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Biomedical subjects

Xiao Lu

Publications and source records attributed to Xiao Lu.

At least 19 recordsLinked to original sources
PubMed2026

Safety and efficacy of recombinant botulinum toxin type A (Eveotox®) in patients with post-stroke upper limb spasticity: Results from a Phase Ib/II clinical trial.

Upper limb spasticity is a common and disabling complication of stroke. Botulinum toxin type A (BoNT-A) is widely used for focal spasticity treatment, but naturally derived products may present limitations related to immunogenicity and manufacturing variability. Recombinant botulinum toxin type A, produced by genetic engineering without complexing proteins, may provide improved product consistency. This Ib/II study evaluated the safety, tolerability, and preliminary efficacy of recombinant botulinum toxin type A in adults with post-stroke upper limb spasticity. This multicenter, seamless Ib/II clinical study included an open-label dose-escalation Ib phase and a randomized, double-blind, placebo-controlled II phase. Adult patients with post-stroke upper limb spasticity received a single intramuscular injection of recombinant botulinum toxin type A or placebo. The primary endpoint in Phase II was the change from baseline in the Modified Ashworth Scale (MAS) score of the primary target muscle group at Week 4. Secondary endpoints included MAS and Tardieu scale changes in individual muscle groups, Disability Assessment Scale (DAS), Physician's Global Assessment (PGA), and immunogenicity. The Ib phase showed improvements in MAS, DAS, and PGA, indicating an early efficacy signal. In Phase II, recombinant botulinum toxin type A produced a significant reduction in MAS score of the primary target muscle group at Week 4 compared with placebo, with effects sustained through Week 12. At Week 4, the PGA score in the Eveotox® group showed a statistically significant improvement compared with the placebo group. While MAS and PGA scores showed significant improvement, DAS functional scores did not differ statistically from the placebo group at week 4. The treatment was generally well tolerated, and low incidence of antibodies were observed. Recombinant botulinum toxin type A was safe and effective in reducing post-stroke upper limb spasticity after a single administration. These results support further Phase III clinical evaluation.

Humans↗
PubMed2007

Vasoactivity of blood vessels using a novel isovolumic myograph.

The vasoactivity of blood vessel is impaired by cardiovascular disease. The ex-vivo measurements of vasoactivity (wire and pressure myographs) have some inherent difficulties in the characterization of pharmacodynamics and biomechanics. Here, we introduce a novel isovolumic myograph which allows simultaneous measurement of both dynamic pressure and dimensional changes during vasoconstriction or vasodilation. The principle of the isovolumic myograph is based on the utility of a hydraulically closed system with low compliance such that contraction against an incompressible fluid increases the pressure with the closed system while dilation decreases it. We demonstrate the sensitivity and utility of the new technique by the response of elastic (carotid), muscular (femoral) arteries, and femoral veins. The results show characteristic dynamic pressure response for each vessel type. Furthermore, our results show a Hill-type equation for the tension-velocity relation for smooth muscles as well as characteristic curves for each contraction. These novel findings for blood vessels will advance our knowledge of endothelium and vascular smooth muscle mechanics and pharmacodynamics.

Animals↗
PubMed2006

Proper orientation of the graft artery is important to ensure physiological flow direction.

Arterial grafts such as right internal mammary artery (RIMA), radial artery (RA) or epigastric artery are being used with increasing frequency as free grafts or as composite grafts with left internal mammary artery (LIMA). Currently, there is no consideration of the orientation of the free artery graft to mimic the in vivo state. Hence, some grafts may be oriented such that the direction of blood flow exerted on the endothelium is reversed relative to the in vivo condition. Previous studies have shown that transient flow reversal lead to atherogenesis. A recent study demonstrated that nitric oxide is significantly reduced during reverse flow and the reduction is mediated through an increase in superoxide production. In light of these data, we suggest that the flow direction is important and recommend the assurance of proper orientation of the free arterial graft. Furthermore, we propose a new surgical procedure to modify the composite LIMA-RA or LIMA-RIMA configuration as a horseshoe or K composite graft to ensure proper orientation of the flow direction relative to the endothelium.

Animals↗
PubMed2006

AMP-activated protein kinase is involved in endothelial NO synthase activation in response to shear stress.

OBJECTIVE: The regulation of AMP-activated protein kinase (AMPK) is implicated in vascular biology because AMPK can phosphorylate endothelial NO synthase (eNOS). In this study, we investigate the regulation of the AMPK-eNOS pathway in vascular endothelial cells (ECs) by shear stress and the activation of aortic AMPK in a mouse model with a high level of voluntary running (High-Runner). METHODS AND RESULTS: By using flow channels with cultured ECs, AMPK Thr172 phosphorylation was increased with changes of flow rate or pulsatility. The activity of LKB1, the upstream kinase of AMPK, and the phosphorylation of eNOS at Ser1179 were concomitant with AMPK activation responding to changes in flow rate or pulsatility. The blockage of AMPK by a dominant-negative mutant of AMPK inhibited shear stress-induced eNOS Ser1179 phosphorylation and NO production. Furthermore, aortic AMPK activity and level of eNOS phosphorylation were significantly elevated in the aortas of High-Runner mice. CONCLUSIONS: Our results suggest that shear stress activates AMPK in ECs, which contributes to elevated eNOS activity and subsequent NO production. Hence, AMPK, in addition to serving as an energy sensor, also plays an important role in regulating vascular tone.

AMP-Activated Protein Kinases↗
PubMed2006

Three-dimensional mechanical properties of porcine coronary arteries: a validated two-layer model.

The normal coronary artery consists of two mechanically distinct layers: intima-media and adventitia. The objective of this study is to establish a two-layer three-dimensional (3-D) stress-strain relation of porcine coronary arteries. Experimental measurements were made by a series of biaxial tests (inflation and axial extension) of intact coronary arteries and, subsequently, their corresponding intima-media or adventitia layer. The Fung-type exponential strain energy function was used to describe the 3-D strain-stress relation for each layer and the intact wall. A genetic algorithm was used to determine the material constants in the Fung-type constitutive equation by curve fitting the experimental data. Because one layer must be sacrificed before the other layer can be tested, the material property of the missing layer was computed from the material constants of the intact vessel and the tested layer. A total of 20 porcine hearts were used: one group of 10 hearts for the left anterior descending artery and another group of 10 hearts for the right coronary artery. Each group was further divided into two subgroups of five specimens tested for the intact wall and the intima-media layer and for the intact wall and the adventitia layer. Our results show statistically significant differences in the material properties of the two layers. The mathematical model was validated by experimental stress-strain data for individual layers. The validated 3-D constitutive model will serve as a foundation for formulation of layer-specific boundary value problems in coronary physiology and cardiology.

Algorithms↗
PubMed2006

Preparation and evaluation of C18-bonded 1-microm silica particles for pressurized capillary electrochromatography.

Nonporous silica spheres (1 microm) were synthesized and bonded with octadecylsilane functionality. These stationary phase particles were packed electrokinetically into fused-silica capillaries with 100 microm id for a length of 20 cm, which was evaluated by using pressurized CEC (pCEC). The efficiency of the C18 RP column was characterized through the theoretical plates of thiourea, benzyl alcohol, toluene, styrene, and naphthalene. The effects of experimental parameters such as the applied voltage, sample size, pump flow rate, pH value and the concentration of the buffer solution, and the content of methanol in the mobile phase, on-column efficiency were evaluated. Column efficiency as high as 200 000 theoretical plates per meter for naphthalene was obtained with the optimal condition of 70% v/v methanol and 30% v/v of 10 mmol/L phosphate buffer (pH 7.8) at an applied voltage of 10 kV and a supplementary pressure of 500 psi.

Benzyl Alcohol↗
PubMed2006

Preparation of particle-fixed silica monoliths used in capillary electrochromatography.

Fused-silica capillarieswere packed with porous 1 microm bare silica microspheres and immobilized by potassium silicate-formamide in order to obtain columns with silica-based monolithic packing. After curing, the particle-fixed monolithic columns were octadecylated insitu with dimethyloctadecylchlorosilane. The columns were mechanically strong and permeable. No noticeable loss in efficiency was found after using a column continuously for 1 month. The performances of the particle-fixed silica monolithic columns were evaluated for CEC under RP conditions. High separation efficiency (about125 200 plates/m) was obtained by using these new types of columns.

Journal Article↗
PubMed2006

Effects of cryopreservation on the developmental competence, ultrastructure and cytoskeletal structure of porcine oocytes.

The purpose of this study was to determine ultrastructural and cytoskeletal changes that result from vitrification of porcine germinal vesicle- (GV-) and meiosis II- (MII-) stage oocytes. To investigate the effects of vitrification on developmental competence, oocytes were divided into three groups: fresh GV-oocytes (control), vitrified GV-oocytes, and vitrified MII-oocytes. In both GV- and MII-oocytes, vitrification resulted in a high proportion with normal morphology (92.4 vs. 94.2%, P > 0.05), while vitrified GV-oocytes yielded a higher survival rate than did vitrified MII-oocytes (56.8 vs. 41.9%, P < 0.05). In vitrified GV-oocytes, 12 of 154 oocytes underwent cleavage after fertilization in vitro, and 6 of these developed to the 8-cell stage, 3 developed to the 16-cell stage, and 3 developed into morulae. No cleavage was obtained from vitrified MII-oocytes. For ultrastructural analysis of oocytes, fresh and vitrified-warmed GV- and MII-oocytes were randomly selected for transmission electron microscopy (TEM). Results showed that vitrification caused various degrees of cryodamage in GV-oocytes. Cumulus cells of some oocytes were separated from the cumulus-oocyte complex (COC), and the zona pellucida adjacent to cumulus cells was fractured. The gap junctions between cumulus cells were ruptured, and many microvilli were disrupted or disappeared. Only homogeneous lipid droplets were observed. After vitrification, cortical granules still lined the oolemma of MII-oocytes. Only morphologically irregular, nonhomogeneous lipid droplets surrounding large vacuoles were found. To examine cytoskeletal structures, fresh and vitrified-warmed MII-oocytes were analyzed by laser-scanning confocal microscopy (LSCM); vitrified-warmed GV-oocytes were cultured for 42-44 hr before LSCM. Of 58 control oocytes, 79.5% displayed normal spindles with chromosomes aligned along the equatorial plate. In vitrified oocytes the percentage with normal spindle organization was decreased significantly in both vitrified GV-oocytes and MII-oocytes (10.1 and 12.9%, respectively, P < 0.05). The proportion of oocytes with normal distribution of F-actin was lower for vitrified GV- and MII-oocytes than for controls (16.9 and 37.2% vs. 72.3%). Results of this experiment suggest that irreversible damage to the cytoskeleton of porcine GV- and MII-oocytes after vitrification could be an important factor affecting developmental competence.

Animals↗
PubMed2005

Duration of no-load state affects opening angle of porcine coronary arteries.

The zero-stress state of a blood vessel has been extensively studied because it is the reference state for which all calculations of intramural stress and strain must be based. It has also been found to reflect nonuniformity in growth and remodeling in response to chemical or physical changes. The zero-stress state can be characterized by an opening angle, defined as the angle subtended by two radii connecting the midpoint of the inner wall. All prior studies documented the zero-stress state or opening angle with no regard to duration of the no-load state. Our hypotheses were that, given the viscoelastic properties of blood vessels, the zero-stress state may have "memory" of prior circumferential and axial loading, i.e., duration of the no-load state influences opening angle. To test these hypotheses, we considered ring pairs of porcine coronary arteries to examine the effect of duration in the no-load state after circumferential distension. Our results show a significant reduction in opening angle as duration of the no-load state increases, i.e., vessels that are reduced to the zero-stress state directly from the loaded state attain much larger opening angles at 30 min after the radial cut than rings that are in the no-load state for various durations. To examine the effect of axial loading, we found similar reductions in opening angle with duration in the no-load from the in situ state, albeit the effect was significantly smaller than that of circumferential loading. Hence, we found that the zero-stress state has memory of both circumferential and axial loading. These results are important for understanding viscoelastic properties of coronary arteries, interpretation of the enormous data on the opening angle and strain in the literature, and standardization of future measurements on the zero-stress state.

Animals↗
PubMed2005

Estrogen modulates the mechanical homeostasis of mouse arterial vessels through nitric oxide.

We have recently shown that estrogen causes vessel dilation through receptor-mediated stimulation of nitric oxide (NO) production. Here, we hypothesize that estrogen modulates the mechanical homeostasis in the blood vessel wall through NO production. The mechanical properties of female ovariectomized (ovx) mice, female mice lacking the gene for endothelial NO synthase (eNOS(-/-)), and control female and male mice were studied to test the hypothesis. The femoral and carotid arteries and aorta were cannulated in situ and mechanically distended. The stress, strain, elastic modulus, and wall thickness of vessels in ovx and eNOS(-/-) mice, as well as intact female and male mice, were determined. Western blot and immunohistochemistry were used to assess eNOS protein expression in the aorta. Moreover, NO by-products of the femoral and carotid artery were determined by measuring the levels of nitrite and nitrate. Our results show that ovariectomy and eNOS(-/-) significantly decrease the strain in all arteries. Furthermore, the eNOS protein was significantly reduced in ovx mice. Finally, the NO metabolites were significantly decreased both in ovx and eNOS(-/-) mice. We found statistically significant correlations between the structural (wall thickness), mechanical (stress, strain, and elastic modulus), and biochemical parameters (NO by-products). These novel results connect NO to the structural and mechanical properties of the vessel wall. Hence, the effect of endogenous estrogen on the arterial mechanical properties is mediated by the regulation of NO derived from eNOS.

Animals↗
PubMed2005

Biaxial elastic material properties of porcine coronary media and adventitia.

The importance of mechanical stresses and strains has become well recognized in vascular physiology and pathology. To compute the stress and strain on the various components of the vessel wall, we must know the constitutive equations for the different layers of the vessel wall. The objective of the present study is to determine the constitutive equation of the coronary artery treated as a two-layer composite: intima-media and adventitial layers. Twelve hearts were obtained from a local slaughterhouse, and the right coronary artery and left anterior descending artery were dissected free from the myocardium. The vessel wall was initially mechanically tested biaxially (inflation and axial extension) as a whole (intact wall) and subsequently as intima-media or adventitial layer. A Fung-type exponential strain energy function was used to curve fit the experimental data for the intact wall and individual layers for the right coronary artery and left anterior descending artery. Two methods were used for the determination of material constants, including the Marquardt-Levenberg nonlinear least squares method and the genetic algorithm method. Our results show that there were no statistically significant differences in the material constants obtained from the two methods and that either set of elastic constants results in good fit of the data. Furthermore, at an in vivo value of axial stretch ratio, we find that the stiffness is as follows: intima-media > intact > adventitia. These results underscore the composite nature of coronary arteries with different material properties in each layer. The present results are necessary for analysis of coronary artery mechanics and to provide a fundamental understanding of vessel physiology.

Animals↗
PubMed2005

Small intestinal morphometric and biomechanical changes during physiological growth in rats.

Changes in small intestinal geometry, residual strain and stress-strain properties during physiological growth were studied in rats ranging from 1 to 32 weeks of age. Small intestinal mass and dimensions increased many-fold with age, e.g. the weight per unit length increased five-fold with age and the wall cross-sectional area increased four-fold. The opening angle of duodenum obtained at zero-stress state was approximately 220 degrees and 290 degrees during the first and second week after birth and decreased to 170 degrees at other ages (p < 0.005). The opening angle of ileum ranged between 120 degrees and 150 degrees . The residual strain of duodenum at the mucosal surface did not vary with age (p > 0.05) whereas the residual strain of ileum at the mucosal surface decreased with age (p < 0.001). The circumferential and longitudinal stress-strain curves fitted well to a mono-exponential function. At a given circumferential stress, the corresponding strain values increased during the first 8 weeks of age (p < 0.05) where after no further change was observed. Hence, the small intestine became more compliant during early life. At a given longitudinal stress, the corresponding strains of ileum and duodenum became larger during the first 2-4 weeks of age (p < 0.05) where after no further change was observed. The small intestine was stiffer in longitudinal direction compared to the circumferential direction. In conclusion, pronounced morphometric and biomechanical changes were observed in the rat small intestine during physiological growth. Such data may prove useful in the understanding of the functional changes of the digestive tract during early life.

Age Factors↗
PubMed2005

Transmural strain distribution in the blood vessel wall.

The transmural distributions of stress and strain at the in vivo state have important implications for the physiology and pathology of the vessel wall. The uniform transmural strain hypothesis was proposed by Takamyzawa and Hayashi (Takamizawa K and Hayashi K. J Biomech 20: 7-17, 1987; Biorheology 25: 555-565, 1988) as describing the state of arteries in vivo. From this hypothesis, they derived the residual stress and strain at the no-load condition and the opening angle at the zero-stress state. However, the experimental evidence cited by Takamyzawa and Hayashi (J Biomech 20: 7-17, 1987; and Biorheology 25: 555-565, 1988) to support this hypothesis was limited to arteries whose opening angles (theta) are <180 degrees. It is well known, however, that theta > 180 degrees do exist in the cardiovascular system. Our hypothesis is that the transmural strain distribution cannot be uniform when theta; is >180 degrees. We present both theoretical and experimental evidence for this hypothesis. Theoretically, we show that the circumferential stretch ratio cannot physically be uniform across the vessel wall when theta; exceeds 180 degrees and the deviation from uniformity will increase with an increase in theta; beyond 180 degrees. Experimentally, we present data on the transmural strain distribution in segments of the porcine aorta and coronary arterial tree. Our data validate the theoretical prediction that the outer strain will exceed the inner strain when theta > 180 degrees. This is the converse of the gradient observed when the residual strain is not taken into account. Although the strain distribution may not be uniform when theta exceeds 180 degrees, the uniformity of stress distribution is still possible because of the composite nature of the blood vessel wall, i.e., the intima-medial layer is stiffer than the adventitial layer. Hence, the larger strain at the adventitia can result in a smaller stress because the adventitia is softer at physiological loading.

Animals↗
PubMed2005

[Construction of standard recombinant plasmids for 7 common mannan-binding lectin gene haplotypes].

OBJECTIVE: To construct the standard recombinant plasmids for 7 common haplotypes of mannan-binding lectin (MBL) gene. METHODS: The DNA samples with known haplotypes and genotypes of MBL gene were used as the templates for amplifying the fragments of MBL gene haplotypes including the promoter region and exon 1 with sequence-specific primer-polymerase chain reaction (SSP-PCR) method. The amplified fragments were cloned into T vector and the bases located at codon 52 and codon 57 of exon 1 in MBL gene were mutated respectively by site-directed mutagenesis. All the 7 recombinant plasmids were identified by PCR and direct sequence analysis. RESULTS: From the DNA samples with known haplotypes and genotypes of MBL gene, the standard plasmids of haplotypes HYPA, LXPA, LYQA, LYPA and LYPB of MBL gene were constructed by SSP-PCR and molecular cloning technique. From the recombinant plasmids of HYPA and LYQA, the standard plasmids of haplotypes HYPD and LYQC of MBL gene were constructed by site-directed mutagenesis, respectively. CONCLUSION: The constructed standard plasmids of haplotypes HYPA, LXPA, LYQA, LYPA, LYPB, HYPD and LYQC of MBL gene provide standard controls for detecting the SNPs, haplotypes and genotypes of MBL gene with such genotyping methods us SSP-PCR and real-time PCR.

Base Sequence↗
PubMed2004

Physiological growth is associated with esophageal morphometric and biomechanical changes in rats.

Esophageal geometry and biomechanical changes were studied during physiological growth in rats aged 1-32 weeks. Histological examination was done after the biomechanical study. The esophageal dimensions increased many-fold from 1-32 weeks, e.g. the weight per unit length increased six-fold and the wall cross-sectional area increased eight-fold. The inner and outer circumferential length of the mucosa and muscle, and the thickness and area of the layers increased as function of age. The opening angle was approximately 140 degrees at age 1 and 2 weeks and gradually decreased to approximately 80 degrees after 16 weeks. The circumferential and longitudinal stress-strain curves were exponential. The circumferential stress-strain curves shifted from left to the right up to 4 weeks of age (P < 0.001) where after no further change was observed, i.e. the esophagus became more compliant during the first 4 weeks of life. The longitudinal stress-strain curves shifted from left to the right up to 16 weeks of age (P < 0.001), i.e. the esophagus became more compliant longitudinally during the first 16 weeks of life. Bi-axial stress-strain analysis with determination of mechanical tissue constants showed that the esophagus was stiffer in the longitudinal direction than in the circumferential direction. In conclusion, a pronounced morphometric and biomechanical remodelling was observed in the rat esophagus during physiological growth. The observed changes likely reflect the development of the physiological function of the esophagus since for other tissues the function dictates the form of the tissue, and growth and remodelling depend on the mechanical loading.

Animals↗
PubMed2004

Biaxial incremental homeostatic elastic moduli of coronary artery: two-layer model.

The detailed mechanical properties of various layers of the coronary artery are important for understanding the function of the vessel. The present article is focused on the determination of the incremental modulus in different layers and directions in the neighborhood of the in vivo state. The incremental modulus can be defined for any material subjected to a large deformation if small perturbations in strain lead to small perturbations of stresses in a linear fashion. This analysis was applied to the porcine coronary artery, which was treated as a two-layered structure consisting of an inner intima-media layer and an outer adventitia layer. We adopted a theory based on small-perturbation experiments at homeostatic conditions for determination of incremental moduli in circumferential, axial, and cross directions in the two layers. The experiments were based on inflation and axial stretch. We demonstrate that under homeostatic conditions the incremental moduli are layer- and direction dependent. The incremental modulus is highest in the circumferential direction. Furthermore, in the circumferential direction, the media is stiffer than the whole wall, which is stiffer than the adventitia. In the axial direction, the adventitia is stiffer than the intact wall, which is stiffer than the media. Hence, the coronary artery must be treated as a composite, nonisotropic body. The data acquire physiological relevance in relation to coronary artery health and disease.

Animals↗
PubMed2004

A new method to denude the endothelium without damage to media: structural, functional, and biomechanical validation.

The intimial thickening that occurs in human and animal atherogenesis can be induced by mechanical injury to the endothelium. The objective of the present study was to develop a new method to induce arterial endothelial injury without damage to the media for future investigations of mechanisms of intimal thickening and atherogenesis. A specifically designed catheter was inserted into the common femoral artery of Wistar rats (n = 9) through an arteriotomic mouth. After application of Tyrode solution containing 0.14 M KCl on the surface of the vessel, the vessel contracted onto the catheter. The catheter was then moved back and forth to scrape away the endothelium. The left common femoral artery of the same rat was subjected to the standard balloon injury model. The two models were evaluated structurally, functionally, and biomechanically. Structurally, we verified that both techniques remove the endothelium, but the balloon method damages the media. Functionally, we examined the contractile response of the artery to [K+] and norepinephrine 2 days after the denudation. We found that the right femoral artery underwent contraction in response to [K+], whereas the left artery did not. Furthermore, neither artery responded to norepinephrine. Biomechanically, we measured the pressure-diameter relationship and the zero-stress state of the vessel and computed the stress-strain relation. The circumferential stretch ratios at 120 mmHg were 1.38 +/- 0.08 for the control, 1.41 +/- 0.08 (P > 0.05) for the new method, and 1.56 +/- 0.09 for the balloon injury (P < 0.05). The opening angles at the zero-stress state were 113 +/- 21 degrees for the control, 102 +/- 18 degrees for the new method (P > 0.05), and 8 +/- 13 degrees for the balloon injury (P < 0.001). In conclusion, the new method removes the endothelium while maintaining the structure, contractile function, and biomechanical properties of the vessel.

Animals↗