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Objectives: Olanzapine is used for treating bipolar disorder (BPD); however, the optimal initial dosing regimen is unclear. The present study aimed to investigate the optimal olanzapine initial dosage in patients with BPD via model-informed precision dosing (MIPD) based on a real-world study. Methods: Thirty-nine patients with BPD from the real-world study were collected to construct the MIPD model. Results: Weight, combined used quetiapine influenced olanzapine clearances in patients with BPD, where the clearance rates were 0.152:1 in patients with or without quetiapine under the same weight. We simulated olanzapine doses once a day or twice a day, of which twice a day was optimal. Without quetiapine, for twice-a-day olanzapine doses, 0.80, 0.70, and 0.60 mg/kg/day were suitable for 40- to 56-kg BPD patients, 56- to 74-kg BPD patients, and 74- to 100-kg BPD patients, respectively. With quetiapine, for twice-a-day olanzapine doses, 0.05 mg/kg/day was suitable for 40- to 100-kg BPD patients. Conclusion: This study was the first to investigate the optimal olanzapine initial dosage in patients with BPD via MIPD based on a real-world study, providing clinical reference for the precision medication of olanzapine in BPD patients. [ABSTRACT FROM AUTHOR]

Background: The present study aimed to investigate the drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics. Research design and methods: A total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects. Results: The weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg-1 day-1 were recommended for patients with schizophrenia weighing 40-95 and 95-120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg-1 day-1 was recommended for those weighing 40-120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg-1 day-1 was recommended for patients with schizophrenia weighing 40-120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg-1 day-1 were recommended for those weighing 40-60 and 60-120 kg, respectively. Conclusion: This is the first investigation of the effects of fluoxetine on aripiprazole via drug-drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Background and aims: An increasing number of studies have confirmed that non-textbook outcomes (non-TO) are a risk factor for the long-term outcome of malignant tumors. It is particularly important to identify the predictive factors of non-TO to improve the quality of surgical treatment. We attempted to construct two nomograms for preoperative and postoperative prediction of non-TO after laparoscopic hepatectomy for hepatocellular carcinoma (HCC). Methods: Patients who underwent curative-intent hepatectomy for HCC between 2014 and 2021 at two Chinese hospitals were analyzed. Using univariate and multivariate analyses, the independent predictors of non-TO were identified. The prediction accuracy is accurately measured by the receiver operating characteristic (ROC) curve and calibration curve. ROC curves for the preoperative and postoperative models, Child-Pugh grade, BCLC staging, and 8th TNM staging were compared relative to predictive accuracy for non-TO. Results: Among 515 patients, 286 patients (55.5%) did not achieve TO in the entire cohort. Seven and eight independent risk factors were included in the preoperative and postoperative predictive models by multivariate logistic regression analysis, respectively. The areas under the ROC curves for the postoperative and preoperative models, Child-Pugh grade, BCLC staging, and 8th TNM staging in predicting non-TO were 0.762, 0.698, 0.579, 0.569, and 0.567, respectively. Conclusion: Our proposed preoperative and postoperative nomogram models were able to identify patients at high risk of non-TO following laparoscopic resection of HCC, which may guide clinicians to make individualized surgical decisions, improve postoperative survival, and plan adjuvant therapy against recurrence. [ABSTRACT FROM AUTHOR]

Dapagliflozin has been used to treat patients with type 1 diabetes mellitus; however, the actual drug efficacy of dapagliflozin on glycated hemoglobin (HbA1c) and whether there is a rebound from dapagliflozin efficacy on HbA1c remain unknown. The present study aimed to explore the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients. A total of 1,594 type 1 diabetes mellitus patients were enrolled for analysis using a non-linear mixed effect model from randomized controlled trials from published literature works including two 5 mg/day dapagliflozin dosage groups and three 10 mg/day dapagliflozin dosage groups. The change rate of HbA1c from a baseline value was chosen as a dapagliflozin pharmacodynamic evaluation index. After deducting control group effects, the therapeutic effect of 5 and 10 mg/day dapagliflozin on HbA1c in type 1 diabetes mellitus patients had no significant difference. In addition, the actual maximal efficacy (AEmax) of dapagliflozin on HbA1c was -6.24% at week 9. When it reached the AEmax, the dapagliflozin pharmacodynamic rebound on HbA1c occurred, and when the treatment was continued for 0.5 and 1 year, the actual efficacies were -4.70% (75% AEmax) and -3.27% (52% AEmax), respectively. This was the first time to clarify the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients, providing a reference value for clinical practices. [ABSTRACT FROM AUTHOR]

The aim of the present study was to detect the association between platelet glycoprotein-specific autoantibodies and the patient response to short-term high-dose dexamethasone (HD-DXM) + prednisone maintenance treatment. The data from 112 adult patients newly diagnosed with ITP who were administered first-line HD-DXM + prednisone maintenance therapy between January 2016 and January 2021 were retrospectively analyzed. A total of 72 patients positive for platelet glycoprotein-specific antibodies were enrolled in the antibody-positive group, and 40 patients not positive for platelet glycoprotein-specific antibodies were enrolled in the antibody-negative group. In the antibody-positive group, six platelet glycoprotein-specific antibody types were found: 41.67% of the patients were anti-GP IIb/IIIa-positive only, 5.56% were anti-GP Ib/IX-positive only, 5.56% were anti-P-selectin-positive only, 19.44% were anti-GP IIb/IIIa- and anti-GP Ib/IX-positive, 16.67% were anti-GP Ib/IX- and P-selectin-positive and 11.11% were positive for all three antibodies. There was no significant difference in the overall response rate between the antibody-positive group and the antibody-negative group (94.44 versus 80.00%, p =.221). However, the CR rate was significantly higher in the antibody-positive group than in the antibody-negative group (69.44% versus 40.00%, p =.032). The logistic regression analysis revealed that platelet glycoprotein-specific antibody positivity and age were two factors that could affect patient response. The present study discovered that adult patients newly diagnosed with ITP who had positive platelet glycoprotein-specific antibody test results were likely to achieve a better response after treatment with HD-DXM + prednisone maintenance. [ABSTRACT FROM AUTHOR]

The aim of the present study is to investigate the quantitative effects of sodium–glucose cotransporter-2 (SGLT-2) inhibitors on the quality of life in heart failure (HF) patients. A total of 14,674 HF patients from two dapagliflozin and three empagliflozin studies is included for analysis via the nonlinear mixed-effect modeling (NONMEM) software, among which the change rate of the Kansas City Cardiomyopathy Questionnaire (KCCQ) score is used as the evaluation index. There is no significant difference in the pharmacodynamics influencing the quality of life in HF patients between the SGLT-2 inhibitors: 10 mg/day dapagliflozin and 10 mg/day empagliflozin. For the clinical summary score (CSS), total symptom score (TSS), and overall summary score (OSS), the Emax of the SGLT-2 inhibitors on the quality of life in HF patients is 3.74%, 4.43%, and 4.84%, respectively, and ET50 is 2.23, 4.37, and 7.15 weeks, respectively. In addition, the time duration of achieving 25%, 50%, 75%, and 80% Emax is 0.75, 2.23, 6.69, and 8.92 weeks for the CSS; 1.46, 4.37, 13.11, and 17.48 weeks for the TSS; and 2.39, 7.15, 21.45, and 28.6 weeks for the OSS, respectively. Therefore, to reach the plateau period (80% of Emax) of SGLT-2 inhibitors on the CSS, TSS, and OSS, 10 mg/day dapagliflozin (or 10 mg/day empagliflozin) is required to be taken for 8.92 weeks, 17.48 weeks, and 28.6 weeks, respectively. This is the first time that the quantitative effects of SGLT-2 inhibitors on the quality of life in HF patients are being explored. [ABSTRACT FROM AUTHOR]

Background & aims: The long-term prognosis of patients with metabolic syndrome (MS) and hepatitis B virus-related hepatocellular carcinoma (HBVHCC) after radical hepatectomy remains unclear. The purpose of this study was to elucidate the effect of MS on long-term survival for patients with HBVrelated HCC after hepatectomy. Methods: Patients with HBV-HCC after hepatectomy were included. Patients were stratified into MS-HBV-HCC and HBV-HCC groups. Clinical features and surgical outcomes were compared between the two groups, and COX regression analysis was used to determine independent risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Result: 389 patients (MS-HBV-HCC group: n=50, HBV-HCC group: n=339) were enrolled for further analysis. Baseline characteristics showed that patients with MS-HBV-HCC were associated with a high rate of elderly patients, ASA score, and co-morbid illness, but a lower rate of anatomy hepatectomy. There were no significant differences in perioperative complications. After excluding patients who relapsed or died within 90 days after surgery, multivariate Cox regression analysis showed MS was an independent risk factor of OS (HR 1.68, 95% CI 1.05-2.70, P = 0.032) and RFS (HR 1.78, 95% CI 1.24-2.57, P = 0.002). Conclusion: MS is an independent risk factor for poor OS and RFS in HBVinfected HCC patients after radical hepatectomy. This suggests that we need to strengthen postoperative follow-up of the relevant population and encourage patients to develop a healthy lifestyle. [ABSTRACT FROM AUTHOR]

Background and aims: Recently, the effectiveness of "textbook outcomes (TO)" in the evaluation of surgical quality has been recognized by more and more scholars. This study tended to examine the association between preoperative albumin-bilirubin (ALBI) grades and the incidence of achieving or not achieving TO (non-TO) in patients with hepatocellular carcinoma (HCC) undergoing laparoscopic hepatectomy. Methods: The patients were stratified into two groups: ALBI grade 1 (ALBI = -2.60) and ALBI grade 2/3 (ALBI > -2.60). The characteristics of patients and the incidence of non-TO were compared. Multivariate analyses were performed to determine whether ALBI grade was independently associated with TO. Results: In total, 378 patients were enrolled, including 194 patients (51.3%) in the ALBI grade 1 group and 184 patients (48.7%) in the ALBI grade 2/3 group. In the whole cohort, 198 patients (52.4%) did not achieve TO, and the incidence of non-TO in the ALBI grade 2/3 group was obviously higher than that in the ALBI grade 1 group (n = 112, 60.9% vs. n = 86, 44.3%, P = 0.001). The multivariate analyses showed that ALBI grade 2/3 was an independent risk factor for non-TO (OR: 1.95, 95%CI: 1.30-2.94, P = 0.023). Conclusions: More than half (52.4%) of the patients with hepatocellular carcinoma did not achieve TO after laparoscopic hepatectomy, and preoperative ALBI grade 2/3 was significantly associated with non-TO. Improving the liver function reserve of patients before operation, thereby reducing the ALBI grade, may increase the probability for patients to reach TO and enable patients to benefit more from surgery. [ABSTRACT FROM AUTHOR]

Prior to micro-arc oxidation (MAO) treatment, a layer of high temperature oxide (HTO) prefab film was fabricated on the surface of 6061 aluminum alloy specimens. The formation mechanisms of the cracks and pores in the MAO coatings were investigated by means of Mg element as the tracer. The results showed that there were several different formation mechanisms for the pores and cracks formed in the MAO coatings as follows. Some of pores were attributed to the residual micro-discharge channels, and the others were attributed to the residual uncovered concave regions locating among the surrounding convex regions. The difference in oxide phase composition caused by the compositional fluctuations in the coating weakened the bond strength at the phase interface and resulted in forming cracks between every two convex regions. Some of cracks were resulted from the solidification and shrinkage of molten coating materials, and the others were resulted from the poor connection between every two convex regions. The surface morphology and the content of each element of the MAO coating were determined using scanning electron microscopy (SEM) equipped with energy dispersive X-ray spectroscopy (EDS). [ABSTRACT FROM AUTHOR]

We present long-term optical multi-band photometric monitoring of the blazar OJ 287 from 6 March 2010 to 3 April 2016, with high temporal resolution in the VRI-bands. The flux variations and colour-magnitude variations on long and short timescales were investigated to understand the emission mechanisms. In our observation, the major outbursts occurred in January 2016, as predicted by the binary pair of black holes model for OJ 287, with Fvar of 1.3~2.1%, and variability amplitude (Amp) of 5.8~9.0%. The intra-night variability (IDV) durations were from 18.5 to 51.3 min, and the minimal variability timescale was about 4.7 min. The colour-magnitude variation showed a weak positive correlation on the long timescale with Pearson’s r = 0.450, while a negative correlation was found on intra-night timescales. We briefly discuss the possible physical mechanisms that are most likely to be responsible for the observed flux and colour-magnitude correlation variability [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of the most important causes that leads to end-stage renal disease and the efficacy of strategies currently available for the prevention of DN remains unsatisfactory. Sitagliptin (SIT), which is a dipeptidyl peptidase-4 inhibitor, exhibited a modest beneficial effect on glycated hemoglobin levels and is capable of ameliorating renal ischemia reperfusion injury. By determining the expression of transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), collagen type IV (ColIV) and fibronectin (FN) levels in high glucose-cultured glomerular mesangial cells (MCs), the present study aimed to assess the anti-proliferative and anti-fibrotic effects of SIT on the therapeutic potential for the prevention of DN and its mechanism. Specifically, cell proliferation was determined via cell counting kit-8 assay, and the expression levels of TGF-ß1 and CTGF mRNA were detected by reverse transcription polymerase chain reaction analysis. Furthermore, the secretion of TGF-ß1, CTGF, ColIV and FN proteins was measured via enzyme-linked immunosorbent assays. The results demonstrated that high glucose induced the proliferation of MCs and enhanced the expression of TGF-ß1, CTGF, ColIV and FN. Furthermore, treatment with SIT inhibited cell proliferation and the expression of TGF-ß1, CTGF, ColIV and FN induced by high glucose. In conclusion, SIT inhibits cell proliferation and the expression of the major extracellular matrix proteins induced by high glucose, indicating its value for treating or relieving DN. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) exhibits a deteriorating course that may lead to end-stage renal failure. Astragalosides have been clinically tested for the treatment of DN, but the mechanism is unclear at present. In this study, the effects of astragalosides were investigated on high glucose-induced proliferation and expression of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), type IV collagen (colIV) and fibronectin (FN) in glomerular mesangial cells (MCs). Cell proliferation was determined by 5-bromo-2'-deoxyuridine assay, and the expression of TGF-β1, CTGF, colIV and FN mRNA and proteins in MCs was detected by reverse transcription-polymerase chain reaction and ELISA assay, respectively. The results showed that high glucose clearly induced the proliferation of MCs and increased the expression of TGF-β1, CTGF, colIV and FN. Treatment with 50, 100, 200 μg/ml astragalosides inhibited cell proliferation and the expression of TGF-β1, CTGF, colIV and FN induced by high glucose. Thus, it is concluded that astragalosides inhibit the increased cell proliferation and expression of major extracellular matrix proteins that are induced by high glucose, indicating their value for the prophylaxis and therapy of DN. [ABSTRACT FROM AUTHOR]

Oxidative stress has a central role in the progression of diabetes mellitus (DM), which can directly result in the injury of islet β cells and consequent hyperglycemia. The aim of the present study was to evaluate the possible protective effects of black bean peel extract (BBPE), pomegranate peel extract (PPE) and a combination of the two (PPE + BBPE) on streptozotocin-induced DM mice. Oxidative stress was assessed by the levels of total antioxidative capability and glutathione in the serum. Fasting blood glucose and insulin levels, as well as the pancreas weight index and the histological changes in the pancreas, were also determined. The results showed that, after fours weeks of treatment with PPE, BBPE or PPE + BBPE, DM mice showed, to different degrees, a decrease in blood glucose, increases in insulin secretion and the pancreas weight index, and an increase in antioxidative activity. These changes were particularly evident in the DM mice subjected to the combined intervention strategy of PPE + BBPE. The histological findings indicated that the injury to the pancreatic islets in DM mice was also ameliorated following treatment. In conclusion, PPE and BBPE, particularly the combination of the two, have the ability to ameliorate hyperglycemia by inhibiting oxidative stress-induced pancreatic damage; this finding may be useful in the prevention and treatment of DM. [ABSTRACT FROM AUTHOR]

Actin dynamics provide an important mechanism for the modification of synaptic plasticity, which is regulated by the actin depolymerizing factor (ADF)/cofilin. However, the role of cofilin regulated actin dynamics in memory extinction process is still unclear. Here, we observed that extinction of conditioned taste aversive (CTA) memory led to temporally enhanced ADF/cofilin activity in the infralimbic cortex (IrL) of the rats. Moreover, temporally elevating ADF/cofilin activity in the IrL could accelerate CTA memory extinction by facilitating AMPAR synaptic surface recruitment, whereas inhibition of ADF/cofilin activity abolished AMPAR synaptic surface trafficking and impaired memory extinction. Finally, we observed that ADF/cofilin-regulated synaptic plasticity was not directly coupled to morphological changes of postsynaptic spines. These findings may help us understand the role of ADF/cofilin-regulated actin dynamics in memory extinction and suggest that appropriate manipulating ADF/cofilin activity might be a suitable way for therapeutic treatment of memory disorders. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) plays important roles in cell survival, neural plasticity, learning, and stress regulation. However, whether the recently found human BDNF Val66Met (BDNFMet) polymorphism could alter stress vulnerability remains controversial. More importantly, the molecular and structural mechanisms underlying the interaction between the BDNFMet polymorphism and stress are unclear. We found that heterozygous BDNF+/Met mice displayed hypothalamic-pituitary-adrenal axis hyperreactivity, increased depressive-like and anxiety-like behaviors, and impaired working memory compared withWTmice after 7 d restraint stress. Moreover,BDNF+/Met mice exhibited more prominent changes in BDNF levels and apical dendritic spine density in the prefrontal cortex and amygdala after stress, which correlated with the impaired working memory and elevated anxiety-like behaviors. Finally, the depressive-like behaviors in BDNF+/Met mice could be selectively rescuedbyacute administration ofdesipraminebutnotfluoxetine.Thesedata indicate selective behavioral, molecular,andstructural deficits resulting from the interaction between stress and the human genetic BDNFMet polymorphism. Importantly, desipramine but not fluoxetine has antidepressant effects onBDNF+/Met mice, suggesting that specific classes of antidepressantmaybe a more effective treatment option for depressive symptoms in humans with this genetic variant BDNF. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB), play a critical role in activity-dependent plasticity processes such as long-term potentiation, learning, and memory. It has been shown that BDNF exerts different or even opposite effects on behavior depending on the neural circuit. However, the detailed role of BDNF in memory process on the basis of its location has not been fully understood. Here, we aim to investigate the regional specific involvement of BDNF/TrkB in hippocampal-independent conditioned taste aversion (CTA) memory processes. We found region-specific changes in BDNF expression during CTA learning. CTA conditioning induced increased BDNF levels in the central nuclei of amygdala (CeA) and insular cortex, but not in the basolateral amygdala (BLA) and ventromedial prefrontal cortex. Interestingly, we found that the enhanced TrkB phosphorylation occurred at the time point before the increased BDNF expression, suggesting rapid induction of activity-dependent BDNF secretion by CTA learning. Moreover, targeted infusion of BDNF antibodies or BDNF antisense oligonucleotides revealed that activity-dependent BDNF secretion and synthesis in the CeA, but not the BLA, was respectively involved in the short- and long-term memory formation of CTA. Finally, we found that infusion of exogenous BDNF into the CeA could enhance CTA learning. These data suggest that region-specific BDNF release and synthesis temporally regulate different CTA memory phases through activation of TrkB receptors. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the phytochemical structure of Cedrus deodara, an evergreen tree growing on the slopes of the Himalayas. The study isolates and elucidates the structure of phenylpropanoid and nine compounds, such as Shikimic Acid, Dibutylphthalate and Protocatechuic Acid, obtained from the pine needles of Cedrus deodara. Result shows that the compound 1-[3-(4-hydroxyphenyl)-2-propenoate]-α-D-glucopyranoside was identified.

We present long-term optical multi-band photometric monitoring of blazar 3C 273, from 2006 May 19 to 2015 March 31 with high temporal resolution in the BVRI bands. The source is in a steady state and showed very small variability, with the values of the fractional variability amplitude of , , and in B, V, R and I, respectively. The intra-night point-to-point fractional variability (Fpp) in each band is below 1.0%, and the Fpp variation amplitude increase from the B-band to the I-band. We find a variability with the timescale of 5.8 ± 2.9 minutes in the I-band on 2009 March 11. This fast variability requires the comoving magnetic field strength in the jet above 18 G with a Doppler factor . Using the discrete correlation function (DCF), the B- and I-band light curves are examined for correlation on whole campaign. Low significance (∼99.73 percent confidence) correlations with the I-band lags the B-band variations are observed. The spectral behaviors in the different variability episodes are studied. “Bluer-when-brighter” spectral behavior is presented for the whole campaign, while there is an opposite tendency when . The weak of the correlation between B- and I-band and the spectrum analysis indicate that the optical radiation consists of two variable components. [ABSTRACT FROM AUTHOR]