Maturation of iPSC-derived cardiomyocytes in a heart-on-a-chip device enables modeling of dilated cardiomyopathy caused by R222Q-SCN5A mutation.

To better understand sodium channel (SCN5A)-related cardiomyopathies, we generated ventricular cardiomyocytes from induced pluripotent stem cells obtained from a dilated cardiomyopathy patient harbouring the R222Q mutation, which is only expressed in adult SCN5A isoforms. Because the adult SCN5A isoform was poorly expressed, without functional differences between R222Q and control in both embryoid bodies and cell sheet preparations (cultured for 29-35 days), we created heart-on-a-chip biowires which promote myocardial maturation. Indeed, biowires expressed primarily adult SCN5A with R222Q preparations displaying (arrhythmogenic) short action potentials, altered Na+ channel biophysical properties and lower contractility compared to corrected controls. Comprehensive RNA sequencing revealed differential gene regulation between R222Q and control biowires in cellular pathways related to sarcoplasmic reticulum and dystroglycan complex as well as biological processes related to calcium ion regulation and action potential. Additionally, R222Q biowires had marked reductions in actin expression accompanied by profound sarcoplasmic disarray, without differences in cell composition (fibroblast, endothelial cells, and cardiomyocytes) compared to corrected biowires. In conclusion, we demonstrate that in addition to altering cardiac electrophysiology and Na+ current, the R222Q mutation also causes profound sarcomere disruptions and mechanical destabilization. Possible mechanisms for these observations are discussed.

A Generalized Multinomial Probabilistic Model for SARS-CoV-2 Infection Prediction and Public Health Intervention Assessment in an Indoor Environment

SARS-CoV-2 Omicron has become the predominant variant globally. Current infection models are limited by the need for large datasets or calibration to specific contexts, making them difficult to cater for different settings. To ensure public health decision-makers can easily consider different public health interventions (PHIs) over a wide range of scenarios, we propose a generalized multinomial probabilistic model of airborne infection to systematically capture group characteristics, epidemiology, viral loads, social activities, environmental conditions, and PHIs, with assumptions made on social distancing and contact duration, and estimate infectivity over short time-span group gatherings. This study is related to our 2021 work published in Nature Scientific Reports that modelled airborne SARS-CoV-2 infection (Han, Lam, Li, et al., 2021).1 It is differentiated from former works on probabilistic infection modelling in terms of the following: (1) predicting new cases arising from more than one infectious in a gathering, (2) incorporating additional key infection factors, and (3) evaluating the effectiveness of multiple PHIs on SARS-CoV-2 infection simultaneously. Although our results reveal that limiting group size has an impact on infection, improving ventilation has a much greater positive health impact. Our model is versatile and can flexibly accommodate other scenarios by allowing new factors to be added, to support public health decision-making.

Mechanical Stress Promotes Maturation of Human Myocardium From Pluripotent Stem Cell-Derived Progenitors.

Recent advances in pluripotent stem cell biology and directed differentiation have identified a population of human cardiovascular progenitors that give rise to cardiomyocytes, smooth muscle, and endothelial cells. Because the heart develops from progenitors in 3D under constant mechanical load, we sought to test the effects of a 3D microenvironment and mechanical stress on differentiation and maturation of human cardiovascular progenitors into myocardial tissue. Progenitors were derived from embryonic stem cells, cast into collagen hydrogels, and left unstressed or subjected to static or cyclic mechanical stress. Compared to 2D culture, the unstressed 3D environment increased cardiomyocyte numbers and decreased smooth muscle numbers. Additionally, 3D culture suppressed smooth muscle α-actin content, suggesting diminished cell maturation. Cyclic stress-conditioning increased expression of several cardiac markers, including ß-myosin heavy chain and cardiac troponin T, and the tissue showed enhanced calcium dynamics and force production. There was no effect of mechanical loading on cardiomyocyte or smooth muscle specification. Thus, 3D growth conditions favor cardiac differentiation from cardiovascular progenitors, whereas 2D conditions promote smooth muscle differentiation. Mechanical loading promotes cardiomyocyte structural and functional maturation. Culture in 3-D facilitates understanding how cues such as mechanical stress affect the differentiation and morphogenesis of distinct cardiovascular cell populations into organized, functional human cardiovascular tissue. Stem Cells 2015;33:2148-2157.

Understanding interactions between Chinese medicines and pharmaceutical drugs in integrative healthcare / 中国结合医学杂志

In the 21st century, the public are more informed, mainly via the Internet, about health and medical products and have become more knowledgeable about matters relating to their health conditions and well-being in curing and preventing illnesses. They often self-medicate themselves with various health products and over-the-counter (OTC) medicines apart from prescribed pharmaceutical drugs (PD). Some of those non-prescribed products may have doubtful quality control and contain harmful additives or unchecked ingredients; thus their usefulness is in doubt. The increasing popularity world-wide of using Chinese medicines (CM) and related OTC functional products has raised concerns over their concomitant use with PD and the consequential adverse effects. In most cases the alleged causes of adverse effects are linked with herbal sources, although the authorised information on the interactions between CM-PD is not plentiful in the literature. There is an urgent need for such a data base. The future professionals in health and medical care should be knowledgeable or aware of what their patients have been taking or given. In actual practice the patients may receive both treatments intentionally or unintentionally, with or without the awareness of the practitioner. In these situations a reliable database for interactions between CM-PD will be extremely useful for consultation when treatment problems appear or during emergency situations. Their combining of medications may be involved with possible outcomes of adverse reactions or beneficial effects. Such a database will be welcomed by both practitioners of herbal medicines and orthodox medicine practitioners in the emerging trend of integrative medicine. The author has been involved in various research projects of basic and clinical aspects in mainly CM among other herbal and PD. Examples will be given largely on those related to these disciplines as illustrations in this overview.

Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes.

BACKGROUND: Human embryonic stem cells (hESCs) can be efficiently and reproducibly directed into cardiomyocytes (CMs) using stage-specific induction protocols. However, their functional properties and suitability for clinical and other applications have not been evaluated. METHODS AND RESULTS: Here we showed that CMs derived from multiple pluripotent human stem cell lines (hESC: H1, HES2) and types (induced pluripotent stem cell) using different in vitro differentiation protocols (embryoid body formation, endodermal induction, directed differentiation) commonly displayed immature, proarrhythmic action potential properties such as high degree of automaticity, depolarized resting membrane potential, Phase 4- depolarization, and delayed after-depolarization. Among the panoply of sarcolemmal ionic currents investigated (I(Na)(+)/I(CaL)(+)/I(Kr)(+)/I(NCX)(+)/I(f)(+)/I(to)(+)/I(K1)(-)/I(Ks)(-)), we pinpointed the lack of the Kir2.1-encoded inwardly rectifying K(+) current (I(K1)) as the single mechanistic contributor to the observed immature electrophysiological properties in hESC-CMs. Forced expression of Kir2.1 in hESC-CMs led to robust expression of Ba(2+)-sensitive I(K1) and, more importantly, completely ablated all the proarrhythmic action potential traits, rendering the electrophysiological phenotype indistinguishable from the adult counterparts. These results provided the first link of a complex developmentally arrested phenotype to a major effector gene, and importantly, further led us to develop a bio-mimetic culturing strategy for enhancing maturation. CONCLUSIONS: By providing the environmental cues that are missing in conventional culturing method, this approach did not require any genetic or pharmacological interventions. Our findings can facilitate clinical applications, drug discovery, and cardiotoxicity screening by improving the yield, safety, and efficacy of derived CMs.

Pharmacovigilance of herbal medicine.

Pharmacovigilance is essential for developing reliable information on the safety of herbal medicines as used in Europe and the US. The existing systems were developed for synthetic medicines and require some modification to address the specific differences of medicinal herbs. Traditional medicine from many different cultures is used in Europe and the US which adds to the complexities and difficulties of even basic questions such as herb naming systems and chemical variability. Allied to this also is the perception that a 'natural' or herbal product must be safe simply because it is not synthetic which means that the safety element of monitoring for such medicines can be overlooked because of the tag associated with such products. Cooperation between orthodox physicians and traditional practitioners is needed to bring together the full case details. Independent scientific assistance on toxicological investigation, botanical verification can be invaluable for full evaluation of any case report. Systematic pharmacovigilance is essential to build up reliable information on the safety of herbal medicines for the development of appropriate guidelines for safe effective use.

Determination of free ferulic acid and total ferulic acid in Chuanxiong by high-performance liquid chromatography for quality assessment / 中国中药杂志

Ferulic acid (FA) is one of the main bioactive compounds in Chuanxiong (CX), the dried rhizome of Ligusticum chuanxiong, but its amount in this herb is difficult to determine accurately. An accurate quantificational method was developed to investigate on the available amount of FA (free FA and total FA). Herbal samples were extracted in methanol-formic acid (95:5) and methanol-0.24 mol x L(-1) sodium hydrogen carbonate in water (95:5), respectively and then quantitatively analyzed by HPLC method. Thirty three CX samples were quantified on free and total FA. Total FA was found more abundant than free FA with an average ratio of 2.38 (n = 32) in the range of 1.03- 4.98 in 32 CX herbs, and a highest ratio of 19.6 was estimated in a rhizome seedling. Results showed that total FA content would be a better marker for the quality assessment of CX herbs. Fifteen CX typical samples were collected from the trueborn cultivating areas in Sichuan province of China. The amount of total FA in these herbs was estimated to be 1.42 mg x g(-1) (n = 15). The proposed limit of total FA in CX samples should not less than 1.25 mg x g(-1) calculated on the dried basis. It was also found that the level of total FA was related to the quality, processing method and store duration of CX samples.

Responsiveness of the Chinese Quality of Life Instrument in patients with congestive heart failure / 中国结合医学杂志

<p><b>OBJECTIVE</b>The Chinese Quality of Life Instrument (ChQOL) was developed as a valid generic health status instrument based on the well-established theory of health in Chinese medicine. Psychometric properties of the ChQOL were good. In the present study, the responsiveness of the ChQOL in patients with congestive heart failure (CHF) were investigated and compared with two generic questionnaires, the Medical Outcomes Study Short Form 36-item Health Survey (SF-36) and World Health Organization Quality of Life Assessment (WHOQOL-BREF), as well as one disease-specific questionnaire, the Minnesota Living with Heart Failure Questionnaire (MLHF).</p><p><b>METHODS</b>Thirty-nine in-patients with CHF who had undergone treatment with integrative medicine were recruited. The health status measurements were performed at enrolment and after a 4-week treatment. The following responsiveness indices were used: the effect size (ES) and standardized response mean (SRM). All patients were classified into those groups with stable measures and those groups with changes after a 4-week treatment, based upon both the doctor's global rating of changes in heart function tests, and the patient's global rating of changes in overall quality of life.</p><p><b>RESULTS</b>All domains of the ChQOL showed significant improvement. In the comparison of the responsiveness indices, the ChQOL was regarded as more responsive than the WHOQOL-BREF or SF-36 utility, but it was less responsive than the MLHF.</p><p><b>CONCLUSIONS</b>The ChQOL was better in sensitivity and responsiveness for assessing congestive heart failure as a generic measure than the SF-36 and WHOQOL-BREF. The ChQOL is considered suitable as an outcome measure for clinical trials in patients with congestive heart failure.</p>

Application of factor analysis in development and validation of a new questionnaire for quality of life / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To explore the application of factor analysis in creating a new health-related questionnaire for evaluating quality of life, the Chinese for Quality of Life Instrument (ChQOL).</p><p><b>METHODS</b>Two hundred and seventy-three subjects selected from two provinces of North China (Ningxia) and South China (Guangdong) were investigated by ChQOL, and the preliminary version was completed with factor analysis.</p><p><b>RESULTS</b>Fifty items were developed using factor analysis. The final structure model of ChQOL was confirmed through the screening and verification of factor structural model on the 78 items of ChQOL, a new questionnaire with more rational structure was confirmed.</p><p><b>CONCLUSION</b>Factor analysis is an effective method in developing new questionnaire.</p>