Influence of trimetazidine on myocardial injury in mice with diabetic cardiomyopathy.

INTRODUCTION: The prevalence of diabetes mellitus is increasing year by year globally, and diabetic cardiomyopathy (DCM), as the most common complication of type 2 diabetes mellitus, seriously affects the prognosis of patients. Trimetazidine (TMZ), as a drug affecting myocardial energy metabolism, mainly reduces the oxidation rate of ß-oxidation by inhibiting 3-ketoacyl-CoA thiolase (3-KAT), a key enzyme in ß-oxidation of free fatty acid (FFA), so that the energy metabolism substrate of cardiomyocytes preferentially selects glucose rather than fatty acids, increases the content of intracellular adenosine triphosphate (ATP), enhances the contractile function of cardiomyocytes, and improves the state of cellular ischemia and hypoxia. Previous studies have shown that TMZ is closely related to the activation and induction of apoptosis of the MAPK pathway and AMPK pathway, and plays a role in the treatment of diabetic cardiomyopathy, but the specific mechanism is still unclear. OBJECTIVE: This study aims to investigate the impact of TMZ on myocardial damage in mice exhibiting diabetic cardiomyopathy (DCM), and to furnish a laboratory foundation for the clinical treatment of diabetic cardiomyopathy. METHOD: Male db/db mice (6 weeks old, n = 21) and male wild-type (wt) (6 weeks old, n = 20) mice were selected for the study. The wt mice were randomly assigned to the wt group (n = 10) and wt + TMZ group (n = 10), while the remaining db/db mice were randomly allocated to the db/db group (n = 11) and db/db + TMZ group (n = 10). Following 8 weeks of feeding, the wt + TMZ group and db/db + TMZ group received TMZ via gavage, whereas the remaining groups were administered physiological saline. Periodic measurements of blood glucose, blood lipids, and myocardial enzymes were conducted in mice, with samples obtained after the 12th week for subsequent biochemical analysis, myocardial pathology assessment, immunohistochemistry, western blot analysis, and TUNEL staining (TdT-mediated dUTP Nick-End Labeling). RESULT: GLU, TC, TG, LDL-C, and CK-MB levels were significantly higher in db/db mice compared to wt mice (GLU: M ± SD wt 5.94 ± 0.37, db/db 17.63 ± 0.89, p < 0.05, ES = 0.991; TC: M ± SD wt 3.01 ± 0.32, db/db 6.97 ± 0.36, p < 0.05, ES = 0.972; TG: M ± SD wt 0.58 ± 0.2, db/db 1.75 ± 0.14, p < 0.05, ES = 0.920; LDL-C: M ± SD wt 1.59 ± 0.12, db/db 3.87 ± 0.14, p < 0.05, ES = 0.989; CK-MB: M ± SD wt 0.12 ± 0.01, db/db 0.31 ± 0.04, p < 0.05, ES = 0.928). HDL-C levels were significantly lower in db/db mice (M ± SD wt 1.89 ± 0.08, db/db 0.64 ± 0.09, p < 0.05, ES = 0.963). Histopathological analysis confirmed myocardial damage in db/db mice. Treatment with TMZ reduced GLU, TC, TG, LDL-C, and CK-MB levels (p < 0.05, ES > 0.9) and increased HDL-C levels compared to untreated db/db mice. Additionally, TMZ treatment significantly decreased myocardial cell apoptosis (p < 0.05, ES = 0.980). These results demonstrate the efficacy of TMZ in reversing myocardial injury in DCM mice. CONCLUSION: TMZ can mitigate myocardial damage in db/db mice by downregulating the expression of caspase-12, a protein associated with the endoplasmic reticulum stress (ERS) cell apoptosis pathway, consequently diminishing cell apoptosis. This underscores the protective efficacy of TMZ against myocardial damage in mice afflicted with DCM.

Modeling Count Outcomes from HIV Risk Reduction Interventions: A Comparison of Competing Statistical Models for Count Responses.

Modeling count data from sexual behavioral outcomes involves many challenges, especially when the data exhibit a preponderance of zeros and overdispersion. In particular, the popular Poisson log-linear model is not appropriate for modeling such outcomes. Although alternatives exist for addressing both issues, they are not widely and effectively used in sex health research, especially in HIV prevention intervention and related studies. In this paper, we discuss how to analyze count outcomes distributed with excess of zeros and overdispersion and introduce appropriate model-fit indices for comparing the performance of competing models, using data from a real study on HIV prevention intervention. The in-depth look at these common issues arising from studies involving behavioral outcomes will promote sound statistical analyses and facilitate research in this and other related areas.

vFitness: a web-based computing tool for improving estimation of in vitro HIV-1 fitness experiments.

BACKGROUND: The replication rate (or fitness) between viral variants has been investigated in vivo and in vitro for human immunodeficiency virus (HIV). HIV fitness plays an important role in the development and persistence of drug resistance. The accurate estimation of viral fitness relies on complicated computations based on statistical methods. This calls for tools that are easy to access and intuitive to use for various experiments of viral fitness. RESULTS: Based on a mathematical model and several statistical methods (least-squares approach and measurement error models), a Web-based computing tool has been developed for improving estimation of virus fitness in growth competition assays of human immunodeficiency virus type 1 (HIV-1). CONCLUSIONS: Unlike the two-point calculation used in previous studies, the estimation here uses linear regression methods with all observed data in the competition experiment to more accurately estimate relative viral fitness parameters. The dilution factor is introduced for making the computational tool more flexible to accommodate various experimental conditions. This Web-based tool is implemented in C# language with Microsoft ASP.NET, and is publicly available on the Web at http://bis.urmc.rochester.edu/vFitness/.

Both viremia and cytokine levels associate with the lack of severe disease in secondary dengue 1 infection among adult Chinese patients.

Secondary dengue infections are frequently associated with increased risk for dengue hemorrhagic fever and dengue shock syndrome. Surprisingly, we observed no dengue hemorrhagic fever cases among 353 hospitalized dengue-infected patients including 212 with primary, and 141 with secondary dengue 1 infection in China. To explore virological and immunological mechanisms which may account for this unexpected clinical observation, we assessed dengue viremia, type I interferon and inflammatory cytokine levels in these patients. While the levels of viremia and inflammatory cytokines are indistinguishable between primary and secondary infections, IFNα levels are significantly higher in primary than that in secondary infection. However, IFNα levels are positively correlated with dengue viremia levels (p<0.0001), but negatively correlated with the platelet counts (p<0.0001) and serum ALT levels (p = 0.0003). These results provide direct in vivo evidence that clinical dengue disease severity is affected by both viral and human immune factors.

Development of a data management system for ELISPOT assay in immunological research.

Clinical immune researches often need data management systems for tracking sample and test data like conventional laboratory information management systems (LIMS), and for managing experiment raw data as well. The enzyme-linked immunospot (ELISPOT) assay has been a primary means in immunological researches (such as HIV-specific T cell response). A typical ELISPOT reader usually generates a huge amount of data, including spot number and well image. Assay protocols and study documents are also needed to be circulated easily within a large scale study involved multiple laboratories. Here, a data management system for ELISPOT, elispotDM, is developed for managing samples, experiment data, assay protocols and study documents in clinical immune research. Besides, the Web-based database system will be definitely benefit to data sharing among broad research communities.

Modeling and estimation of replication fitness of human immunodeficiency virus type 1 in vitro experiments by using a growth competition assay.

Growth competition assays have been developed to quantify the relative fitnesses of human immunodeficiency virus (HIV-1) mutants. In this article we develop mathematical models to describe viral/cellular dynamic interactions in the assay experiment, from which new competitive fitness indices or parameters are defined. These indices include the log fitness ratio (LFR), the log relative fitness (LRF), and the production rate ratio (PRR). From the population genetics perspective, we clarify the confusion and correct the inconsistency in the definition of relative fitness in the literature of HIV-1 viral fitness. The LFR and LRF are easier to estimate from the experimental data than the PRR, which was misleadingly defined as the relative fitness in recent HIV-1 research literature. Calculation and estimation methods based on two data points and multiple data points were proposed and were carefully studied. In particular, we suggest using both standard linear regression (method of least squares) and a measurement error model approach for more-accurate estimates of competitive fitness parameters from multiple data points. The developed methodologies are generally applicable to any growth competition assays. A user-friendly computational tool also has been developed and is publicly available on the World Wide Web at http://www.urmc.rochester.edu/bstools/vfitness/virusfitness.htm.

Building an ontology-driven database for clinical immune research.

The clinical researches of immune response usually generate a huge amount of biomedical testing data over a certain period of time. The user-friendly data management systems based on the relational database will help immunologists/clinicians to fully manage the data. On the other hand, the same biological assays such as ELISPOT and flow cytometric assays are involved in immunological experiments no matter of different study purposes. The reuse of biological knowledge is one of driving forces behind this ontology-driven data management. Therefore, an ontology-driven database will help to handle different clinical immune researches and help immunologists/clinicians easily understand the immunological data from each other. We will discuss some outlines for building an ontology-driven data management for clinical immune researches (ODMim).

Design considerations for a web-based database system of ELISpot assay in immunological research.

The enzyme-linked immunospot (ELISpot) assay has been a primary means in immunological researches (such as HIV-specific T cell response). Due to huge amount of data involved in ELISpot assay testing, the database system is needed for efficient data entry, easy retrieval, secure storage, and convenient data process. Besides, the NIH has recently issued a policy to promote the sharing of research data (see http://grants.nih.gov/grants/policy/data_sharing). The Web-based database system will be definitely benefit to data sharing among broad research communities. Here are some considerations for a database system of ELISpot assay (DBSEA).