Risk stratification and predictive modeling of postoperative delirium in chronic subdural hematoma.

Background- Postoperative delirium is a common complication associated with the elderly, causing increased morbidity and prolonged hospital stay. However, its risk factors in chronic subdural hematoma patients have not been well studied. Methods- A total of 202 consecutive patients with chronic subdural hematoma at Peking University Third Hospital between January 2018 and January 2023 were enrolled. Various clinical indicators were analyzed to identify independent risk factors for postoperative delirium using univariate and multivariate regression analyses. Delirium risk prediction models were developed as a nomogram and a Markov chain. Results- Out of the 202 patients (age, 71 (IQR, 18); female-to-male ratio, 1:2.7) studied, 63 (31.2%) experienced postoperative delirium. Univariate analysis identified age (p < 0.001), gender (p = 0.014), restraint belt use (p < 0.001), electrolyte imbalance (p < 0.001), visual analog scale score (p < 0.001), hematoma thickness (p < 0.001), midline shift (p < 0.001), hematoma side (p = 0.013), hematoma location (p = 0.018), and urinal catheterization (p = 0.028) as significant factors. Multivariate regression analysis confirmed the significance of restraint belt use (B = 7.657, p < 0.001), electrolyte imbalance (B = -3.993, p = 0.001), visual analog scale score (B = 2.331, p = 0.016), and midline shift (B = 0.335, p = 0.007). Hematoma thickness and age had no significant impact. Conclusion- Increased midline shift and visual analog scale scores, alongside restraint belt use and electrolyte imbalance elevate delirium risk in chronic subdural hematoma surgery. Our prediction models may offer reference value in this context.

Acid sphingomyelinase promotes diabetic cardiomyopathy via NADPH oxidase 4 mediated apoptosis.

BACKGROUND: Increased acid sphingomyelinase (ASMase) activity is associated with insulin resistance and cardiac dysfunction. However, the effects of ASMase on diabetic cardiomyopathy (DCM) and the molecular mechanism(s) underlying remain to be elucidated. We here investigated whether ASMase caused DCM through NADPH oxidase 4-mediated apoptosis. METHODS AND RESULTS: We used pharmacological and genetic approaches coupled with study of murine and cell line samples to reveal the mechanisms initiated by ASMase in diabetic hearts. The protein expression and activity of ASMase were upregulated, meanwhile ceramide accumulation was increased in the myocardium of HFD mice. Inhibition of ASMase with imipramine (20 mg Kg-1 d-1) or siRNA reduced cardiomyocyte apoptosis, fibrosis, and mitigated cardiac hypertrophy and cardiac dysfunction in HFD mice. The similar effects were observed in cardiomyocytes treated with high glucose (HG, 30 mmol L-1) + palmitic acid (PA, 100 µmol L-1) or C16 ceramide (CER, 20 µmol L-1). Interestingly, the cardioprotective effect of ASMase inhibition was not accompanied by reduced ceramide accumulation, indicating a ceramide-independent manner. The mechanism may involve activated NADPH oxidase 4 (NOX4), increased ROS generation and triggered apoptosis. Suppression of NOX4 with apocynin prevented HG + PA and CER incubation induced Nppb and Myh7 pro-hypertrophic gene expression, ROS production and apoptosis in H9c2 cells. Furthermore, cardiomyocyte-specific ASMase knockout (ASMaseMyh6KO) restored HFD-induced cardiac dysfunction, remodeling, and apoptosis, whereas NOX4 protein expression was downregulated. CONCLUSIONS: These results demonstrated that HFD-mediated activation of cardiomyocyte ASMase could increase NOX4 expression, which may stimulate oxidative stress, apoptosis, and then cause metabolic cardiomyopathy.

Effect of miRNA-200b on the proliferation of liver cancer cells via targeting SMYD2/p53 signaling pathway. / MiR-200b通过靶向调控SMYD2/p53信号通路抑制肝癌细胞增殖（英文）.

OBJECTIVES: Our previous study has verified that high level of SET and MYND domain-containing protein 2 (SMYD2) plays an important role in acquiring aggressive ability for liver cancer cells in hepatocellular carcinoma. MiR-200b as a tumor suppressor gene involves in a variety of cancers. This study aims to investigate the correlation between miR-200b and SMYD2 in hepatocellular carcinoma and the underlying mechanism. METHODS: Firstly, the levels of SMYD2 and miR-200b in hepatocellular carcinoma tissues and matched adjacent non-tumor liver tissues were tested with real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Secondly, we evaluated the interaction between miR-200b and SMYD2 using dual-luciferase reporter assay. Thirdly, we elucidated the effect of miR-200b on SMYD2 and its downstream targets p53/CyclinE1. Finally, we silenced SMYD2 in hepatocellular carcinoma cell lines to investigate its effect on tumor proliferation and cell cycle progression, and further confirmed the correlation among SMYD2 and p53/CyclinE1. RESULTS: Compared with the matched adjacent non-tumor liver tissues, miR-200b was obviously decreased, and SMYD2 was significantly increased in hepatocellular carcinoma (both P<0.05). Spearman's rank correlation revealed that miR-200b expression was negatively correlated with SMYD2 (P<0.01). Computer algorithm and dual-luciferase reporter assay revealed that miR-200b directly targeted and suppressed SMYD2 in HEK 293T cells. The down-regulated miR-200b expression promoted hepatoma cell proliferation (P<0.05) and increased SMYD2 expression(P<0.01), while the up-regulated expression of miR-200b had an opposite effect. The knockdown of SMYD2 suppressed the proliferation of MHCC-97L cells (P<0.01), down-regulated CyclinE1, and up-regulated p53 expression (both P<0.05). CONCLUSIONS: MiR-200b is involved in hepatocellular carcinoma progression via targeting SMYD2 and regulating SMYD2/p53/CyclinE1 signaling pathway and may be used as a potential target for hepatocellular carcinoma treatment.

Inhibitory effects of oxymatrine on hepatic stellate cells activation through TGF-ß/miR-195/Smad signaling pathway.

BACKGROUND: Oxymatrine (OM), a quinolizidine alkaloid extracted from a herb Sophorae Flavescentis Radix, has been used to treat liver fibrotic diseases. However, the mechanism of its anti-fibrosis effects is still unclear. TGF-ß/Smad signaling and miR-195 have been proved to paly an important role in hepatic stellate cells (HSCs) activation and liver fibrosis. In this study, we investigated whether OM could inhibit HSCs activation through TGF-ß1/miR-195/Smads signaling or not. METHODS: First, the effects of OM on HSC-T6 in different concentrations and time points were tested by MTT assay. We choose three appropriate concentrations of OM as treatment concentrations in following experiment. By Quantitative Real-time PCR and Western Blot, then we investigated the effect of OM on miR-195, Smad7 and α-SMA's expressions to prove the correlation between OM and the TGF-ß1/miR-195/Smads signaling. Last, miR-195 mimic and INF-γ were used to investigate the relation between miR-195 and OM in HSC activation. RESULTS: Our results showed that the proliferation of HSC was significantly inhibited when OM concentration was higher than 200 µg/mL after 24 h, 100 µg/mL after 48 h and 10 µg/mL after 72 h. The IC50 of OM after 24, 48 and 72 h were 539, 454, 387 µg/mL respectively. OM could down-regulate miR-195 and α-SMA (P < 0.01), while up-regulate Smad7 (P < 0.05). In HSC-T6 cells transfected with miR-195 mimic and pretreated with OM, miR-195 and α-SMA were up-regulated (P < 0.05), and Smad7 was down-regulated (P < 0.05) . CONCLUSIONS: Given these results, OM could inhibit TGF-ß1 induced activation of HSC-T6 proliferation in a dose-dependent and time-dependent manner to some extent. We proved that OM inhibited HSC activation through down-regulating the expression of miR-195 and up-regulating Smad7.

Repaglinide-irbesartan drug interaction: effects of SLCO1B1 polymorphism on repaglinide pharmacokinetics and pharmacodynamics in Chinese population.

PURPOSE: On account of the potential inhibition of OATP1B1 (organic anion transporting polypeptide) by angiotensin II receptor blockers (ARBs) and the effects of SLCO1B1 (solute carrier organic anion transporter family member) polymorphism, the aim of current study is to assess the impact of ARBs on the pharmacokinetics (PK) and pharmacodynamics (PD) of repaglinide in Chinese healthy volunteers with different SLCO1B1 genotypes. METHODS: The in vitro study was conducted on irbesartan, valsartan, olmesartan, and losartan by using HEK293 cells transfected with OATP1B1. Data on drug interactions between repaglinide and irbesartan from 21 healthy Chinese-Han male volunteers were collected and analyzed. RESULTS: IC50 from in vitro study suggested irbesartan was the most potent inhibitor of OATP1B1 transporter. Clinical data from single dose of repaglinide indicated SLCO1B1 c.521 T>C polymorphism influenced the PK and PD of repaglinide in healthy Chinese-Han male volunteers. In subjects with SLCO1B1 c.521 TT genotype, irbesartan comedication increased the exposure of repaglinide. In details, the peak plasma concentration [Cmax] increased 84% (P = 0.003) and the area under the curve of plasma concentration 0-8 h [AUC0-8] increased 34% (P = 0.004), while the minimum blood glucose concentration [Cmin] decreased 33.8% (P = 0.005). No significant change was observed in repaglinide exposure in subjects with SLCO1B1 c.521 TC genotype in presence or absence of irbesartan. CONCLUSION: SLCO1B1 c.521 T>C polymorphism affects the PK of repaglinide in Chinese population. Irbesartan increased repaglinide exposure in subjects with SLCO1B1 c.521 TT genotype, but not SLCO1B1 c.521 TC genotype.

Resveratrol alleviates diabetic cardiomyopathy in rats by improving mitochondrial function through PGC-1α deacetylation.

Recent evidence shows that resveratrol (RSV) may ameliorate high-glucose-induced cardiac oxidative stress, mitochondrial dysfunction and myocardial fibrosis in diabetes. However, the mechanisms by which RSV regulates mitochondrial function in diabetic cardiomyopathy have not been fully elucidated. Mitochondrial dysfunction contributes to cardiac dysfunction in diabetic patients, which is associated with dysregulation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). In this study we examined whether resveratrol alleviated cardiac dysfunction in diabetes by improving mitochondrial function via SIRT1-mediated PGC-1α deacetylation. T2DM was induced in rats by a high-fat diet combined with STZ injection. Diabetic rats were orally administered RSV (50 mg·kg-1·d-1) for 16 weeks. RSV administration significantly attenuated diabetes-induced cardiac dysfunction and hypertrophy evidenced by increasing ejection fraction (EF%), fraction shortening (FS%), ratio of early diastolic peak velocity (E velocity) and late diastolic peak velocity (A velocity) of the LV inflow (E/A ratio) and reducing expression levels of pro-hypertrophic markers ANP, BNP and ß-MHC. Furthermore, manganese superoxide dismutase (SOD) activity, ATP content, mitochondrial DNA copy number, mitochondrial membrane potential and the expression of nuclear respiration factor (NRF) were all significantly increased in diabetic hearts by RSV administration, whereas the levels of malondialdehvde (MDA) and uncoupling protein 2 (UCP2) were significantly decreased. Moreover, RSV administration significantly activated SIRT1 expression and increased PGC-1α deacetylation. H9c2 cells cultured in a high glucose (HG, 30 mmol/L) condition were used for further analyzing the role of SIRT1/PGC-1α pathway in RSV regulation of mitochondrial function. RSV (20 µmol/L) caused similar beneficial effects in HG-treated H9c2 cells in vitro as in diabetic rats, but these protective effects were abolished by addition of a SIRT1 inhibitor sirtinol (25 µmol/L) or by SIRT1 siRNA transfection. In H9c2 cells, RSV-induced PGC-1α deacetylation was dependent on SIRT1, which was also abolished by a SIRT1 inhibitor and SIRT1 siRNA transfection. Our results demonstrate that resveratrol attenuates cardiac injury in diabetic rats through regulation of mitochondrial function, which is mediated partly through SIRT1 activation and increased PGC-1α deacetylation.

The Effect of Dexmedetomidine on Oxidative Stress Response Following Cerebral Ischemia-Reperfusion in Rats and the Expression of Intracellular Adhesion Molecule-1 (ICAM-1) and S100B.

BACKGROUND Ischemia-reperfusion injury of whole brain involves a complicated pathophysiology mechanism. Dexmedetomidine (Dex) has been shown to have neuro protective functions. This study observed the effect of Dex on serum S100B and cerebral intracellular adhesion molecule-1 (ICAM-1) in a rat model of cerebral ischemia-reperfusion. MATERIAL AND METHODS Healthy Sprague Dawley (SD) rats (males, 7 weeks old) were randomly divided into sham, model, and Dex groups (n=20 each). A cerebral ischemia-reperfusion model was prepared by clipping of the bilateral common carotid artery combined with hypotension. Dex (9 µg/kg) was infused intravenously immediately after reperfusion in the Dex group, while the other two groups received an equal volume of saline. Neural defect score (NDS) was measured at 6 hours, 24 hours, and 72 hours after surgery, with pathological observation of brain tissues. ELISA was then used to test serum S100B protein level. Malondialdehyde (MDA) and superoxide dismutase (SOD) were assayed by spectrometry. Nuclear factor-kappa B (NF-kB) and ICAM-1 levels were determined by real-time (RT)-PCR. RESULTS Model rats had significant injury in the hippocampal CA1 region as shown by elevated NDS, S100B, and MDA levels, higher NF-κB and ICAM-1 mRNA expression, and lower SOD levels (p<0.05). Dex treatment improved pathological injury, decreased NDS, S100B, and MDA levels, decreased expression of mRNA of NF-κB and ICAM-1, and increased SOD levels. CONCLUSIONS Dex alleviated ischemia-reperfusion damage to rat brains, and inhibited NF-κB and ICAM-1 expression in brain tissues, possibly via inhibiting oxidative stress and inflammatory response.

Effects of genetic variants in UGT1A1, SLCO1B3, ABCB1, ABCC2, ABCG2, ORM1 on PK/PD of telmisartan in Chinese patients with mild to moderate essential hypertension
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PURPOSE: This study aimed to understand the effects of single nucleotide polymorphisms (SNPs) in UGT1A1, SLCO1B3, ABCB1, ABCC2, ABCG2, and ORM1 on the pharmacokinetics (PK) (plasma concentration) and pharmacodynamics (PD) (blood pressure) of telmisartan in Chinese patients. METHODS: 58 Han Chinese patients (aged 45 - 72 years) with mild to moderate essential hypertension were included and received 80 mg/day telmisartan for 4 weeks. The plasma concentration and genetic variants were determined by LC/MS/MS and MALDI-TOF mass spectrometry, respectively. Multivariable linear analysis was used to examine the relationships between PK/PD and genetic variants. RESULTS: Females showed a significantly higher AUClast than males (n = 22, 4,879.48 ± 3,449.33 h×ng/mL vs. n = 36, 2,715.59 ± 2,223.77 h×ng/mL, p = 0.047). Amongst all genetic variants investigated, the patients with UGT1A1 rs4124874 AA (n = 11, 1,730.51 ± 1,325.79 h×ng/mL) had a significantly lower AUClast compared with patients with UGT1A1 rs4124874 CC+AC (n = 19 + 28, 4,177.44 ± 3,222.11 h×ng/mL and 3,810.82 ± 2,960.43 h×ng/mL, p = 0.027). None of the SNPs investigated was associated with the PD responses to telmisartan. CONCLUSION: Variation of UGT1A1 (rs4124874) affects PK of telmisartan in Chinese patients, highlighting the value of genetic testing in precision medicine as the telmisartan dose could be adjusted based on UGT1A1 genetic variations.
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[UPLC-MS/MS determination of tanshinone â ¡A, salvianolic acid B and ginsenoside Rg1 in Fufang Danshen preparation in rat plasma and brain tissues].

A sensitive and specific ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed for analysis of tanshinone ⅡA(TSⅡA), salvianolic acid B(SAB) and ginsenoside Rg1 (GRg1) in rat plasma and brain tissues. Male healthy Sprague-Dawley(SD) rats were orally given single dose of Fufang Danshen preparation (TS ⅡA 60 mg•kg⁻¹, SAB 300 mg•kg⁻¹, GRg1 150 mg•kg⁻¹, borneol 300 mg•kg⁻¹), and their blood samples and brain tissues were collected at different time points. The drug plasma and brain tissue concentrations of the three analytes were determined by UPLC-MS/MS method. Subsequently, the main pharmacokinetics parameters of plasma and brain tissues were calculated by using Phoenix WinNolin 6.1 software. The methodological test showed that all of analytes in both plasma and brain homogenate exhibited a good linearity within the concentration range(r>0.992 2). Their mean recoveries were between 58.86% and 112.1%. Intra-day and inter-day precisions of the investigated components exhibited RSD≤9.7%, and the accuracy(RE) ranged from -9.68% to 8.20% at all quality control levels. The results of accuracy and stability meet the requirements for biopharmaceutical analysis. For TSⅡA, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the plasma were (1.58±0.081) h, (725.4±88.20) µg•L⁻¹, (2 101.3±124.85) µg•h•L⁻¹ and (3.66±0.05) h, respectively. For SAB, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the plasma were (1.29±0.21) h, (307.9±46.75) µg•L⁻¹, (537.4±88.24) µg•h•L⁻¹ and (2.08±0.11) h, respectively. For GRg1, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the plasma were (1.42±0.20) h, (460.38±154.60) µg•L⁻¹, (383.4±88.16) µg•h•L⁻¹ and (1.87±0.046) h, respectively. For TSⅡA, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the brain tissue were (0.75±0.22) h, (1.41±0.42) ng•g⁻¹, (4.34±2.48) ng•h•g⁻¹ and (4.00±1.90) h, respectively. For SAB, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the plasma were (1.08±0.20) h, (21.09±4.850) ng•g⁻¹, (14.83±3.160) ng•h•g⁻¹ and (0.99±0.08) h, respectively. For GRg1, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the plasma were (0.50±0.16) h, (130.96±54.220) ng•g⁻¹, (136.24±34.350) ng•h•g⁻¹ and (2.87±0.33) h, respectively. The developed method was successfully applied in pharmacokinetic studies on content of TS ⅡA, SAB and GRg1 in rat plasma and brain tissues.

[Effect of lamivudine and silymarin on liver fibrosis-relevant factors in HBV transgenic mice with alcohol drinking].

OBJECTIVE: To observe the role of lamividine and silymarin preventing and curing liver fibrosis-relevant factors induced by alcohol drinking in hepatitis B virus (HBV) transgenic mice (Tg mice).
 Methods: Forty HBV-Tg BALB/C mice with 1.3 copy were randomly divided into 4 groups: a control group, a model group, a lamivudine group and a silymarin group. Tg mice in control group were treated with normal saline via intragastric administration; Tg-mice in the model group were treated with 50% alcohol (5 mL/kg) once a day via intragastric administration; while Tg-mice in lamivudine group and silymarin group were treated with alcohol (5 mL/kg) plus laminvudine (100 mg/kg) and silymarin (200 mg/kg) once a day via intragastric administration respectively. All groups were raised for 10 weeks. The levels of HBV-DNA copy number, ALT, AST in serum, the degree of inflammation, the degree of fibrosis, the mRNA expression levels of TGF-ß1, Smad3, Smad7 and connective tissue growth factor (CTGF), and the protein expression levels of TGF-ß1, CTGF and α-SMA in liver tissue were detected. All the images were scanned with electronic computer and the data were analyzed with SPSS13.0 software.
 Results: Compared with the control group, liver injury were significantly aggravated, while HBV-DNA copies, mRNA levels of TGF-ß1, Smad3, Smad7 and CTGF as well as the protein levels of TGF-ß1, CTGF and α-SMA were significantly increased (P<0.05). Compared with the model group, liver injury were significantly attenuated in silymarine group and lamivudine group, while mRNA levels of TGF-ß1, Smad3 and CTGF as well as the protein levels of TGF-ß1, CTGF and α-SMA were significantly decreased; mRNA level of Smad7 was further increased (P<0.05); the levels of ALT and AST in serum were decreased in the silymarine group (P<0.05).
 Conclusion: Lamivudine and silymarin relieve the histological damage in the liver of alcohol-fed Tg mice. The mechanisms for the beneficial effects of lamivudine or silymarin might be related to inhibiting the expression of TGF-ß1, Smad3 and CTGF, modulating the expression of Smads and suppressing the activation of HSC.

Rational selection of amorphous or crystalline V2O5 cathode for sodium-ion batteries.

Vanadium oxide (V2O5), as a potential positive electrode for sodium ion batteries (SIBs), has attracted considerable attention from researchers. Herein, amorphous and crystalline V2O5 cathodes on a graphite paper without a binder and conductive additives have been synthesized via facile anodic electrochemical deposition following different heat treatments. Both the amorphous V2O5 (a-V2O5) cathode and crystalline V2O5 (c-V2O5) cathode show good rate cycling performance and long cycling life. After five rate cycles, the reversible capacities of both the cathodes were almost unchanged at different current densities from 40 to 5120 mA g-1. Long cycling tests with 10 000 cycles were carried out and the two cathodes exhibit excellent cycling stability. The c-V2O5 cathode retains a high specific capacity of 54 mA h g-1 after 10 000 cycles at 2560 mA g-1 and can be charged within 80 s. Interestingly, the a-V2O5 cathode possesses higher reversible capacities than the c-V2O5 cathode at low current densities, whereas it is inversed at high current densities. The c-V2O5 cathode shows faster capacity recovery from 5120 to 40 mA g-1 than the a-V2O5 cathode. When discharged at 80 mA g-1 (long discharge time of 140 min) and charged at 640 mA g-1 (short charge time of 17 min), the a-V2O5 cathode shows a higher discharge capacity than its c-V2O5 counterpart. The different electrochemical performance of a-V2O5 and c-V2O5 cathodes during various electrochemical processes can provide a rational selection of amorphous or crystalline V2O5 cathode materials for SIBs in their practical applications to meet the variable requirements.

Influences of CYP2D6*10 polymorphisms on the pharmacokinetics of iloperidone and its metabolites in Chinese patients with schizophrenia: a population pharmacokinetic analysis.

AIM: Iloperidone is an atypical antipsychotic drug that is mainly metabolized by CYP2D6, CYP3A4, and cytosolic enzymes. Previous studies show that extensive and poor metabolizers of CYP2D6 exhibit different plasma concentrations of iloperidone and its metabolites. The aim of this study was to develop a parent-metabolite population pharmacokinetic (PPK) model to quantify the effects of CYP2D6*10 allele on the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients. METHODS: Seventy Chinese schizophrenia patients were enrolled, from whom limited blood samples were collected on d 15 (0 h) and d 28 (0, 4 and 12 h after drug administration). The plasma concentrations of iloperidone and its metabolites M1 (P-88) and M2 (P-95) were simultaneously detected using a validated HPLC-MS assay. CYP2D6*10 (rs1065852) genotyping was performed. A PPK model was developed based on data from the patients using the NONMEM software (version 7.2). A one-compartment model with first-order absorption and elimination was used to describe the pharmacokinetic data related to iloperidone and its metabolites. RESULTS: Patients with the CYP2D6*10 T/T genotype had significantly higher concentrations of iloperidone and M1, and lower concentrations of M2 than the patients with C/C or C/T genotypes. The CYP2D6*10 genotype affected the elimination constants for transformation of iloperidone to the metabolites M1 (K23) and M2 (K24). The K23 value of the patients with T/T genotype was 1.34-fold as great as that of the patients with C/C or C/T genotype. The K24 value of the patients with C/T and T/T genotypes was 0.693- and 0.492-fold, respectively, as low as that of the patients with C/C genotype. CONCLUSION: CYP2D6*10 mutations affect the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients, suggesting that the clinical doses of iloperidone for patients with CYP2D6*10 mutations need to be optimized.

Tacrolimus decreases insulin sensitivity without reducing fasting insulin concentration: a 2-year follow-up study in kidney transplant recipients.

New Onset Diabetes after Transplantation (NODAT) is defined as sustained hyperglycemia developing in patients without diabetes history before transplantation. A cohort study was performed to access the effects of tacrolimus on insulin secretion and insulin sensitivity and consequently in the development of NODAT in kidney transplant recipients. Then, we further investigated the association between NODAT and single-nucleotide polymorphisms of IRS-1 and IRS-2 in renal allograft recipients. One hundred and fifty-eight kidney transplant patients, receiving tacrolimus as the base immunosuppressant, were divided into two groups: with or without NODAT. Plasma levels of fasting insulin concentration (FINS) and C-peptide were determined by enhanced chemiluminescence immunoassay and ADVIA Centaur C peptide assay, respectively. The genotypes of Gly1057Asp in IRS-2 and Gly972Arg in IRS-1 were detected through polymerase chain reaction fragment length polymorphism in NODAT and non-NODAT patients. It was found that the concentrations of fasting plasma insulin and C-peptide in NODAT and non-NODAT patients treated with tacrolimus were higher than that in healthy volunteers (p < 0.05). Fasting plasma insulin concentration in NODAT was significantly elevated compared with than that in non-NODAT group (p < 0.05). But there are no statistical differences in fasting plasma C-peptide concentrations between NODAT and non-NODAT groups. The allele and genotype frequencies of IRS-2 Gly1057Asp and IRS-1 Gly972Arg in NODAT patients were not significantly different from non-NODAT patients (p > 0.05). In conclusion, insulin resistance is the primary cause of tacrolimus-induced NODAT. The IRS-2 Gly1057Asp and IRS-1 Gly972Arg genotypes are not related to NODAT.

Transforming growth factor-ß1 regulates the telomerase reverse transcriptase in rat hepatic stellate cells.

OBJECTIVE: To determine the effect of transforming growth factor-ß1 (TGF-ß1) on the expression of telomerase in hepatic stellate cells (HSCs) in rats and the role of TGF-ß1 in the development of liver fibrosis. METHODS: Primary HSCs were isolated from normal rats by density gradient separation and divided into 2 groups for culturing. The morphology of HSCs was identified by the inverted fluorescence microscope. The purity of HSCs was identified by immunohistological expression and fluorescence analysis. One group of HSCs was treated with different concentrations (0, 0.1, 1, and 10 ng/mL) of TGF-ß1 for 24 h, while the other group was treated with 1 ng/mL TGF-ß1 and cultured for 3, 6, and 9 days. The mRNA expression of telomerase reverse transcriptase (TERT) was assessed and compared by polymerase chain reaction. RESULTS: Cell morphology showed that TGF-ß1 triggered the differentiation of HSCs from a quiescent phenotype into highly activated myofibroblasts. TERT mRNA expression in the primary HSCs showed slight increase with the culture time, though with no statistical difference between the results at various time points (P>0.05). TGF-ß1 at 0.1 ng/mL did not significantly affect the TERT mRNA level compared with the 0 ng/mL group, while 1 ng/mL and 10 ng/mL TGF-ß1 significantly decreased the level of TERT mRNA (P<0.05). TGF-ß1 at 1 ng/mL had only weak effect on TERT mRNA expression after the 3 day treatment compared with the 0 ng/mL group (P>0.05). TGF-ß1 at 1 ng/mL significantly inhibited TERT mRNA expression 6 days after the treatment (P<0.05). TGF-ß1 inhibited the expression of TERT mRNA level in the HSCs in both dose- and time-dependent manner. CONCLUSION: TGF-ß1 may contribute to the transdifferentiation of HSCs by reducing TERT levels to develop hepatic fibrosis.

Analysis of pre-crash scenarios and contributing factors for autonomous vehicle crashes at intersections.

Intersections are high-risk locations for autonomous vehicles (AVs). Crash causation analysis based on pre-crash scenarios can provide new insight into these crashes that can lead to effective countermeasures, but there are significant differences in pre-crash scenarios between autonomous and conventional vehicles, and inadequate AV data has put limits on research. The association rule method, however, can yield useful results despite these limits. This study therefore aims to use the method with pre-crash scenarios to understand the characteristics and contributing factors of AV crashes at intersections from the latest 5-year AV crash data. Analysis of 197 AV crashes at intersections revealed 30 types of pre-crash scenarios. The rear-end crash (58.88%) and lane change crash (16.24%) were the most frequently occurring scenarios for AVs. The proportion of AVs being rear-ended by conventional vehicles was 58.38%. The main contributing factors of these two most common AV scenarios were identified by association rules and crash causes were analyzed from the perspective of AV decision-making. The main factors contributing to the AV rear-end scenario were location outside the intersection in the intersection-related area, traffic signal control, autonomous engaged mode, mixed-use or public land, and weekdays, while those for lane change scenarios were on-street parking and the time of 8:00 a.m. Important causes of rear-end crashes attributable to the AV were inadequate stop and deceleration decisions by the AV's automated driving system (ADS) and insufficient collision avoidance decisions in lane change crashes. Identification of the pre-crash characteristics and contributing factors provide new insight into AV crash causation and can be used in the determination of the AV's operational design domain and the development and optimization of the AV's ADS at intersections. These findings can also play a role in guiding traffic safety agencies to discover AV hotspots and propose AV management regulations.

From glioma gloom to immune bloom: unveiling novel immunotherapeutic paradigms-a review.

In tumor therapeutics, the transition from conventional cytotoxic drugs to targeted molecular therapies, such as those targeting receptor tyrosine kinases, has been pivotal. Despite this progress, the clinical outcomes have remained modest, with glioblastoma patients' median survival stagnating at less than 15 months. This underscores the urgent need for more specialized treatment strategies. Our review delves into the progression toward immunomodulation in glioma treatment. We dissect critical discoveries in immunotherapy, such as spotlighting the instrumental role of tumor-associated macrophages, which account for approximately half of the immune cells in the glioma microenvironment, and myeloid-derived suppressor cells. The complex interplay between tumor cells and the immune microenvironment has been explored, revealing novel therapeutic targets. The uniqueness of our review is its exhaustive approach, synthesizing current research to elucidate the intricate roles of various molecules and receptors within the glioma microenvironment. This comprehensive synthesis not only maps the current landscape but also provides a blueprint for refining immunotherapy for glioma, signifying a paradigm shift toward leveraging immune mechanisms for improved patient prognosis.

Enhancing root physiology for increased yield in water-saving and drought-resistance rice with optimal irrigation and nitrogen.

Objectives: Water-saving and drought-resistance rice (WDR) plays a vital role in the sustainable development of agriculture. Nevertheless, the impacts and processes of water and nitrogen on grain yield in WDR remain unclear. Methods: In this study, Hanyou 73 (WDR) and Hyou 518 (rice) were used as materials. Three kinds of nitrogen fertilizer application rate (NFAR) were set in the pot experiment, including no NFAR (nitrogen as urea applied at 0 g/pot), medium NFAR (nitrogen as urea applied at 15.6 g/pot), and high NFAR (nitrogen as urea applied at 31.2 g/pot). Two irrigation regimes, continuous flooding cultivation and water stress, were set under each NFAR. The relationships between root and shoot morphophysiology and grain yield in WDR were explored. Results: The results demonstrated the following: 1) under the same irrigation regime, the grain yield of two varieties increased with the increase of NFAR. Under the same NFAR, the reduction of irrigation amount significantly reduced the grain yield in Hyou 518 (7.1%-15.1%) but had no substantial influence on the grain yield in Hanyou 73. 2) Under the same irrigation regime, increasing the NFAR could improve the root morphophysiology (root dry weight, root oxidation activity, root bleeding rate, root total absorbing surface area, root active absorbing surface area, and zeatin + zeatin riboside contents in roots) and aboveground physiological indexes (leaf photosynthetic rate, non-structural carbohydrate accumulation in stems, and nitrate reductase activity in leaves) in two varieties. Under the same NFAR, increasing the irrigation amount could significantly increase the above indexes in Hyou 518 (except root dry weight) but has little effect on Hanyou 73. 3) Analysis of correlations revealed that the grain yield of Hyou 518 and Hanyou 73 was basically positively correlated with aboveground physiology and root morphophysiology, respectively. Conclusion: The grain yield could be maintained by water stress under medium NFAR in WDR. The improvement of root morphophysiology is a major factor for high yield under the irrigation regime and NFAR treatments in WDR.

Intraoperative fluorescence redefining neurosurgical precision.

Surgical resection is essential for treating solid tumors, with success largely dependent on the complete excision of neoplastic cells. However, neurosurgical procedures must delicately balance tumor removal with the preservation of surrounding tissue. Achieving clear margins is particularly challenging in cases like glioblastoma due to the limitations of traditional white light visualization. These limitations often result in incomplete resections, leading to frequent recurrences, or excessive resection that harms vital neural structures, causing iatrogenic nerve damage which can lead to sensory and functional deficits. Current statistics reveal a 90% recurrence rate for malignant gliomas. Similarly, an 8% incidence of iatrogenic nerve trauma contributes to an estimated 25 million cases of peripheral nerve injury globally each year. These figures underscore the urgent need for improved intraoperative techniques for lesion margin and nerve identification and visualization. Recent advances in neurosurgical imaging, such as fluorescence-guided surgery (FGS), have begun to address these challenges. Fluorescent agents used in FGS illuminate target tissues, although not all do so selectively. Despite the promising results of agents such as 5-aminolevulinic acid and indocyanine green, their applications are mainly limited by issues of sensitivity and specificity. Furthermore, these agents do not effectively address the need for precise nerve visualization. Nerve Peptide 41, a novel systemically administered fluorescent nerve-targeted probe, shows promise in filling this gap. This review assesses the major fluorescent imaging modalities in neurosurgery, highlighting each of their benefits, limitations, and potential.

Synthesis and analytical application of a novel fluorescent Hg2+ probe 3', 6'-bis(diethylamino)-2-((2,4-dimethoxybenzylidene)amino)spiro[isoindoline-1,9'-xanthene]-3-thione.

A novel probe, 3',6' - bis(diethylamino) -2- ((2,4-dimethoxybenzylidene)amino) spiro [isoindoline-1,9'-xanthene]-3-thione (RBS), was designed and synthesized. Its structure was characterized with elemental analysis, IR spectra and (1)H NMR. The probe displayed highly selective and sensitive recognition of Hg(2+). Reacting with mercury ions in aqueous solution, its fluorescence intensity was enhanced significantly, while its color was changed from colorless to pink. So, a new fluorescence method of detection of Hg(2+) was proposed. Its dynamic response concentration range and detection limit for Hg(2+) were 5.00 × 10(-9) M to 1.00 × 10(-6) M detected and 1.83 × 10(-9) M, respectively. Satisfying results were obtained when the probe was applied to detect spiked Hg(2+) in samples.

[Effect of notoginseng radix on expression quantity of TGF-beta1/ Smads and CTGF mRNA in rats with alcoholic liver disease].

OBJECTIVE: To evaluate the effect of Notoginseng Radix on hepatic expression of transforming growth factor beta1 (TGF-beta1) and connective tissue growth factor (CTGF) in rats with alcoholic liver disease (ALD), in order to discuss its protective effect on alcoholic cirrhosis. METHOD: Fifty SD male rats were divided into the normal control group, the model group, the high-dose and low-dose Notoginseng Radix groups (3.0, 12.0 g x kg(-1)) and the magnesium isoglycyrrhizinate group (24 mg x kg(-1)), with 10 rats in each group. Apart from the control group, other groups were administered with ethanol-cornoil-pyrazole for 14 weeks to establish the alcoholic liver disease model. During the establishment of the model, the high-dose and low-dose Notoginseng Radix groups were administered with 12 g x kg(-1) x d(-1) Notoginseng Radix for 14 weeks, once everyday. Efforts were made to detect liver function, pathology with Masson staining, and the expressions of TGF-beta1, Smad3, Smad7 and CTGF mRNA. RESULT: Compared with the rats in model group, rats in Notoginseng Radix groups showed significant reduction in liver ALT, AST, collagen fiber deposition, and TGF-beta1, Smad3 and CTGF mRNA expressions in liver tissues, with the increase in the expression quantity of Smad7 mRNA. There were differences between the Notoginseng Radix groups. No significant difference was observed between the high-dose Notoginseng Radix group and the magnesium isoglycyrrhizinate group. CONCLUSION: Notoginseng Radix can affect TGF-beta1/Smads signaling pathway and reduce the expression of CTGF.