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Search Results: 1 - 10 of 53027 matches for " David Zurakowski "
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Nonlinear observer output-feedback MPC treatment scheduling for HIV
Ryan Zurakowski
BioMedical Engineering OnLine , 2011, DOI: 10.1186/1475-925x-10-40
Abstract: In previous work we have developed a model predictive control (MPC) based method for determining optimal treatment interruption schedules for this purpose. In this paper, we introduce a nonlinear observer for the HIV-immune response system and an integrated output-feedback MPC approach for implementing the treatment interruption scheduling algorithm using the easily available viral load measurements. We use Monte-Carlo approaches to test robustness of the algorithm.The nonlinear observer shows robust state tracking while preserving state positivity both for continuous and discrete measurements. The integrated output-feedback MPC algorithm stabilizes the desired steady-state. Monte-Carlo testing shows significant robustness to modeling error, with 90% success rates in stabilizing the desired steady-state with 15% variance from nominal on all model parameters.The possibility of enhancing immune responsiveness to HIV through dynamic scheduling of treatment is exciting. Output-feedback Model Predictive Control is uniquely well-suited to solutions of these types of problems. The unique constraints of state positivity and very slow sampling are addressable by using a special-purpose nonlinear state estimator, as described in this paper. This shows the possibility of using output-feedback MPC-based algorithms for this purpose.The majority of untreated HIV patients, following a brief period of acute infection, enter a long asymptomatic phase of infection characterized by high viral loads, persistent immune activation, and a slow decline in the helper-T cell concentration [1]. Eventually, the concentration of helper-T cells becomes too low to sustain effective immune responses, and opportunistic infections cause a dramatic decline in the patient's health. The slow decline of helper-T cells during the asymptomatic phase was once thought to indicate a slow rate of infection and cell turnover, but it is now known that very fast rates of virus and host cell turnover, as high as
Inhaled Carbon Monoxide Provides Cerebral Cytoprotection in Pigs
Vicki L. Mahan, David Zurakowski, Leo E. Otterbein, Frank A. Pigula
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041982
Abstract: Carbon monoxide (CO) at low concentrations imparts protective effects in numerous preclinical small animal models of brain injury. Evidence of protection in large animal models of cerebral injury, however, has not been tested. Neurologic deficits following open heart surgery are likely related in part to ischemia reperfusion injury that occurs during cardiopulmonary bypass surgery. Using a model of deep hypothermic circulatory arrest (DHCA) in piglets, we evaluated the effects of CO to reduce cerebral injury. DHCA and cardiopulmonary bypass (CPB) induced significant alterations in metabolic demands, including a decrease in the oxygen/glucose index (OGI), an increase in lactate/glucose index (LGI) and a rise in cerebral blood pressure that ultimately resulted in increased cell death in the neocortex and hippocampus that was completely abrogated in piglets preconditioned with a low, safe dose of CO. Moreover CO-treated animals maintained normal, pre-CPB OGI and LGI and corresponding cerebral sinus pressures with no change in systemic hemodynamics or metabolic intermediates. Collectively, our data demonstrate that inhaled CO may be beneficial in preventing cerebral injury resulting from DHCA and offer important therapeutic options in newborns undergoing DHCA for open heart surgery.
Tetrodotoxin-Bupivacaine-Epinephrine Combinations for Prolonged Local Anesthesia
Charles B. Berde,Umeshkumar Athiraman,Barak Yahalom,David Zurakowski,Gabriel Corfas,Christina Bognet
Marine Drugs , 2011, DOI: 10.3390/md9122717
Abstract: Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX) with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL) solutions, with or without epinephrine 5 μg/mL (1:200,000) in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 μM and epinephrine 5 μg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain ( P < 0.001) or bupivacaine 0.25% with epinephrine 5 μg/mL ( P < 0.001). Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 μg/mL appear promising for prolonged duration of local anesthesia.
School-age effects of the newborn individualized developmental care and assessment program for preterm infants with intrauterine growth restriction: preliminary findings
Gloria McAnulty, Frank H Duffy, Sandra Kosta, Neil I Weisenfeld, Simon K Warfield, Samantha C Butler, Moona Alidoost, Jane Holmes Bernstein, Richard Robertson, David Zurakowski, Heidelise Als
BMC Pediatrics , 2013, DOI: 10.1186/1471-2431-13-25
Abstract: Twenty-three 9-year-old former growth-restricted preterms, randomized at birth to standard care (14 controls) or to the Newborn Individualized Developmental Care and Assessment Program (9 experimentals) were assessed with standardized measures of cognition, achievement, executive function, electroencephalography, and magnetic resonance imaging. The participating children were comparable to those lost to follow-up, and the controls to the experimentals, in terms of newborn background health and demographics. All outcome measures were corrected for mother's intelligence. Analysis techniques included two-group analysis of variance and stepwise discriminate analysis for the outcome measures, Wilks' lambda and jackknifed classification to ascertain two-group classification success per and across domains; canonical correlation analysis to explore relationships among neuropsychological, electrophysiological and neurostructural domains at school-age, and from the newborn period to school-age.Controls and experimentals were comparable in age at testing, anthropometric and health parameters, and in cognitive and achievement scores. Experimentals scored better in executive function, spectral coherence, and cerebellar volumes. Furthermore, executive function, spectral coherence and brain structural measures discriminated controls from experimentals. Executive function correlated with coherence and brain structure measures, and with newborn-period neurobehavioral assessment.The intervention in the intensive care nursery improved executive function as well as spectral coherence between occipital and frontal as well as parietal regions. The experimentals' cerebella were significantly larger than the controls'. These results, while preliminary, point to the possibility of long-term brain improvement even of intrauterine growth compromised preterms if individualized intervention begins with admission to the NICU and extends throughout transition home. Larger sample replications are
Cartilage constructs engineered from chondrocytes overexpressing IGF-I improve the repair of osteochondral defects in a rabbit model
H Madry,G Kaul,D Zurakowski,G Vunjak-Novakovic
European Cells and Materials (ECM) , 2013,
Abstract: Tissue engineering combined with gene therapy is a promising approach for promoting articular cartilage repair. Here, we tested the hypothesis that engineered cartilage with chondrocytes overexpressing a human insulin-like growth factor I (IGF-I) gene can enhance the repair of osteochondral defects, in a manner dependent on the duration of cultivation. Genetically modified chondrocytes were cultured on biodegradable polyglycolic acid scaffolds in dynamic flow rotating bioreactors for either 10 or 28 d. The resulting cartilaginous constructs were implanted into osteochondral defects in rabbit knee joints. After 28 weeks of in vivo implantation, immunoreactivity to -gal was detectable in the repair tissue of defects that received lacZ constructs. Engineered cartilaginous constructs based on IGF-I-overexpressing chondrocytes markedly improved osteochondral repair compared with control (lacZ) constructs. Moreover, IGF-I constructs cultivated for 28 d in vitro significantly promoted osteochondral repair vis-à-vis similar constructs cultivated for 10 d, leading to significantly decreased osteoarthritic changes in the cartilage adjacent to the defects. Hence, the combination of spatially defined overexpression of human IGF-I within a tissue-engineered construct and prolonged bioreactor cultivation resulted in most enhanced articular cartilage repair and reduction of osteoarthritic changes in the cartilage adjacent to the defect. Such genetically enhanced tissue engineering provides a versatile tool to evaluate potential therapeutic genes in vivo and to improve our comprehension of the development of the repair tissue within articular cartilage defects. Insights gained with additional exploration using this model may lead to more effective treatment options for acute cartilage defects.
Human Amniotic Fluid Cells Form Functional Gap Junctions with Cortical Cells
Anna Jezierski,Kerry Rennie,Roger Tremblay,Bogdan Zurakowski,Andreé Gruslin,Marianna Sikorska,Mahmud Bani-Yaghoub
Stem Cells International , 2012, DOI: 10.1155/2012/607161
Abstract: The usage of stem cells is a promising strategy for the repair of damaged tissue in the injured brain. Recently, amniotic fluid (AF) cells have received a lot of attention as an alternative source of stem cells for cell-based therapies. However, the success of this approach relies significantly on proper interactions between graft and host tissue. In particular, the reestablishment of functional brain networks requires formation of gap junctions, as a key step to provide sufficient intercellular communication. In this study, we show that AF cells express high levels of CX43 (GJA1) and are able to establish functional gap junctions with cortical cultures. Furthermore, we report an induction of Cx43 expression in astrocytes following injury to the mouse motor cortex and demonstrate for the first time CX43 expression at the interface between implanted AF cells and host brain cells. These findings suggest that CX43-mediated intercellular communication between AF cells and cortical astrocytes may contribute to the reconstruction of damaged tissue by mediating modulatory, homeostatic, and protective factors in the injured brain and hence warrants further investigation. 1. Introduction Recent advances in regenerative medicine have boosted efforts to explore the therapeutic potentials of stem cells to repair damaged tissue in the injured brain (reviewed in [1–4]). In particular, the transplantation of embryonic stem cells [5], fetal neural stem or progenitor cells [6–8], or bone-marrow-derived stem cells [9, 10] into the injured brain has been explored extensively. However, human embryonic stem (ES) cells and fetal neural stem cells are subject to ethical considerations and the risk of tumor development, whereas adult neural stem cells have limited proliferation capabilities and lineage restriction. Therefore, other stem cell sources, such as human amniotic fluid (AF) [11–13], are being considered for therapeutic applications. There is evidence that AF contains stem cell subpopulation(s) [14] isolated based on c-Kit (CD117–the receptor for stem cell factor [15]) expression, which share some of the characteristics of embryonic and adult stem cells [14]. For instance, several reports have shown that AF cells can differentiate along the adipogenic and osteogenic [16–18], myogenic [19, 20], and endothelial [21] pathways. Furthermore, AF cells have also been shown to harbour the potential for neurogenic differentiation, using different induction protocols [14, 18, 22–25]; however, the proof that these cells can differentiate into functional neurons remains elusive
Optimal Antiviral Switching to Minimize Resistance Risk in HIV Therapy
Rutao Luo, Michael J. Piovoso, Javier Martinez-Picado, Ryan Zurakowski
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027047
Abstract: The development of resistant strains of HIV is the most significant barrier to effective long-term treatment of HIV infection. The most common causes of resistance development are patient noncompliance and pre-existence of resistant strains. In this paper, methods of antiviral regimen switching are developed that minimize the risk of pre-existing resistant virus emerging during therapy switches necessitated by virological failure. Two distinct cases are considered; a single previous virological failure and multiple virological failures. These methods use optimal control approaches on experimentally verified mathematical models of HIV strain competition and statistical models of resistance risk. It is shown that, theoretically, order-of-magnitude reduction in risk can be achieved, and multiple previous virological failures enable greater success of these methods in reducing the risk of subsequent treatment failures.
HIV Model Parameter Estimates from Interruption Trial Data including Drug Efficacy and Reservoir Dynamics
Rutao Luo, Michael J. Piovoso, Javier Martinez-Picado, Ryan Zurakowski
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040198
Abstract: Mathematical models based on ordinary differential equations (ODE) have had significant impact on understanding HIV disease dynamics and optimizing patient treatment. A model that characterizes the essential disease dynamics can be used for prediction only if the model parameters are identifiable from clinical data. Most previous parameter identification studies for HIV have used sparsely sampled data from the decay phase following the introduction of therapy. In this paper, model parameters are identified from frequently sampled viral-load data taken from ten patients enrolled in the previously published AutoVac HAART interruption study, providing between 69 and 114 viral load measurements from 3–5 phases of viral decay and rebound for each patient. This dataset is considerably larger than those used in previously published parameter estimation studies. Furthermore, the measurements come from two separate experimental conditions, which allows for the direct estimation of drug efficacy and reservoir contribution rates, two parameters that cannot be identified from decay-phase data alone. A Markov-Chain Monte-Carlo method is used to estimate the model parameter values, with initial estimates obtained using nonlinear least-squares methods. The posterior distributions of the parameter estimates are reported and compared for all patients.
Development of environmentally friendly cast alloys. High-zinc Al alloys
W.K. Krajewski,J. Buras,M. Zurakowski,A.L. Greer
Archives of Materials Science and Engineering , 2010,
Abstract: Purpose: The main purpose of this paper is presenting the results obtained in years 2007 – 2010 in frame of the project Marie Curie Transfer of Knowledge – CastModel. The project was focused, among others, at elaborating new, environmentally friendly cast alloys based on the Al-Zn system. Particularly, efforts were aimed at improving ductility of the sand cast high-zinc aluminium alloys (HZnAl) by using the newly elaborated master alloys, based on the Al-Zn-Ti system.Design/methodology/approach: The presented work is focused on the nucleation of the high-zinc Al-20 wt% Zn (HZnAl AlZn20) alloy, known as the high damping one, aiming at improving plastic properties of the sand castings. The melted alloy was nucleated with AlTi5B1 (TiBAl) and AlTi3C0.15 (TiCAl) refiners as well as with the newly introduced ZnAl-Ti3 one. During the research the following experimental techniques were used: LM, SEM-EBSD, EDS, TA, DSC, Quantitative Metallography, UTS, Elongation and Attenuation coefficient measurements.Findings: During the performed examinations it was found out that significant increasing of the grain population of the inoculated alloy increases plasticity represented by elongation. The attenuation coefficient of the nucleated alloy, measured using an Olympus Epoch XT device, preserves its high value. The results obtained allow to characterize the examined AlZn20 alloy as promissive, having good strength and damping properties as well as the environmentally friendly alloy because of its comparatively low melting temperatures.Practical implications: The grain-refined high-zinc aluminium alloys can be used as the high damping substitutes of the traditional, more energy consumable Fe-based foundry alloys.Originality/value: The newly elaborated ZnAl-Ti based master alloys show high refining potency and quick dissolution in low melting temperatures of about 500°C, and are the promissive alternatives of the traditional AlTi-based ones.
The influence of the different elements of an organic molecule structure on the main kinetic parameters of its unimolecular reaction in the high-pressure region  [PDF]
David Krinkin
Natural Science (NS) , 2011, DOI: 10.4236/ns.2011.38090
Abstract: The most general dynamic tendencies of the energy redistribution in the high-pressure region are considered. Their influence on the possible deviations from the kinetic conceptions, which is now generally accepted, is examined. In this way, the structural elements of an organic molecule that promote internal energy mobilization in the high-pressure region and, conversely, hamper it, are defined. The first of these elements reduces both the Arrhenius parameters of the unimolecular reactions while the second leads to the opposite results. Some well-known exceptions to existing kinetic theories, which find an explanation in the framework of these proposed concepts, is considered. The proposed concept is very general as distinct from the existing dynamic studies, which investigate more particular details of the separate bond behaviors. The proposed general concept can broaden the study of chemical kinetics.
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