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Biomedical subjects

Kai Wang

Publications and source records attributed to Kai Wang.

At least 91 records · Page 5Linked to original sources
PubMed2004

Halothane sensitizes the canine heart to pharmacological IKr blockade.

The effects of halothane and pentobarbital on the cardiovascular system were compared using the in vivo canine models. The ventricular repolarization process was longer under the halothane-anesthesia than pentobarbital-anesthesia. Intravenous administration of a selective blocker of rapidly activating delayed rectifier K+ currents (I(Kr)) sematilide prolonged the ventricular repolarization period without affecting the intraventricular conduction under both anesthesia; however, the potency was about 1.5-folds greater under the halothane-anesthesia than pentobarbital-anesthesia. These results suggest that halothane can more effectively sensitize the heart to pharmacological I(Kr) blockade, resulting in the excessive QT interval prolongation. Thus, the halothane-anesthetized canine model can be useful for predicting the in vivo I(Kr) blocking property of new drugs.

Animals↗
PubMed2004

Electropharmacological effects of a spironolactone derivative, potassium canrenoate, assessed in the halothane-anesthetized canine model.

While aldosterone receptor blockers improve survival of patients with congestive heart failure, spironolactone and its derivatives were recently shown to block ether-a-go-go-related gene (HERG) channels and native IKs and IKr currents in guinea pig ventricular myocytes. In this study, we examined in vivo electropharmacological effects of an active derivative of spironolactone, potassium canrenoate, using a halothane-anesthetized canine model. Potassium canrenoate was intravenously administered in three doses of 1, 10, and 100 mg/kg per 10 min with a pause of 20 min between doses (n = 5). The low dose hardly affected any of the cardiovascular parameters. The middle dose, a clinically recommended daily maximum i.v. dose, slightly inhibited the intraventricular conduction. The high dose decreased the heart rate, ventricular contraction and blood pressure, delayed the atrioventricular and intraventricular conduction, and prolonged the ventricular repolarization and refractory period. Increment in the refractoriness by the high dose was greater than that in the repolarization, resulting in the reduction of ventricular electrical vulnerability. This unique electrophysiological profile of potassium canrenoate may in part contribute to the favorable clinical results, whereas caution has to be paid on the cardiohemodynamic actions, particularly for patients with risk of elevated plasma drug concentration.

Action Potentials↗
PubMed2004

Vimentin-expressing proximal reactive astrocytes correlate with migration rather than proliferation following focal brain injury.

Vimentin-expressing astrocytes in the adult are commonly associated with the proximal, most reactive gliotic response ultimately leading to the formation of a new glial limitans. It was thought, since vimentin expression and astroglial proliferation are most prominent nearest the lesion site, that vimentin may be a characteristic of immature newly divided astrocytes. We recently established a unique distribution of vimentin-expressing reactive astrocytes at the base of a focal cortical ischemic lesion in rats. The purpose of the present study was to assess the correlation of proliferation and migration with this unique distribution following focal injury. With the use of bromodeoxyuridine (BrdU) and immunohistochemistry for astrocytes and microglia/macrophages, proliferation and migration of cells was shown to be throughout the ipsilateral hemisphere on day one and become progressively more centralized to the lesion by day 3. The vimentin-expressing area at the base of the lesion does not exhibit distinguishable proliferation rates from non-vimentin-expressing regions surrounding the lesion and did not demonstrate obvious double labeling with BrdU+ cells, although on occasion vimentin expression is closely associated with BrdU. However, this region did become a focal point for migration into and around the lesion by day 3. Additionally, asymmetrical distribution of vimentin was shown in four different injury models with vimentin+ cells always situated between the lesion and the corpus callosum. It is concluded that although vimentin-expressing cells did not correlate with proliferating cells in these focal injury models, perhaps this distinct population of reactive astrocytes serve as a source of cytokines or as a physical conduit for migrating cells from distant sites through the corpus callosum.

Animals↗
PubMed2004

Endothelium-targeted gene and cell-based therapies for cardiovascular disease.

Most common cardiovascular diseases are accompanied by endothelial dysfunction. Because of its predominant role in the pathogenesis of cardiovascular disease, the vascular endothelium is an attractive therapeutic target. The identification of promoter sequences capable of rendering endothelial-specific transgene expression together with the recent development of vectors with enhanced tropism for endothelium may offer opportunities for the design of new strategies for modulation of endothelial function. Such strategies may be useful in the treatment of chronic diseases such as hypertension, atherosclerosis, and ischemic artery disease, as well as in acute myocardial infarction and during open heart surgery for prevention of ischemia and reperfusion (I/R)-induced injury. The recent identification of putative endothelial progenitor cells in peripheral blood may allow the design of autologous cell-based strategies for neovascularization of ischemic tissues and for the repair of injured blood vessels and bioengineering of vascular prosthesis. "Proof-of-concept" for some of these strategies has been established in animal models of cardiovascular disease. However the successful translation of these novel strategies into clinical application will require further developments in vector and delivery technologies. Further characterization of the processes involved in mobilization, migration, homing, and incorporation of endothelial progenitor cells into the target tissues is necessary, and the optimal conditions for therapeutic application of these cells need to be defined and standardized.

Animals↗
PubMed2004

A non-parametric approach to the design and analysis of two-dimensional dose-finding trials.

This paper investigates the design and analysis of dose-finding trials with two agents. The set of doses for each agent is fixed in advance. The goal of the trial is to find the set of dose combinations with probability of toxicity closest to a pre-specified value. For each of the two agents we assume that the probability of toxicity of an agent is non-decreasing with dose when the dose of the other agent is fixed. Using this assumption we construct a new non-parametric design that operates on a two-dimensional grid of all possible dose combinations. A bivariate isotonic regression estimator of the maximum tolerated combinations is described. We conclude that the new design and the bivariate isotonic estimator are superior to the procedure where several independent dose-finding trials are run.

Antineoplastic Agents↗
PubMed2004

Improved protein structure selection using decoy-dependent discriminatory functions.

BACKGROUND: A key component in protein structure prediction is a scoring or discriminatory function that can distinguish near-native conformations from misfolded ones. Various types of scoring functions have been developed to accomplish this goal, but their performance is not adequate to solve the structure selection problem. In addition, there is poor correlation between the scores and the accuracy of the generated conformations. RESULTS: We present a simple and nonparametric formula to estimate the accuracy of predicted conformations (or decoys). This scoring function, called the density score function, evaluates decoy conformations by performing an all-against-all Calpha RMSD (Root Mean Square Deviation) calculation in a given decoy set. We tested the density score function on 83 decoy sets grouped by their generation methods (4state_reduced, fisa, fisa_casp3, lmds, lattice_ssfit, semfold and Rosetta). The density scores have correlations as high as 0.9 with the Calpha RMSDs of the decoy conformations, measured relative to the experimental conformation for each decoy. We previously developed a residue-specific all-atom probability discriminatory function (RAPDF), which compiles statistics from a database of experimentally determined conformations, to aid in structure selection. Here, we present a decoy-dependent discriminatory function called self-RAPDF, where we compiled the atom-atom contact probabilities from all the conformations in a decoy set instead of using an ensemble of native conformations, with a weighting scheme based on the density scores. The self-RAPDF has a higher correlation with Calpha RMSD than RAPDF for 76/83 decoy sets, and selects better near-native conformations for 62/83 decoy sets. Self-RAPDF may be useful not only for selecting near-native conformations from decoy sets, but also for fold simulations and protein structure refinement. CONCLUSIONS: Both the density score and the self-RAPDF functions are decoy-dependent scoring functions for improved protein structure selection. Their success indicates that information from the ensemble of decoy conformations can be used to derive statistical probabilities and facilitate the identification of near-native structures.

Computational Biology↗
PubMed2004

Cooperativity can reduce stochasticity in intracellular calcium dynamics.

The opening of inositol (1,4,5)-triphosphate (IP(3)) receptors, clustered at discrete sites on the endoplasmic reticulum, can lead to large-scale intracellular calcium waves. Recent experiments in Xenopus oocytes have shown that the inter-wave intervals for these waves have a standard deviation that is much smaller than their mean and that the background calcium concentration exhibits a slow rise during the interwave interval. Using a simple mathematical model, we examine the possibility that this slow rise increases the cooperativity between the openings of the clusters. We find that our model, coupled to the usual assumption that the pumps on the endoplasmic reticulum are activated instantaneously, is unable to explain the observed data: the clusters are found to fire independently and the inter-wave interval distribution is a Poisson distribution with a standard deviation that is approximately equal to its mean. On the other hand, we find that incorporating pumps that slowly activate leads to a slow increase in the background calcium concentration which makes global events progressively more likely to occur. We show that this cooperativity results in much smaller standard deviations and inter-wave interval distributions that are clearly not Poisson distributions.

Animals↗
PubMed2004

Gene and cell-based therapies for heart disease.

Heart disease remains the prevalent cause of premature death and accounts for a significant proportion of all hospital admissions. Recent developments in understanding the molecular mechanisms of myocardial disease have led to the identification of new therapeutic targets, and the availability of vectors with enhanced myocardial tropism offers the opportunity for the design of gene therapies for both protection and rescue of the myocardium. Genetic therapies have been devised to treat complex diseases such as myocardial ischemia, heart failure, and inherited myopathies in various animal models. Some of these experimental therapies have made a successful transition to clinical trial and are being considered for use in human patients. The recent isolation of endothelial and cardiomyocyte precursor cells from adult bone marrow may permit the design of strategies for repair of the damaged heart. Cell-based therapies may have potential application in neovascularization and regeneration of ischemic and infarcted myocardium, in blood vessel reconstruction, and in bioengineering of artificial organs and prostheses. We expect that advances in the field will lead to the development of safer and more efficient vectors. The advent of genomic screening technology should allow the identification of novel therapeutic targets and facilitate the detection of disease-causing polymorphisms that may lead to the design of individualized gene and cell-based therapies.

Coronary Artery Disease↗
PubMed2004

Profile-based string kernels for remote homology detection and motif extraction.

We introduce novel profile-based string kernels for use with support vector machines (SVMs) for the problems of protein classification and remote homology detection. These kernels use probabilistic profiles, such as those produced by the PSI-BLAST algorithm, to define position-dependent mutation neighborhoods along protein sequences for inexact matching of k-length subsequences ("k-mers") in the data. By use of an efficient data structure, the kernels are fast to compute once the profiles have been obtained. For example, the time needed to run PSI-BLAST in order to build the pro- files is significantly longer than both the kernel computation time and the SVM training time. We present remote homology detection experiments based on the SCOP database where we show that profile-based string kernels used with SVM classifiers strongly outperform all recently presented supervised SVM methods. We also show how we can use the learned SVM classifier to extract "discriminative sequence motifs" -- short regions of the original profile that contribute almost all the weight of the SVM classification score -- and show that these discriminative motifs correspond to meaningful structural features in the protein data. The use of PSI-BLAST profiles can be seen as a semi-supervised learning technique, since PSI-BLAST leverages unlabeled data from a large sequence database to build more informative profiles. Recently presented "cluster kernels" give general semi-supervised methods for improving SVM protein classification performance. We show that our profile kernel results are comparable to cluster kernels while providing much better scalability to large datasets.

Algorithms↗
PubMed2004

Quantitative analysis of mitochondrial DNAs in macaque embryos reprogrammed by rabbit oocytes.

In cloned animals where somatic cell nuclei and oocytes are from the same or closely related species, the mitochondrial DNA (mtDNA) of the oocyte is dominantly inherited. However, in nuclear transfer (NT) embryos where nuclear donor and oocyte are from two distantly related species, the distribution of the mtDNA species is not known. Here we determined the levels of macaque and rabbit mtDNAs in macaque embryos reprogrammed by rabbit oocytes. Quantification using a real-time PCR method showed that both macaque and rabbit mtDNAs coexist in NT embryos at all preimplantation stages, with maternal mtDNA being dominant. Single NT embryos at the 1-cell stage immediately after fusion contained 2.6 x 10(4) copies of macaque mtDNA and 1.3 x 10(6) copies of rabbit mtDNA. Copy numbers of both mtDNA species did not change significantly from the 1-cell to the morula stages. In the single blastocyst, however, the number of rabbit mtDNA increased dramatically while macaque mtDNA decreased. The ratio of nuclear donor mtDNA to oocyte mtDNA dropped sharply from 2% at the 1-cell stage to 0.011% at the blastocyst stage. These results suggest that maternal mtDNA replicates after the morula stage.

Animals↗
PubMed2004

Simple linear model provides highly accurate genotypic predictions of HIV-1 drug resistance.

Drug resistance is a major obstacle to the successful treatment of HIV-1 infection. Genotypic assays are used widely to provide indirect evidence of drug resistance, but the performance of these assays has been mixed. We used standard stepwise linear regression to construct drug resistance models for seven protease inhibitors and 10 reverse transcriptase inhibitors using data obtained from the Stanford HIV drug resistance database. We evaluated these models by hold-one-out experiments and by tests on an independent dataset. Our linear model outperformed other publicly available genotypic interpretation algorithms, including decision tree, support vector machine and four rules-based algorithms (HIVdb, VGI, ANRS and Rega) under both tests. Interestingly, our model did well despite the absence of any terms for interactions between different residues in protease or reverse transcriptase. The resulting linear models are easy to understand and can potentially assist in choosing combination therapy regimens.

Algorithms↗
PubMed2004

[Oxidative stress in patients with chronic hepatitis B].

BACKGROUND: To study oxidative stress in patients with chronic hepatitis B. METHODS: Malondialdehyde (MDA), total anti-oxidative ability and ascorbic acid were measured as markers of oxidative stress in 30 patients with chronic hepatitis B, besides HBV DNA and ALT. RESULTS: MDA was significantly higher in patients with hepatitis B than the controls (P less than 0.05). Ascorbic acid was significantly higher in patients with normal ALT than the controls (P less than 0.01). MDA was significantly higher in patients with increased ALT than the controls and in patients with normal ALT. MDA was significantly positively correlated with ALT (r=0.61), and ascorbic acid was significantly negatively correlated with ALT (r=-0.64) in patients with hepatitis B. No significant relationship was found between HBV DNA and other indices of oxidative stress. No significant difference in total anti-oxidative ability was found among all groups. CONCLUSION: There was a disturbance between oxidative stress and anti-oxidative ability in patients with chronic hepatitis B. In patients with increased ALT, oxidative stress became high. In patients with normal ALT, oxidative stress level was low. The indices of oxidative stress should be detected in patients with hepatitis B, in addition to HBV markers.

Adolescent↗
PubMed2004

Antivirogram or phenosense: a comparison of their reproducibility and an analysis of their correlation.

The Antivirogram and PhenoSense assays are widely used phenotypic tests for HIV drug resistance. There are limited data on the reproducibility of each assay, and little is known about the correlation between the two. Using data from the Stanford HIV drug resistance database, we performed a comprehensive analysis of the reproducibility of each assay, and calculated the correlation and concordance of the two assays using both general IC50 fold change cutoff values and drug-specific cutoff values. Although the within-assay correlations were high (rank correlation coefficients r=0.94 and r=0.95 for the Antivirogram and PhenoSense assays, respectively), the between-assay correlation was considerably lower (r=0.36). Using drug-specific cutoff values for viruses classified as resistant by the Antivirogram or PhenoSense assays, respectively, only 71.4% [95% confidence intervals (95% CI): 58.7-82.1%] and 57.0% (95% CI: 45.3-68.1%) of the samples were classified as resistant using the other assay. The poor agreement between the assays was primarily due to the extremely poor correlation between these assays for samples with low resistance values (r=0.02 and r=0.61 for samples with the Antivirogram measurements lower or higher than 2.0, respectively). Since the cutoff values for both assays are relatively low, our analysis suggests that one should be very careful when interpreting measurements that are near the cutoff values for drug resistance.

Anti-HIV Agents↗
PubMed2003

Bivariate linkage analysis of cholesterol and triglyceride levels in the Framingham Heart Study.

We performed a bivariate analysis on cholesterol and triglyceride levels on data from the Framingham Heart Study using a new score statistic developed for the detection of potential pleiotropic, or cluster, genes. Univariate score statistics were also computed for each trait. At a significance level 0.001, linkage signals were found at markers GATA48B01 on chromosome 1, GATA21C12 on chromosome 8, and ATA55A11 on chromosome 16 using the bivariate analysis. At the same significance level, linkage signals were found at markers 036yb8 on chromosome 3 and GATA3F02 on chromosome 12 using the univariate analysis. A strong linkage signal was also found at marker GATA112F07 by both the bivariate analysis and the univariate analysis, a marker for which evidence for linkage had been reported previously in a related study.

Age Factors↗