Adherence to Antiplatelet Therapy after Coronary Intervention among Patients with Myocardial Infarction Attending Vietnam National Heart Institute.

Adherence to antiplatelet therapy is critical to successful treatment of cardiovascular conditions. However, little has been known about this issue in the context of constrained resources such as in Vietnam. The objective of this study was to examine the adherence to antiplatelet therapy among patients receiving acute myocardial infarction interventions and its associated factors. In a cross-sectional survey design, 175 adult patients revisiting Vietnam National Heart Institute diagnosed with acute myocardial infarction were approached for data collection from October 2014 to June 2015. Adherence to antiplatelet therapy was assessed by asking patients whether they took taking antiplatelet regularly as per medication (do not miss any dose at the specified time) for any type of antiplatelet (aspirin, clopidogrel, ticlopidine...) during the last month before the participants came back to take re-examinations. The results indicated that the adherence to antiplatelet therapy among patients was quite high at 1 month; it begins to decline by 6 months, 12 months, and more than 12 months (less than 1 month was 90.29%; from 1 to 6 months 88.0%, from 6 to 12 months 75.43%, and after 12 months only 46.29% of patients). Multivariable logistic regression was utilized to detect factors associated with the adherence to antiplatelet therapy. It showed that patients with average income per month of $300 or more (OR=2.92, 95% CI=1.24-6.89), distance to the hospital of less than 50km (OR=2.48, 95% CI: 1.12-5.52), taking medicine under doctor's instructions (OR=3.65; 95% CI=1.13-11.70), and timely re-examination (OR=3.99, 95% CI=1.08-14.73) were more likely to follow the therapy. In general, the study suggested that to increase the likelihood of adherence to antiplatelet therapy it is important to establish a continuous care system after discharging from hospital.

Endocytic pathway rapidly delivers internalized molecules to lysosomes: an analysis of vesicle trafficking, clustering and mass transfer.

Lysosomes play a critical role in intracellular drug delivery. For enzyme-based therapies, they represent a potential target site whereas for nucleic acid or many protein drugs, they represent the potential degradation site. Either way, understanding the mechanisms and processes involved in routing of materials to lysosomes after cellular entry is of high interest to the field of drug delivery. Most therapeutic cargoes other than small hydrophobic molecules enter the cells through endocytosis. Endocytosed cargoes are routed to lysosomes via microtubule-based transport and are ultimately shared by various lysosomes via tethering and clustering of endocytic vesicles followed by exchange of their contents. Using a combined experimental and numerical approach, here we studied the rates of mass transfer into and among the endocytic vesicles in a model cell line, 3T3 fibroblasts. In order to understand the relationship of mass transfer with microtubular transport and vesicle clustering, we varied both properties through various pharmacological agents. At the same time, microtubular transport and vesicle clustering were modeled through diffusion-advection equations and the Smoluchowski equations, respectively. Our analysis revealed that the rate of mass transfer is optimally related to microtubular transport and clustering properties of vesicles. Further, the rate of mass transfer is highest in the innate state of the cell. Any perturbation to either microtubular transport or vesicle aggregation led to reduced mass transfer to lysosome. These results suggest that in the absence of an external intervention the endocytic pathway appears to maximize molecular delivery to lysosomes. Strategies are discussed to reduce mass transfer to lysosomes so as to extend the residence time of molecules in endosomes or late endosomes, thus potentially increasing the likelihood of their escape before disposition in the lysosomes.

Modeling of pattern regulation in melanophores.

Melanosomes, pigment granules in melanophores, play a principal role in physiological color adaptation of fish and frog. Melanophores regulate melanosome trafficking on cytoskeletal filaments to generate a range of spatiotemporal patterns. Here, we present the first comprehensive model of spatiotemporal evolution of melanosome patterns. The model encompasses both physical and biochemical aspects of melanosome dynamics. It consists of (i) a kinetic description of biochemical reactions involved in intracellular signaling, (ii) a system of macroscopic reaction-diffusion-convection equations for melanosome concentration, and (iii) a set of constitutive relationships for coupling transport with the biochemical network. The model relates molecular-level regulatory actions to cell-level melanosome distribution, allowing unification of existing experimental observations and qualitative hypotheses into an integrated, consistent framework. The model reproduces salient features of melanosome patterns, both during transient and steady state. It gives useful insights into how cells coordinate motor-assisted transport to maintain and adapt spatial organization of intracellular organelles. In particular, we calculate the optimal transition paths from aggregation to dispersion in fish melanophores. The calculations suggest that fish melanophores optimally control intracellular signaling to maximize the efficiency of motor-assisted transport during dispersion.

Understanding intracellular transport processes pertinent to synthetic gene delivery via stochastic simulations and sensitivity analyses.

A major challenge in synthetic gene delivery is to quantitatively predict the optimal design of polymer-based gene carriers (polyplexes). Here, we report a consistent, integrated, and fundamentally grounded computational methodology to address this challenge. This is achieved by accurately representing the spatio-temporal dynamics of intracellular structures and by describing the interactions between gene carriers and cellular components at a discrete, nanoscale level. This enables the applications of systems tools such as optimization and sensitivity analysis to search for the best combination of systems parameters. We validate the approach using DNA delivery by polyethylenimine as an example. We show that the cell topology (e.g., size, circularity, and dimensionality) strongly influences the spatiotemporal distribution of gene carriers, and consequently, their optimal intracellular pathways. The model shows that there exists an upper limit on polyplexes' intracellular delivery efficiency due to their inability to protect DNA until nuclear entry. The model predicts that even for optimally designed polyethylenimine vectors, only approximately 1% of total DNA is delivered to the nucleus. Based on comparison with gene delivery by viruses, the model suggests possible strategies to significantly improve transfection efficiencies of synthetic gene vectors.

Theory of spatial patterns of intracellular organelles.

Here we report on a generalized theory of spatial patterns of intracellular organelles, which are controlled by cells using cytoskeleton-based movements powered by molecular motors. The theory reveals that organelles exhibit one of the four distinct, stable patterns, namely aggregation, hyperdispersion, radial dispersion, and areal dispersion. Existence of specific patterns is determined by the contributions from three transport mechanisms, characterized by two Peclet numbers. The predicted patterns compare well with experimental data. This study provides a firm theoretical ground for classification of spatial patterns of organelles and understanding their regulation by cells.

Dynamics and spatial organization of endosomes in mammalian cells.

We combine particle tracking and stochastic simulations to analyze the dynamics and organization of early endocytic vesicles in mammalian cells. At short time scales (<10(1) sec) vesicles exhibit 1D symmetric bidirectional motor-driven transport on microtubules such that the mean squared displacement (MSD) scales as t3/2, but the MSD shows a crossover to facilitated diffusion at longer times (>10(1) sec). Facilitated diffusion results in rapid equilibration of vesicles on microtubules. The asterlike organization of microtubules causes perinuclear accumulation of vesicles despite symmetric transport.

A model for intracellular trafficking of adenoviral vectors.

Here we develop an integrative computational framework to model biophysical processes involved in viral gene delivery. The model combines reaction-diffusion-advection equations that describe intracellular trafficking with kinetic equations that describe transcription and translation of the exogenous DNA. It relates molecular-level trafficking events to whole-cell distribution of viruses. The approach makes use of the current understanding of cellular processes and data from single-particle single-cell imaging experiments. The model reveals two important parameters that characterize viral transport at the population level, namely, the effective velocity, V(eff), and the effective diffusion coefficient, D(eff). V(eff) measures virus's net movement rate and D(eff) represents the total dispersion rate. We employ the model to study the influence of microtubule-mediated movements on nuclear targeting and gene expression of adenoviruses of type 2 and type 5 in HeLa and A549 cells. Effects of microtubule organization and the presence of microtubule-destabilizing drugs on viral transport were analyzed and quantified. Model predictions agree well with experimental data available in literature. The paper serves as a guide for future theoretical and experimental efforts to understand viral gene delivery.