Initial treatment with a single capsule containing half-dose quadruple therapy vs standard-dose dual therapy in hypertensive patients (QUADUAL): Study protocol for a randomized, blinded, crossover trial.

BACKGROUND: Combined antihypertensive therapy has obvious advantages over single drug therapy. Hypertension guidelines fully affirm the efficacy of dual combination in initial antihypertensive therapy. Recent studies have also pointed out that the quadruple combination of very low-dose antihypertensive drugs is superior to single drugs. However, whether low-dose quadruple therapy is better than dual combination is unknown. OBJECTIVE: To evaluate and compare the efficacy and safety of half-dose quadruple therapy vs standard-dose dual therapy in the initial treatment of hypertensive patients with systolic/diastolic blood pressure 140-179/90-109 mm Hg. METHODS: A randomized double-blind crossover clinical trial will be conducted to compare the efficacy and safety of low-dose quadruple antihypertensives (irbesartan 75 mg + metoprolol 23.75 mg + amlodipine 2.5 mg + indapamide 1.25 mg) with standard-dose dual antihypertensives (irbesartan 150 mg + amlodipine 5 mg) in the initial treatment of patients with mild to moderate hypertension (140-179/90-109 mm Hg). Ninety patients are required and will be recruited and randomly assigned in a 1:1 ratio to 2 crossover groups. Two groups will receive a different combination therapy for 4 weeks, then switch to the other combination therapy for 4 weeks, with a 2-week wash-out. The patients will be followed up for 4 weeks to compare the antihypertensive effects and related adverse effects of the 2 antihypertensive combination treatments. CONCLUSIONS: We present the rationale for the design of the QUADUAL trial. The trial started in July 2022 and is expected to be completed by August 2023. The study aims to evaluate if an initial treatment regimen of quadruple combination of half-dose blood pressure medications will result in greater reduction in blood pressure and fewer side effects compared to standard dose dual therapy. REGISTRATION: www. CLINICALTRIALS: gov (NCT05377203).

A review on the effect of light-thermal-humidity environment in sow houses on sow reproduction and welfare.

The environment in sow houses is the key to restrict sow production due to its significant effect on sow growth and reproduction. In this article, the effect of light, thermal and light-thermal-humidity environment in sow houses is systematically reviewed for sow reproduction and welfare according to the existing literature. The results show the optimal ambient temperature range for sows is approximately 16-22°C, as well as the lowest and highest critical temperature are 16 and 27°C respectively. Meanwhile, the increase of relative humidity from 50% to 70% is equivalent to the increase of effective temperature by 0.9°C in sow houses. In addition, the evaluation indexes are summarized to the future research direction is proposed according to the reviewed results. It can be concluded that the current research mainly focuses on the effect mechanism of light-thermal-humidity environment on sow growth and reproductive performance, as well as the optimal regulation range of light-thermal-humidity environment. In particular, it is a popular topic to further study the effect of light-thermal-humidity environment on the genetic material of sows, as well as metabolic parameters and body composition of their offspring. The above conclusions can contribute to guiding the regulation of light-thermal-humidity environment in sow houses and improving the sow welfare.

Application Effect of Medical Care Integration Combined with Family Intervention under the Evidence-Based Nursing Mode on Child Patients with Severe Hand-Foot-Mouth Disease and Its Influence on Intestinal Function.

OBJECTIVE: To explore the application effect of medical care integration combined with family intervention under the evidence-based nursing mode on child patients with severe hand-foot-mouth disease (HFMD) and its influence on intestinal function. METHODS: 120 child patients with severe HFMD admitted to Qilu Children's Hospital of Shandong University from January 2019 to January 2020 were selected as the research object and randomly divided into group A and group B, with 60 cases each. Conventional nursing was performed on patients in group B, and medical care integration combined with family intervention under the evidence-based nursing mode was performed on patients in group A. Patients were assessed after the intervention using the hospital-made treatment adherence scale, PedsQLTM 4.0 (Pediatric Quality of Life Inventory Version 4.0) scale, and the faces pain scale-revised (FPS-R). The levels of gastrointestinal function indicators such as serum endotoxin (ET), diamine oxidase (DAO), and d-lactic acid (D-LA) were measured before and after the intervention, and recovery such as time to clear fever and time to relief of oral pain were recorded in both groups. RESULTS: Children in group A had significantly higher compliance in diet, behaviour, exercise, and medication than group B (P < 0.05); the time to clear fever, time to relief of oral pain, time to healing of oral ulcers, time to relief of skin herpes, time to hospitalization, and time to eating were shorter in group A than those in group B (P < 0.001); all scores on the PedsQLTM 4.0 scale were higher in group A than those in group B after the intervention (P < 0.001); ET, DAO, and D-LA levels decreased in both groups after the intervention, with group A having lower levels than group B (P < 0.001), in addition, group A had lower eating pain scores after the intervention (P < 0.05). CONCLUSION: Medical care integration combined with family intervention under the evidence-based nursing mode can effectively improve the treatment compliance of child patients with severe HFMD, accelerate their recovery progress, ensure a better prognostic quality of life and gastrointestinal tract function, and reduce the eating pain, indicating that such comprehensive nursing intervention mode should be promoted in practice.

MiR-467a-5p aggravates myocardial infarction by modulating ZEB1 expression in mice.

Myocardial infarction (MI) is a great threat to patients all over the word. MicroRNAs (miRNAs) are a group of non-coding RNAs and can regulate initiation and progression of MI. The current research aimed to investigate the role of miR-467a-5p in MI. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was conducted to detective relative expression of miR-467a-5p in cardiac tissues and mouse cardiomyocytes (MCMs). Hematoxylin and eosin staining was used to reveal the histology of the myocardium. Echocardiography was utilized to reveal cardiac function of mice. Flow cytometer analysis was used to reveal cell apoptosis. Luciferase reporter assay was applied for determining the binding capacity between molecules. We discovered that the level of miR-467a-5p was up-regulated in MI mice and in MCMs induced by H2O2 or hypoxia. Functionally, an elevation of left ventricular end-diastolic diameter and left ventricular end-systolic diameter, as well as a decrease of left ventricular ejection fraction and left ventricular fractional shortening were observed in MI mice. In addition, deficiency of miR-467a-5p improved MI in mice by increasing the contents of lactate dehydrogenase, creatine kinase and malondialdehyde and reducing the activity of superoxide dismutase in serum. Moreover, silencing of miR-467a-5p reversed hypoxia-induced apoptosis of MCMs. Mechanistically, zinc finger E-box binding homeobox 1 (ZEB1) was confirmed as the target of miR-467a-5p. Moreover, miR-467a-5p negatively regulated ZEB1 level in MI mice and MCMs. Finally, the promotive effect of miR-467a-5p inhibition on cell apoptosis was reversed by knockdown of ZEB1. All the experimental results demonstrate that miR-467a-5p aggravates MI by modulating ZEB1 expression in mice, which may provide a novel therapeutic strategy for MI.

Expression of the C677T Polymorphism of the 5, 10-Methylenetetrahydrofolate Reductase (MTHFR) Gene in Patients with Carotid Artery Atherosclerosis.

BACKGROUND The C677T polymorphism of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism has been associated with hypertension and coronary heart disease, but its relationship with carotid artery remains unknown. This study aimed to investigate the association between the C677T polymorphism of the MTHFR gene in patients with confirmed carotid artery atherosclerosis. MATERIAL AND METHODS This retrospective study included 210 patients with carotid artery atherosclerosis (the patient group) and 210 controls (the control group). Color Doppler ultrasound was used to identify carotid artery intimo-medial thickness and atherosclerotic plaques. Sanger sequencing using the polymerase chain reaction (PCR) was used to detect the MTHFR C677T gene polymorphism. Systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), glycosylated hemoglobin (HbA1c), and other laboratory indicators were measured. RESULTS SBP, DBP, FPG, TC, LDL-C, HbA1c, and intimo-medial thickness were significantly increased in the patient group compared with the control group, and HDL-C was significantly lower. The allele frequencies of the C667T locus of MTHFR gene were significantly different between the two groups (P<0.05), and the TT genotype and the T allele frequencies in the patient group were higher than in the control group. Logistic regression analysis showed that SBP, TC, LDL-C, and the C667T MTHFR gene polymorphism were risk factors for carotid artery atherosclerosis. CONCLUSIONS The C677T polymorphism of the MTHFR gene was expressed in patients with carotid artery atherosclerosis.

Trimetazidine protects against hypoxia-reperfusion-induced cardiomyocyte apoptosis by increasing microRNA-21 expression.

Myocardial tissue injury caused by ischemia and hypoxia is a major cause of fatal diseases, including coronary atherosclerosis resulting from myocardial infarction and stroke. Trimetazidine (TMZ), as an anti-ischemic and antioxidant agent, has been demonstrated to preventing ischemia/reperfusion-induced cardiomyocyte apoptosis. However, the anti-apoptosis mechanism of TMZ has not been fully elucidated. The present study demonstrated that miR-21 involved trimetazidine-induced anti-apoptosis during H/R injury in H9C2 cell. In this study, TMZ increased miR-21 expression which further upregulated the Akt signaling activity via suppressing the expression of phosphatase and tensin homolog (PTEN) in H/R H9C2 cell. The increased activity of Akt signaling decreased the ratio of Bax/Bcl-2 and the expression of caspase-3 and inhibited H/R induced apoptosis. In conclusion, this study revealed the mechanism that TMZ up-regulated miR-21 expression, then miR-21 targeted PTEN increasing the PI3K pathway and finally the activation of this pathway counteracted the apoptotic effect of hypoxia/reperfusion.

miR-133a mediates the hypoxia-induced apoptosis by inhibiting TAGLN2 expression in cardiac myocytes.

Myocardial hypoxia is a major cause of cardiac dysfunction due to its triggering cell injury and apoptosis. Deregulated microRNAs and their roles in cardiomyocyte apoptosis have attracted much attention. miR-133a is among the most abundant of the miRNAs present in the normal heart, and significant changes in expression of miR-133a were observed in response to anoxia stress. However, the role of this microRNA in myocardial hypoxia-induced apoptosis is presently unclear. In this study, we identified that miR-133a expression was down-regulated in hypoxic H9c2 cells, and its expression gradually decreased with hypoxia time. Functional analysis revealed that miR-133a attenuated hypoxia-induced apoptosis. We further detected expression of apoptosis-related proteins. The results showed that miR-133a suppressed the expression of apoptotic proteins caspase-8, caspase-9, and caspase-3 significantly, while improved the expression of Bcl-2. Bioinformatics analysis, combined with dual-luciferase reporter analysis, was applied to determine that miR-133a directly was binded to the 3'-untranslated region (3'-UTR) of TAGLN2 mRNA and suppressed expression at both transcriptional and translational levels. Next, TAGLN2 knockout was used to reveal that TAGLN2 modulated hypoxia-induced apoptosis via caspase-8 apoptotic pathway. Taken together, our data demonstrated the roles of miR-133a in hypoxia-induced apoptotic and implicate its potential in cardiac dysfunctions therapy.

microRNA-21 protects against ischemia-reperfusion and hypoxia-reperfusion-induced cardiocyte apoptosis via the phosphatase and tensin homolog/Akt-dependent mechanism.

Myocardial tissue injury caused by ischemia and hypoxia is a major cause of fatal diseases, including coronary atherosclerosis resulting from myocardial infarction and stroke. A number of microRNAs have been demonstrated to function as protectors against ischemia-reperfusion (I/R) and/or hypoxia-reperfusion (H/R)-induced myocardial injury, including microRNA-21 (miR-21). However, the protective mechanism of miR-21 has not been fully elucidated. The present study demonstrated that miR-21 had an anti-apoptotic role in I/R-induced myocardial damage in vivo and in H/R-induced H9C2 cell death in vitro. Of note, the present study indicates that a common molecular mechanism is likely to exist in I/R- and H/R-induced cardiocyte apoptosis. During I/R and H/R, forced expression of miR-21 upregulated the Akt signaling activity via suppressing the expression of phosphatase and tensin homolog (PTEN) and the increased activity of Akt signaling further inhibited apoptosis partially by increasing the ratio of B-cell lymphoma 2(Bcl-2)/Bcl-2-associated X protein, which further suppressed the expression of caspase-3. In conclusion, to the best of our knowledge, it was shown for the first time that miR-21 had a protective role in I/R- and H/R-induced cardiocyte apoptosis via the PTEN/Akt-dependent mechanism. The present study indicates that miR-21 may be a promising agent for the treatment of I/R and H/R-induced myocardial injury.

[Anti-apoptosis and expression of microRNA-21 in rat myocardium during early ischemia-reperfusion injury].

OBJECTIVE: To observe the expression and anti-apoptosis of microRNA-21(miR-21) in rat myocardium during early ischemia-reperfusion injury (I/R). METHODS: Sprague-Dawley rats were randomly divided into 5 groups: a control group (transfected with rAAV9-ZsGreen by coronary injection), a miR-21group (transfected rAAV9-ZsGreen-premiR- 21 by coronary injection), a sham group (open-chest only), an I/R group (I/R), and an I/ R+miR-21 (I/R after transfected rAAV9-ZsGreen-pre-miR-21 by coronary injection). Realtime PCR was used to assess the expression level of miR-21. Immunohistochemistry and Western blot were used to determine the expression of Bcl-2, Bax, caspase-3 and Bcl-2/Bax. RESULTS: MiR-21 was increased by 4.43 times in the miR-21 group (P<0.001). MiR-21 was downregulated in the ischemia zone after I/R compared with the sham group (P<0.05), but that in the non-ischemia zone was significantly increased compared with the sham group (P<0.01). MiR- 21 expression was decreased in the I/R group compared with that in the sham group at 1 h, 2 h and 6 h after I/R (P<0.05), and it was up-regulated in the I/R+miR-21 group at the same time point compared with the I/R group (P<0.01). The expression of Bcl-2, Bax, and caspase-3 was upregulated and Bcl-2/Bax was decreased in the ischemia zone in the I/R group and I/R+miR-21 group than the sham group(P<0.05). Compared with the I/R group, the expression of Bcl-2 and caspase-3 was down-regulated and Bcl-2/Bax was increased in the ischemia zone in the I/ R+miR-21 group (P<0.05). CONCLUSION: MiR-21 expression is down-regulated and cell apoptosis is increased in rat myocardium during early ischemia-reperfusion injury. Myocardial cell apoptosis may be alleviated by miR-21 over-expression.