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Search Results: 1 - 7 of 7 matches for " Thusitha Gajanayake "
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Sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells
Shengsi Zhu, Hema Viswambharan, Thusitha Gajanayake, Xiu-Fen Ming, Zhihong Yang
BMC Cardiovascular Disorders , 2005, DOI: 10.1186/1471-2261-5-22
Abstract: SMCs were cultured from human saphenous veins and aortas. Quiescent cells were stimulated with sirolimus (0.1 – 20 ng/ml) over 24 hours. Cellular TF expression and activity released into culture medium were measured. The effect of sirolimus on activation of mammalian target of rapamycin (mTOR) was measured by phosphorylation of the substrate p70s6k at T389, and activation of RhoA was measured by pull-down assay.Sirolimus increased TF protein level in cultured human SMCs in a concentration and time-dependent manner (about 2-fold, p < 0.01) reaching maximal effect at 5 ng/ml. The stimulation of TF expression by sirolimus was associated with inhibition of basal activity of mTOR. No effects of sirolimus on RhoA or p38mapk activation that are positive regulators of TF in vascular wall cells were observed. The stimulation of TF expression by sirolimus (20 ng/ml) was prevented by the HMG-CoA reductase inhibitor fluvastatin (1 μmol/L). However, no increase in TF activity released from SMC into culture medium was observed after sirolimus treatment.Although sirolimus stimulates TF protein expression in human SMC associated with inhibition of mTOR, it does not enhance TF activity released from the cells, suggesting a relatively safe profile of CYPHER stents. The inhibition of TF expression by fluvastatin favors clinical use of statins in patients undergoing coronary stenting.Since the first human study with sirolimus (rapamycin)-eluting stents (Cordis CYPHER? stent) by Sousa [1], considerable promise of sirolimus-eluting stents for reducing restenosis rates and clinical parameters was subsequently demonstrated by several randomized clinical trials [2-7]. The mechanism of inhibition of restenosis by sirolimus has been suggested to be attributed to the blockade of smooth muscle cell (SMC) cycle progression from G1 to S phase via inhibition of the protein kinase, mammalian target of rapamycin (mTOR)[8].Despite the promising results on restenosis rates, there is concern that drug-
Assessment of endothelium and inflammatory response at the onset of reperfusion injury in hand surgery
Pranitha Kamat, Bettina Juon, Brigitte Jossen, Thusitha Gajanayake, Robert Rieben, Esther V?gelin
Journal of Inflammation , 2012, DOI: 10.1186/1476-9255-9-18
Abstract: Ten patients were included in the study after obtaining informed consent. A tourniquet was placed on the upper arm and inflated to 250?mmHg for 116 ± 16 min, during which the surgery was performed. Venous blood and tissue samples from the surgical area were taken at baseline as well as 0, 2, and 10?min after reperfusion and analyzed for the following parameters: Endothelial integrity and/or activation were analyzed by measuring heparan sulfate and syndecan-1 in serum, and vWF, heparan sulfate proteoglycan as well as CD31on tissue. Complement activation was determined by C3a and C4d levels in plasma, levels of C1-inhibitor in serum, and IgG, IgM, C3b/c, and C4b/c deposition on tissue. Cytokines and growth factors IL-5, IL-6, IL-7, IL-8, IL-10, IL-17, G-CSF, GM-CSF, MCP-1, TNFα, VEGF, and PDGF bb were measured in the serum. Finally, CK-MM levels were determined in plasma as a measure for muscle necrosis.Markers for endothelial activation and/or integrity as well as complement activation showed no significant changes until 10?min reperfusion. Among the measured cytokines, IL-6, IL-7, IL-17, TNFα, GM-CSF, VEGF, and PDGF bb were significantly increased at 10?min reperfusion with respect to baseline. CK-MM showed a rise from baseline at the onset of reperfusion (p?<?0.001) and dropped again at 2?min (p?<?0.01) reperfusion, suggesting ischemic muscle damage.In this clinical model of I/R injury no damage to the endothelium, antibody deposition or complement activation were observed during early reperfusion. However, an increase of pro-inflammatory cytokines and growth factors was shown, suggesting a contribution of these molecules in the early stages of I/R injury.
Do All Prostate Cancers Behave the Same?  [PDF]
Dissanayake Thusitha, Arze Elizabeth, Rogers Mailien
Journal of Cancer Therapy (JCT) , 2013, DOI: 10.4236/jct.2013.49169
Abstract:

Two different immunohistochemical types suggestive of Large Cell Neuroendocrine (NE) carcinoma and Adenocarcinoma in a patient with known diffusely metastatic, hormone refractory prostate carcinoma are rarities. Interestingly, our patient had documented history of exposure to Agent Orange during his time of service. The use of routinely used immunohistochemical stains for pathological diagnosis was a challenge in this case, though throughout his disease course, the diagnosis was confirmed as Adenocarcinoma of prostate with biopsies from all various sites of metastases. Systemic chemotherapy has been historically suboptimal in management of aggressively behaved prostate carcinomas. Finding any association of Agent Orange as a causative etiology and improving diagnosis and management of such aggressive hormone refractory prostate carcinoma need further investigations.

A model of blood flow in the mesenteric arterial system
Thusitha DS Mabotuwana, Leo K Cheng, Andrew J Pullan
BioMedical Engineering OnLine , 2007, DOI: 10.1186/1475-925x-6-17
Abstract: Understanding how perfusion is affected during ischemic conditions can be a useful clinical tool which can help clinicians during the diagnosis process. As a first step towards this final goal, a computational model of the gastrointestinal system has been developed and used to simulate realistic blood flow during normal conditions.An anatomically and biophysically based model of the major mesenteric arteries has been developed to be used to simulate normal blood flows. The computational mesh used for the simulations has been generated using data from the Visible Human project. The 3D Navier-Stokes equations that govern flow within this mesh have been simplified to an efficient 1D scheme. This scheme, together with a constitutive pressure-radius relationship, has been solved numerically for pressure, vessel radius and velocity for the entire mesenteric arterial network.The computational model developed shows close agreement with physiologically realistic geometries other researchers have recorded in vivo. Using this model as a framework, results were analyzed for the four distinct phases of the cardiac cycle – diastole, isovolumic contraction, ejection and isovolumic relaxation. Profiles showing the temporally varying pressure and velocity for a periodic input varying between 10.2 kPa (77 mmHg) and 14.6 kPa (110 mmHg) at the abdominal aorta are presented. An analytical solution has been developed to model blood flow in tapering vessels and when compared with the numerical solution, showed excellent agreement.An anatomically and physiologically realistic computational model of the major mesenteric arteries has been developed for the gastrointestinal system. Using this model, blood flow has been simulated which show physiologically realistic flow profiles.The purpose of our current research is to develop an extensible anatomically and biophysically based computational model of the mesenteric arterial system, which is the main blood supply to the human intestine, and to
Z-source Inverter Based Grid-interface For Variable-speed Permanent Magnet Wind Turbine Generators
D. Mahinda Vilathgamuwa,X. Y. Wang,King Jet Tseng,C. J. Gajanayake
Computer Science , 2013,
Abstract: A Z-source inverter based grid-interface for a variable-speed wind turbine connected to a permanent magnet synchronous generator is proposed. A control system is designed to harvest maximum wind energy under varied wind conditions with the use of a permanent magnet synchronous generator, a diode-rectifier and a Z-source inverter. Control systems for speed regulation of the generator and for DC- and AC- sides of the Z-source inverter are implemented. Laboratory experiments are used to verify the efficacy of the proposed approach.
Shiga Toxin Binding to Glycolipids and Glycans
Karen M. Gallegos, Deborah G. Conrady, Sayali S. Karve, Thusitha S. Gunasekera, Andrew B. Herr, Alison A. Weiss
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030368
Abstract: Background Immunologically distinct forms of Shiga toxin (Stx1 and Stx2) display different potencies and disease outcomes, likely due to differences in host cell binding. The glycolipid globotriaosylceramide (Gb3) has been reported to be the receptor for both toxins. While there is considerable data to suggest that Gb3 can bind Stx1, binding of Stx2 to Gb3 is variable. Methodology We used isothermal titration calorimetry (ITC) and enzyme-linked immunosorbent assay (ELISA) to examine binding of Stx1 and Stx2 to various glycans, glycosphingolipids, and glycosphingolipid mixtures in the presence or absence of membrane components, phosphatidylcholine, and cholesterol. We have also assessed the ability of glycolipids mixtures to neutralize Stx-mediated inhibition of protein synthesis in Vero kidney cells. Results By ITC, Stx1 bound both Pk (the trisaccharide on Gb3) and P (the tetrasaccharide on globotetraosylceramide, Gb4), while Stx2 did not bind to either glycan. Binding to neutral glycolipids individually and in combination was assessed by ELISA. Stx1 bound to glycolipids Gb3 and Gb4, and Gb3 mixed with other neural glycolipids, while Stx2 only bound to Gb3 mixtures. In the presence of phosphatidylcholine and cholesterol, both Stx1 and Stx2 bound well to Gb3 or Gb4 alone or mixed with other neutral glycolipids. Pre-incubation with Gb3 in the presence of phosphatidylcholine and cholesterol neutralized Stx1, but not Stx2 toxicity to Vero cells. Conclusions Stx1 binds primarily to the glycan, but Stx2 binding is influenced by residues in the ceramide portion of Gb3 and the lipid environment. Nanomolar affinities were obtained for both toxins to immobilized glycolipids mixtures, while the effective dose for 50% inhibition (ED50) of protein synthesis was about 10?11 M. The failure of preincubation with Gb3 to protect cells from Stx2 suggests that in addition to glycolipid expression, other cellular components contribute to toxin potency.
Intracellular Survival of Leishmania major Depends on Uptake and Degradation of Extracellular Matrix Glycosaminoglycans by Macrophages
Thomas Naderer?,Joanne Heng?,Eleanor C. Saunders?,Joachim Kloehn?,Thusitha W. Rupasinghe?,Tracey J. Brown?,Malcolm J. McConville
PLOS Pathogens , 2015, DOI: 10.1371/journal.ppat.1005136
Abstract: Leishmania parasites replicate within the phagolysosome compartment of mammalian macrophages. Although Leishmania depend on sugars as a major carbon source during infections, the nutrient composition of the phagolysosome remains poorly described. To determine the origin of the sugar carbon source in macrophage phagolysosomes, we have generated a N-acetylglucosamine acetyltransferase (GNAT) deficient Leishmania major mutant (?gnat) that is auxotrophic for the amino sugar, N-acetylglucosamine (GlcNAc). This mutant was unable to grow or survive in ex vivo infected macrophages even when macrophages were cultivated in presence of exogenous GlcNAc. In contrast, the L. major ?gnat mutant induced normal skin lesions in mice, suggesting that these parasites have access to GlcNAc in tissue macrophages. Intracellular growth of the mutant in ex vivo infected macrophages was restored by supplementation of the macrophage medium with hyaluronan, a GlcNAc-rich extracellular matrix glycosaminoglycan. Hyaluronan is present and constitutively turned-over in Leishmania-induced skin lesions and is efficiently internalized into Leishmania containing phagolysosomes. These findings suggest that the constitutive internalization and degradation of host glycosaminoglycans by macrophages provides Leishmania with essential carbon sources, creating a uniquely favorable niche for these parasites.
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