.6 and 157.7 per 10000 population (more than twice the national rate). Conclusion: In recent years, alcohol consumption and consequent alcohol-attributable deaths and hospitalisations for both Aboriginal and non-Aboriginal people in the NT MJA 2010; 193: 269–272 have occurred at levels far higher than elsewhere in Australia.

Zero-stress state of the main pulmonary arteries, from the main trunk to a vessel with a lumen diameter approximately 60 microns, was determined in 25 normal control and 38 hypoxic pulmonary hypertensive rats. Pulmonary hypertension was induced by placing the rats in a hypoxic chamber with 10% O2-90% N2 at atmospheric pressure. The zero-stress state of each vessel was obtained by first cutting the vessel transversely into a series of rings and then cutting each ring radially, whereupon the ring opened into a sector, which is characterized by an opening angle defined as the angle subtended between two lines originating from the midpoint of the inner wall (endothelium) to the tips of the inner wall. Whereas the pulmonary blood pressure increased monotonically during the development of pulmonary hypertension, the opening angle followed a different course; e.g., the values (means +/- SD) of the opening angle at the pulmonary trunk at times 0 (control) and 2, 12, 28, 96, 144, 240, 480, and 720 h after exposure to hypoxia are, respectively, 294 +/- 30 degrees, 378 +/- 24 degrees, 385 +/- 12 degrees, 374 +/- 11 degrees, 246 +/- 63 degrees, 267 +/- 49 degrees, 193 +/- 19 degrees, 195 +/- 83 degrees, and 239 +/- 38 degrees. Trends at other places on the artery are similar, but the magnitudes differ. In this period of time, intimal edema and thickening were found. The intima media thickened rapidly from 48 to 240 h and then more slowly from 240 to 720 h. Adventitia thickened later; its thickness exceeded that of the intima media at approximately 96 h. Thus the changes of zero-stress state of the pulmonary arteries are seen to be related to the nonuniform remodeling of the vessel wall as revealed by the edema, blebs, and thickening of different layers.

This preliminary study was conducted to explore different analytical shape methods for use in evaluating children born with cranial vault deformities. Twenty skull outlines from patients with metopic craniosynostosis were ascribed landmarks. Scale, location, and rotational factors were removed using Procrustes analysis. A single index of severity from 0-5, with 5 being the most severe, was developed using Procrustes distance in shape space. Skull 20 had the highest score in our data set. Principal component analysis was performed to determine areas of large shape variability. Principal component 1 and 2 accounted for 86 % of the shape variability which was attributed to early closure of the metopic suture. Procrustes analysis used in combination with Procrustes distance and principal component analysis are powerful tools for the evaluation of cranial vault deformities and can be used to objectively categorize the severity of the skull deformity and outcome from surgical reconstructive surgery.

Vein grafts, a unique type of blood vessels, are subject to increased tensile stress due to exposure to arterial blood pressure, and have been used to study the mechanism of mechanical regulation of vascular remodeling. As shown in a previous study, the average tensile stress in an experimental vein graft could be two orders of magnitude higher than that in a vein upon reopening of blood flow. This stress has been shown to be associated with smooth muscle cell (SMC) death and SMC actin filament degradation within one day, followed by SMC proliferation after five days after surgery. However, it remains unclear whether tensile stress and strain were responsible for the early death of SMCs. This study was designed to clarify this issue.

Impingement of the anterior cruciate ligament (ACL) against the intercondylar notch (lCN) may play a significant role in ACL injuries. However, there is a lack of convenient and accurate methods for evaluating ACL impingement with consideration of the three-dimensional (3-D) notch shape and ACL fibers. In the current study, ACL impingement was modeled using a 3-D geometric knee model that includes multiple ACL pseudofibers, which allowed us to identify the sites of ACL impingement during simulated tibiofemoral movements. The simulation results were compared with impingement force data measured in three cadaveric knees with ACL impingement. Results show that ACL impingement can occur on fibers at the anterolateral aspect of the anteromedial band of the ACL during tibial external rotation and abduction. The computed peak ACL strains of the three knees were 5-8%. The proposed analysis is a practical method for quantitatively evaluating ACL impingement against the ICN, and may lead to useful tools for evaluating ACL impingement in individual patients based on their magnetic resonance imaging data. These analytical tools may guide individualized rehabilitation and reduce potential ACL impingement against the ICN during strenuous tibiofemoral movements.