Application of Monte Carlo simulation to optimise the dosage regimen of meropenem in patients with augmented renal clearance for Pseudomonas aeruginosa infection.

Objective: To optimise the dosing regimen of meropenem for treating Pseudomonas aeruginosa (PA) infections in critically ill patients with augmented renal clearance (ARC) using pharmacokinetic/pharmacodynamic (PK/PD) principles and Monte Carlo simulation (MCS). Methods: This research involves an MCS based on PK data from patients with ARC and a minimum inhibitory concentration (MIC) distribution of PA. This study simplifies the methods section, focusing on the critical aspects of simulation and target values for effective treatment. Results: The study highlights key findings and emphasises that tailored dosing based on bacterial MIC values is essential for patients with ARC. It also notes that empirical treatment in patients with ARC should consider the MIC distribution, with 2 g every (q) 6 h administered to achieve the PK/PD target, while 3 g q 6 h is effective in inhibiting resistance. Conclusion: Tailored dosing based on bacterial MIC values is crucial for patients with ARC. Prolonged infusion time alone does not enhance efficacy. Empirical treatment in patients with ARC should consider MIC distribution; a dosage of 2 g q 6 h achieves the PK/PD target, while 3 g q 6 h (≥12 g daily) inhibits resistance.

The effect of early oral nutritional supplements on improving nutritional outcomes and radiation-induced oral mucositis for nasopharyngeal carcinoma patients undergoing concurrent chemoradiotherapy.

BACKGROUND: To explore the value of early oral nutritional supplements (ONS) in patients with nasopharyngeal carcinoma (NPC) treated with concurrent chemoradiotherapy (CCRT). METHODS: Patients with newly diagnosed II-IVA stage NPC were analyzed and divided into Early and Routine ONS groups according to whether they received early ONS at the beginning of CCRT. Changes in nutritional indicators, incidence of treatment-related toxicity, radiation interruption, and completion of CCRT were compared. RESULTS: In total, 161 patients with NPC were analyzed, including 72 in the Early ONS group and 89 in the Routine ONS group. Multivariate analysis showed that early ONS was an independent protective factor for concurrent chemotherapy ≥2 cycles, and a protective factor against ≥grade 3 radiation-induced oral mucositis (RIOM) and weight loss >5%. In stage III-IVA patients, early ONS was beneficial in decreasing the risk of severe malnutrition. CONCLUSIONS: Early ONS can improve nutritional outcomes, reduce RIOM, and enhance treatment adherence.

Salidroside ameliorates pathological cardiac hypertrophy via TLR4-TAK1-dependent signaling.

Salidroside, a prominent active ingredient in traditional Chinese medicines, is garnering increased attention because of its unique pharmacological effects against ischemic heart disease via MAPK signaling, which plays a critical role in regulating the evolution of ventricular hypertrophy. However, the function of Salidroside on myocardial hypertrophy has not yet been elucidated. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with Salidroside (100 mg kg-1  day-1 ) by oral gavage for 3 weeks starting 1 week after surgery. Four weeks after TAC surgery, the mice were subjected to echocardiography and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes were used to validate the protective effects of Salidroside in response to Angiotensin II (Ang II, 1 µM) stimulation. Here, we proved that Salidroside dramatically inhibited hypertrophic reactions generated by pressure overload and isoproterenol (ISO) injection. Salidroside prevented the activation of the TAK1-JNK/p38 axis. Salidroside pretreatment of TAK1-inhibited cardiomyocytes shows no additional attenuation of Ang II-induced cardiomyocytes hypertrophy and signaling pathway activation. The overexpression of constitutively active TAK1 removed the protective effects of Salidroside on myocardial hypertrophy. TAC-induced increase of TLR4 protein expression was reduced considerably in the Salidroside treated mice. Transient transfection of small interfering RNA targeting TLR4 (siTLR4) in cardiomyocytes did not further decrease the activation of the TAK1/JNK-p38 axis. In conclusion, Salidroside functioned as a TLR4 inhibitor and displayed anti-hypertrophic action via the TAK1/JNK-p38 pathway.

NEU1 Regulates Mitochondrial Energy Metabolism and Oxidative Stress Post-myocardial Infarction in Mice via the SIRT1/PGC-1 Alpha Axis.

Objective: Neuraminidase 1 (NEU1) participates in the response to multiple receptor signals and regulates various cellular metabolic behaviors. Importantly, it is closely related to the occurrence and progression of cardiovascular diseases. Because ischemic heart disease is often accompanied by impaired mitochondrial energy metabolism and oxidative stress. The purpose of this study was to investigate the functions and possible mechanisms of NEU1 in myocardial remodeling and mitochondrial metabolism induced by myocardial infarction (MI). Methods: In this study, the MI-induced mouse mode, hypoxia-treated H9C2 cells model, and hypoxia-treated neonatal rat cardiomyocytes (NRCMs) model were constructed. Echocardiography and histological analysis were adopted to evaluate the morphology and function of the heart at the whole heart level. Western blot was adopted to determine the related expression level of signaling pathway proteins and mitochondria. Mitochondrial energy metabolism and oxidative stress were detected by various testing kits. Results: Neuraminidase 1 was markedly upregulated in MI cardiac tissue. Cardiomyocyte-specific NEU1 deficiency restored cardiac function, cardiac hypertrophy, and myocardial interstitial fibrosis. What is more, cardiomyocyte-specific NEU1 deficiency inhibited mitochondrial dysfunction and oxidative stress induced by MI. Further experiments found that the sirtuin-1/peroxisome proliferator-activated receptor γ coactivator α (SIRT1/PGC-1α) protein level in MI myocardium was down-regulated, which was closely related to the above-mentioned mitochondrial changes. Cardiomyocyte-specific NEU1 deficiency increased the expression of SIRT1, PGC-1α, and mitochondrial transcription factor A (TFAM); which improved mitochondrial metabolism and oxidative stress. Inhibition of SIRT1 activity or PGC-1α activity eliminated the beneficial effects of cardiomyocyte-specific NEU1 deficiency. PGC-1α knockout mice experiments verified that NEU1 inhibition restored cardiac function induced by MI through SIRT1/PGC-1α signaling pathway. Conclusion: Cardiomyocyte-specific NEU1 deficiency can alleviate MI-induced myocardial remodeling, oxidative stress, and mitochondrial energy metabolism disorder. In terms of mechanism, the specific deletion of NEU1 may play a role by enhancing the SIRT1/PGC-1α signaling pathway. Therefore, cardiomyocyte-specific NEU1 may provide an alternative treatment strategy for heart failure post-MI.

Neuraminidase 1 deficiency attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory via AMPK-SIRT3 pathway in diabetic cardiomyopathy mice.

Diabetic cardiomyopathy (DCM) is associated with oxidative stress and augmented inflammation in the heart. Neuraminidases (NEU) 1 has initially been described as a lysosomal protein which plays a role in the catabolism of glycosylated proteins. We investigated the role of NEU1 in the myocardium in diabetic heart. Streptozotocin (STZ) was injected intraperitoneally to induce diabetes in mice. Neonatal rat ventricular myocytes (NRVMs) were used to verify the effect of shNEU1 in vitro. NEU1 is up-regulated in cardiomyocytes under diabetic conditions. NEU1 inhibition alleviated oxidative stress, inflammation and apoptosis, and improved cardiac function in STZ-induced diabetic mice. Furthermore, NEU1 inhibition also attenuated the high glucose-induced increased reactive oxygen species generation, inflammation and, cell death in vitro. ShNEU1 activated Sirtuin 3 (SIRT3) signaling pathway, and SIRT3 deficiency blocked shNEU1-mediated cardioprotective effects in vitro. More importantly, we found AMPKα was responsible for the elevation of SIRT3 expression via AMPKα-deficiency studies in vitro and in vivo. Knockdown of LKB1 reversed the effect elicited by shNEU1 in vitro. In conclusion, NEU1 inhibition activates AMPKα via LKB1, and subsequently activates sirt3, thereby regulating fibrosis, inflammation, apoptosis and oxidative stress in diabetic myocardial tissue.

6-Gingerol protects against cardiac remodeling by inhibiting the p38 mitogen-activated protein kinase pathway.

6-Gingerol, a pungent ingredient of ginger, has been reported to possess anti-inflammatory and antioxidant activities, but the effect of 6-gingerol on pressure overload-induced cardiac remodeling remains inconclusive. In this study, we investigated the effect of 6-gingerol on cardiac remodeling in in vivo and in vitro models, and to clarify the underlying mechanisms. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 6-gingerol (20 mg/kg, ig) three times a week (1 week in advance and continued until the end of the experiment). Four weeks after TAC surgery, the mice were subjected to echocardiography, and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes and cardiac fibroblasts were used to validate the protective effects of 6-gingerol in response to phenylephrine (PE) and transforming growth factor-ß (TGF-ß) challenge. We showed that 6-gingerol administration protected against pressure overload-induced cardiac hypertrophy, fibrosis, inflammation, and dysfunction in TAC mice. In the in vitro study, we showed that treatment with 6-gingerol (20 µM) blocked PE-induced-cardiomyocyte hypertrophy and TGF-ß-induced cardiac fibroblast activation. Furthermore, 6-gingerol treatment significantly decreased mitogen-activated protein kinase p38 (p38) phosphorylation in response to pressure overload in vivo and extracellular stimuli in vitro, which was upregulated in the absence of 6-gingerol treatment. Moreover, transfection with mitogen-activated protein kinase kinase 6 expressing adenoviruses (Ad-MKK6), which specifically activated p38, abolished the protective effects of 6-gingerol in both in vitro and in vivo models. In conclusion, 6-gingerol improves cardiac function and alleviates cardiac remodeling induced by pressure overload in a p38-dependent manner. The present study demonstrates that 6-gingerol is a promising agent for the intervention of pathological cardiac remodeling.

Critical roles of macrophages in pressure overload-induced cardiac remodeling.

Macrophages are integral components of the mammalian heart that show extensive expansion in response to various internal or external stimuli. After the onset of sustained pressure overload (PO), the accumulation of cardiac macrophages through local macrophage proliferation and monocyte migration has profound effects on the transition to cardiac hypertrophy and remodeling. In this review, we describe the heterogeneity and diversity of cardiac macrophages and summarize the current understanding of the important roles of macrophages in PO-induced cardiac remodeling. In addition, the possible mechanisms involved in macrophage modulation are also described. Finally, considering the significant effects of cardiac macrophages, we highlight their emerging role as therapeutic targets for alleviating pathological cardiac remodeling after PO.

TLR9 deficiency alleviates doxorubicin-induced cardiotoxicity via the regulation of autophagy.

Doxorubicin is a commonly used anthracycline chemotherapeutic drug. Its application for treatment has been impeded by its cardiotoxicity as it is detrimental and fatal. DNA damage, cardiac inflammation, oxidative stress and cell death are the critical links in DOX-induced myocardial injury. Previous studies found that TLR9-related signalling pathways are associated with the inflammatory response of cardiac myocytes, mitochondrial dysfunction and cardiomyocyte death, but it remains unclear whether TLR9 could influence DOX-induced heart injury. Our current data imply that DOX-induced cardiotoxicity is ameliorated by TLR9 deficiency both in vivo and in vitro, manifested as improved cardiac function and reduced cardiomyocyte apoptosis and oxidative stress. Furthermore, the deletion of TLR9 rescued DOX-induced abnormal autophagy flux in vivo and in vitro. However, the inhibition of autophagy by 3-MA abolished the protective effects of TLR9 deletion on DOX-induced cardiotoxicity. Moreover, TLR9 ablation suppressed the activation of p38 MAPK during DOX administration and may promote autophagy via the TLR9-p38 MAPK signalling pathway. Our study suggests that the deletion of TLR9 exhibits a protective effect on doxorubicin-induced cardiotoxicity by enhancing p38-dependent autophagy. This finding could be used as a basis for the development of a prospective therapy against DOX-induced cardiotoxicity.

The Roles of Noncardiomyocytes in Cardiac Remodeling.

Cardiac remodeling is a common characteristic of almost all forms of heart disease, including cardiac infarction, valvular diseases, hypertension, arrhythmia, dilated cardiomyopathy and other conditions. It is not merely a simple outcome induced by an increase in the workload of cardiomyocytes (CMs). The remodeling process is accompanied by abnormalities of cardiac structure as well as disturbance of cardiac function, and emerging evidence suggests that a wide range of cells in the heart participate in the initiation and development of cardiac remodeling. Other than CMs, there are numerous noncardiomyocytes (non-CMs) that regulate the process of cardiac remodeling, such as cardiac fibroblasts and immune cells (including macrophages, lymphocytes, neutrophils, and mast cells). In this review, we summarize recent knowledge regarding the definition and significant effects of various non-CMs in the pathogenesis of cardiac remodeling, with a particular emphasis on the involved signaling mechanisms. In addition, we discuss the properties of non-CMs, which serve as targets of many cardiovascular drugs that reduce adverse cardiac remodeling.

TLR9 is essential for HMGB1-mediated post-myocardial infarction tissue repair through affecting apoptosis, cardiac healing, and angiogenesis.

The poor prognosis of patients with acute myocardial infarction is partially attributed to a large number of cardiomyocyte apoptosis, necrosis, limited cardiac healing and angiogenesis, and cardiac dysfunction. Immune cells dysfunction leads to nonhealing or poor healing of wounds after acute myocardial infarction. Toll-like receptor 9 (TLR9) as an essential part of the innate immune system plays a vital role in regulating cardiomyocyte survival and wound healing. During hypoxia, High Mobility Group Box 1 (HMGB1), as the typical damage-associated molecular patterns (DAMPs) or alarmin, is rapidly released extracellularly and translocates from the nucleus to bind with cytoplasmic TLR9. However, the mechanism by which TLR9 interacts with HMGB1 and regulates myocardial damage remains unclear. Our current study found that the survival rate of TLR9KO mice with a higher rate of cardiac rupture was significantly lower than that in WT mice after 28 days post-operation. The effect of TLR9 knockout on insufficient wound healing in experimental MI was caused by a diminished number of myofibroblast and defective matrix synthetic capability. Moreover, the increased myocardial apoptotic cells and decreased angiogenic capacity were found in TLR9 knockout mice after MI. The results showed contrary in Recombinant Human High Mobility Group Box 1 (rhHMGB1) treated WT mice and similarity after applying rhHMGB1 in TLR9KO mice. This study demonstrates that TLR9 is essential for the repair of infarcted myocardium and interaction of HMGB1 and TLR9 is involved in the survival of myocardial cells, wound healing, and angiogenesis after myocardial infarction.

[Impact of low temperature in young ear formation stage on rice seed setting.] / 幼穗形成期低温对水稻结实的影响.

A low temperature treatment in rice booting key period was executed on the north slope of Changbai Mountains to construct the impact model of low temperature on rice shell rate, and to reveal the effects of low temperature at different stages of rice young panicle on seed setting. The results showed that effects of low temperature in the young ear formation stage on rice shell rate generally followed the logarithmic function, the lower the temperature was, the greater the temperature influence coefficient was, and the longer the low temperature duration was, the higher rice shell rate was. The seed setting rate was most sensitive to low temperature in the middle time of booting stage (the period from formation to meiosis of the pollen mother cell), followed by the early and later stages. During the booting stage, with 1 ℃ decrease of daily temperature under 2-, 3- and 5-day low temperature treatments, the shell rate increased by 0.5, 1.7 and 4.3 percentage, respectively, and with 1 ℃ decrease of daily minimum temperature, the shell rate increased by 0.4,1.8 and 4.5 percentage, respectively. The impact of 2-day low temperature was smaller than that of 3 days or more. The impact of accumulative cold-temperature on the shell rate followed exponential function. In the range of harmful low temperature, rice shell rate increased about 8.5 percentage with the accumulative cold-temperature increasing 10 ℃·d. When the 3 days average temperature dropped to 21.6, 18.0 and 15.0 ℃, or the 5 days average temperature dropped to 22.0, 20.4 and 18.5 ℃, or the accumulative cold-temperature was more than 8, 19, 26 ℃·d, the light, moderate and severe booting stage chilling injury would occur, respectively. In Northeast China, low temperature within 2 d in rice booting stage might not cause moderate and severe chilling injury.

Parental health and social support in the first trimester of pregnancy and the risk of oral clefts: a questionnaire-based, case-control study.

BACKGROUND: Nonsyndromic oral clefts are complex in cause and have multiple genetic and environmental risk factors. This retrospective, questionnaire-based, case-control study investigated the relationship between oral clefts and parental mental and physical health and social support. METHODS: Three hundred forty-seven parents of children with nonsyndromic oral clefts and 420 controls were included. Maternal and paternal health during the first trimester was assessed using interviews and questionnaires modeled from the Cornell Medical Index and the Social Support Rating Scale. Case-control analyses were performed using t tests, chi-square tests, and logistic regression. RESULTS: Parental age, household income, and subsisting on farming were significantly different for cases and controls. The Cornell Medical Index for cases was significantly worse compared with controls for physical and psychological health. Logistic regression showed that nine factors were significantly associated with oral clefts: paternal respiratory health (OR, 1.56; p = 0.03), maternal gastrointestinal health (OR, 1.71; p < 0.01), maternal musculoskeletal health (OR, 1.50; p < 0.01), paternal nervous system health (OR, 2.82; p < 0.01), maternal frequency of illness (OR, 2.21; p = 0.01), maternal diseases (OR, 2.44; p < 0.01), maternal health habits (OR, 1.73; p < 0.01), paternal feelings of inadequacy (OR, 2.28; p = 0.03), and maternal anger (OR, 2.28; p < 0.01) in the first trimester. Weaker social support from the community was associated with oral clefts (p < 0.01). CONCLUSION: Maternal and paternal health and social support may affect a family's risk of having a child with a cleft. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

[Response of maize emergence rate and yield to soil water stress in period of seeding emergence and its meteorological assessment in central area of Jilin Province].

In spring of 2010-2011, an experiment with treatments on soil water stress and sowing by stages of spring maize (Zea mays) was conducted in the central Jilin Province. The responses of maize emergence rate and yield to soil water stress were analyzed, and the assessment models of the emergence rate and reduction of yield caused by drought were established based on meteorological conditions. The results showed that during the study period, the relationship between maize emergence rate or per unit yield, and the soil moisture in 0-20 cm layer or soil available water content presented a significant quadratic function. The emergence rate and yield increased with the higher surface soil moisture, while decreased obviously under the drought condition. The emergence rate and yield were higher in the conditions of soil moisture in the range of 22%-24% or soil available water content in 50-65 mm, while the emergence rate and yield decreased obviously with the soil moisture less than 19% or available water content less than 35 mm. The soil moisture decreased 1% each, along with the emergence rate decreased by about 6% , and the yield decreased by about 7%. The soil available water content decreased by 10 mm, along with the emergence rate and yield decreased by about 13% and 14%, respectively. The indicators and models in this article could be applied to assessment and prediction of maize emergence rate and the reduction of yield caused by drought.