In-cell Catalysis by Tethered Organo-Osmium Complexes Generates Selectivity for Breast Cancer Cells.

Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi-targeting strategy to overcome drug resistance. Nonetheless, many in-cell catalysts in development are hindered by deactivation by endogenous nucleophiles. We have synthesised a highly potent, stable Os-based 16-electron half-sandwich ('piano stool') catalyst by introducing a permanent covalent tether between the arene and chelated diamine ligand. This catalyst exhibits antiproliferative activity comparable to the clinical drug cisplatin towards triple-negative breast cancer cells and can overcome tamoxifen resistance. Speciation experiments revealed Os to be almost exclusively albumin-bound in the extracellular medium, while cellular accumulation studies identified an energy-dependent, protein-mediated Os accumulation pathway, consistent with albumin-mediated uptake. Importantly, the tethered Os complex was active for in-cell transfer hydrogenation catalysis, initiated by co-administration of a non-toxic dose of sodium formate as a source of hydride, indicating that the Os catalyst is delivered to the cytosol of cancer cells intact. The mechanism of action involves the generation of reactive oxygen species (ROS), thus exploiting the inherent redox vulnerability of cancer cells, accompanied by selectivity for cancerous cells over non-tumorigenic cells.

Bacterial community structure analysis of sludge from Taozi lake and isolation of an efficient 17ß-Estradiol (E2) degrading strain Sphingobacterium sp. GEMB-CSS-01.

Environmental challenges arising from organic pollutants pose a significant problem for modern societies. Efficient microbial resources for the degradation of these pollutants are highly valuable. In this study, the bacterial community structure of sludge samples from Taozi Lake (polluted by urban sewage) was studied using 16S rRNA sequencing. The bacterial phyla Proteobacteria, Bacteroidetes, and Chloroflexi, which are potentially important in organic matter degradation by previous studies, were identified as the predominant phyla in our samples, with relative abundances of 48.5%, 8.3%, and 6.6%, respectively. Additionally, the FAPROTAX and co-occurrence network analysis suggested that the core microbial populations in the samples may be closely associated with organic matter metabolism. Subsequently, sludge samples from Taozi Lake were subjected to enrichment cultivation to isolate organic pollutant-degrading microorganisms. The strain Sphingobacterium sp. GEMB-CSS-01, tolerant to sulfanilamide, was successfully isolated. Subsequent investigations demonstrated that Sphingobacterium sp. GEMB-CSS-01 efficiently degraded the endocrine-disrupting compound 17ß-Estradiol (E2). It achieved degradation efficiencies of 80.0% and 53.5% for E2 concentrations of 10 mg/L and 20 mg/L, respectively, within 10 days. Notably, despite a reduction in degradation efficiency, Sphingobacterium sp. GEMB-CSS-01 retained its ability to degrade E2 even in the presence of sulfanilamide concentrations ranging from 50 to 200 mg/L. The findings of this research identify potential microbial resources for environmental bioremediation, and concurrently provide valuable information about the microbial community structure and patterns within Taozi Lake.

Two undescribed benzopyran derivatives from Ranunculus sceleratus L. with their in vitro anti-inflammatory activity in lipopolysaccharide-activated RAW 264.7 cells.

Previous studies on Ranunculus sceleratus L. have shown the existence of coumarins and their anti-inflammatory effect. Phytochemical work was conducted to investigate the bioactive compounds, leading to the isolation of two undescribed benzopyran derivatives, namely ranunsceleroside A (1) and B (3), together with two known coumarins (2, 4) from the whole plant of R. sceleratus L. All compounds were structurally identified by extensive spectroscopic analysis and then investigated for their inhibitory effect on nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) production induced by lipopolysaccharide (LPS) in RAW 264.7 murine macrophages, repectively. As a result, compound 1-4 presented inhibitory effects on the production of NO, TNF-α, IL-1ß, and IL-6 in a concentration-dependent manner, which provides a potential chemical basis for the traditional use of R. sceleratus L. as an anti-inflammatory plant.

Clinical analysis of acute postoperative pain after total laparoscopic hysterectomy for adenomyosis and uterine fibroids - a prospective observational study.

OBJECTIVE: To investigate the outcome of total laparoscopic hysterectomy (TLH) and postoperative pain characteristics and compare the pain severity after TLH for adenomyosis or uterine fibroids. METHODS: This prospective observational study collected 101 patients received TLH for adenomyosis (AD group) including 41 patients were injected goserelin (3.6 mg) 28 days before TLH, while other adenomyosis patients received TLH without preoperative treatment, and 113 patients received TLH for uterine fibroids (UF group). Pain scores were evaluated at different time sites from operation day to postoperative 72 h using the numeric rating scale. Clinical data were collected from clinical record. RESULTS: Operative time and anaesthetic time were longer in the AD group than those in the UF group (66.88 ± 8.65 vs. 64.46 ± 7.21, p = 0.04; 83.95 ± 10.05 vs. 79.77 ± 6.88, p < 0.01), severe endometriosis was quite more common in AD group (23.76% vs. 2.65%, p < 0.01). Postoperative usage of Flurbiprofen in AD group were more than that of UF group (15.48 ± 38.00 vs. 4.79 ± 18.16, p = 0.02). Total pains and abdominal visceral pains of AD group were more severe compared with UF group in motion and rest pattern at several time sites, while incision pain and shoulder pain were similar. The total postoperative pains after goserelin preoperative treatment in AD group were less than that without goserelin preoperative treatment (p < 0.05). The levels of serum NPY, PGE2 and NGF after laparoscopic hysterectomy of adenomyosis reduced with GnRH agonist pretreatment. CONCLUSIONS: Acute postoperative pain for adenomyosis and uterine fibroids showed considerably different severity, postoperative total pain and abdominal visceral pains of TLH for adenomyosis were more severe compared with uterine fibroids. While patients received goserelin before laparoscopic hysterectomy of adenomyosis suffered from less severity of postoperative total pain than that without goserelin preoperative treatment.

Acute postoperative pain for adenomyosis and uterine fibroids showed considerably different severity, postoperative total pain and abdominal visceral pains of TLH for adenomyosis were more severe compared with uterine fibroids.Patients received goserelin before laparoscopic hysterectomy of adenomyosis suffered from less severity of postoperative total pain than that without goserelin preoperative treatment.

First-line treatments for advanced hepatocellular carcinoma: a network meta-analysis and cost-effectiveness analysis in China and the United States.

Background: Various therapeutic strategies are available for the first-line treatment of patients with advanced hepatocellular carcinoma (aHCC). But which approach is the most cost-effective remains uncertain. Objectives: This study aims to evaluate the cost-effectiveness of first-line strategies in aHCC patients from the perspective of Chinese and US payers. Design: A network meta-analysis (NMA) and cost-effectiveness study. Data sources and methods: A NMA was conducted to collect all first-line strategies with aHCC from 1 October 1 2018 until 1 January 2022. The relevant randomized controlled trial literature in PubMed, Embase, and Cochrane Library for the last 3 years were searched. The abstracts of meetings of the American Society of Clinical Oncology, European Society of Medical Oncology, and American Association for Cancer Research were also reviewed. A Markov model that included three states was developed. One-way sensitivity and probabilistic sensitivity analysis were performed to investigate the uncertainty of the economic evaluation. Scenario analysis was conducted to explore the economic benefits of treatment strategies in low-income populations. Results: Base-case analysis in China included 1712 patients showed that atezolizumab combined with bevacizumab, sintilimab combined with bevacizumab, lenvatinib (LEVA), and sorafenib (SORA) added 0.46, 1.25, 0.77, and -1.08 quality-adjusted life-years (QALYs), respectively, compared with donafenib, resulting in an incremental cost-effective ratio of $85607.88, $12109.27, and $1651.47 per QALY at a willingness-to-pay (WTP) of $11101.70/QALY. In the United States, only the incremental cost-effectiveness ratios (ICERs) of SORA was higher that were lower than the WTP threshold ($69375/QALY), and LEVA was the most cost-effective strategy with the ICERs were 25022.13/QALY. Conclusion: The NMA and cost-effectiveness analysis revealed that LEVA is the favorite choice in the first-line treatment of Chinese aHCC patients and US payers' perspective when the WTP was $11101.70/QALY in China and $69375.0/QALY in the United States. Registration: This study has been registered on the PROSPERO database with the registration number CRD42021286575.

Analysis of a machine learning-based risk stratification scheme for acute kidney injury in vancomycin.

Vancomycin-associated acute kidney injury (AKI) continues to pose a major challenge to both patients and healthcare providers. The purpose of this study is to construct a machine learning framework for stratified predicting and interpreting vancomycin-associated AKI. Our study is a retrospective analysis of medical records of 724 patients who have received vancomycin therapy from 1 January 2015 through 30 September 2020. The basic clinical information, vancomycin dosage and days, comorbidities and medication, laboratory indicators of the patients were recorded. Machine learning algorithm of XGBoost was used to construct a series risk prediction model for vancomycin-associated AKI in different underlying diseases. The vast majority of sub-model performed best on the corresponding sub-dataset. Additionally, the aim of this study was to explain each model and to explore the influence of clinical variables on prediction. As the results of the analysis showed that in addition to the common indicators (serum creatinine and creatinine clearance rate), some other underappreciated indicators such as serum cystatin and cumulative days of vancomycin administration, weight and age, neutrophils and hemoglobin were the risk factors for cancer, diabetes mellitus, heptic insufficiency respectively. Stratified analysis of the comorbidities in patients with vancomycin-associated AKI further confirmed the necessity for different patient populations to be studied.

Overexpression of miR-383-3p protects cardiomyocytes against hypoxia/reoxygenation injury via regulating PTEN/PI3K/AKT signal pathway.

MicroRNAs are widely reported as biomarkers and therapeutic targets in cardiovascular diseases. This study is aimed to expound on the regulatory responsibility of miR-383-3p in H/R-induced injury of H9c2 cells. In this study, H9c2 cells were administrated with H/R. MiR-383-3p expression was measured using qRT-PCR. ELISA was used to determine lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA) levels. Reactive oxygen species (ROS) were detected with 2,7-Dichlorodihydrofluorescein diacetate probe. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide, flow cytometry, and TUNEL experiments were conducted to measure cell viability and apoptosis. Cleaved caspase-3, caspase-3, Bax, Bcl-2, PTEN, PI3K, p-PI3K, Akt, p-AKT expression levels were examined by Western blot. Cleaved caspase-3 expression was also measured by immunofluorescence staining. Dual-luciferase reporter gene assay was applied to validate the binding sites in miR-383-3p and the 3'UTR of PTEN. We reported that, miR-383-3p expression in H9c2 cells treated with H/R was remarkably decreased. MiR-383-3p overexpression ameliorated oxidative stress and apoptosis and promoted cell viability in H9c2 cells treated with H/R, while miR-383-3p inhibitor showed the reverse effects. PTEN was identified as a target gene of miR-383-3p. Additionally, enhancement of PTEN expression abolished the influences of miR-383-3p on H9c2 cells. MiR-383-3p mimics could significantly decrease PTEN expression in H9c2 cells while increasing p-PI3K expression and p-AKT expression, while the miR-383-3p inhibitors showed the opposed effects. In conclusion, miR-383-3p protected H9c2 cells from H/R-induced injury via regulating PTEN/PI3K/AKT signal pathway.

[Spatial characteristics and source apportionment of urban environmental black carbon concentrations based on mobile monitoring]. / 基于移动监测的城市环境大气黑碳浓度空间特征及来源解析.

Black carbon (BC) is an important component of airborne fine particulate matter, with significant impacts on global climate change and human health. Taking Minhang District of Shanghai as the study area, a microaethalometer (MA200) and GPS were installed on the electric taxi to form a mobile observation platform to identify the spatial distribution and hot spots of atmospheric BC in urban environment. We analyzed the sources and influencing factors of BC. The results showed that the overall characteristics of the spatial distribution pattern of near surface atmospheric BC in Minhang District of Shanghai were high in the north and low in the south. The average BC concentration was (4.11±4.87) µg·m-3. The average concentrations of BC in working days and non-working days were (4.22±1.49) and (3.52±2.26) µg·m-3. The variability of BC concentration in the high value area was large, indicating that the increases of BC concentration in mobile observation were related to traffic accidents in the road section. In addition to human activities, large-scale dense vegetation might inhibit BC diffusion. The Absorption ngström Exponent (AAE) was (0.82±0.54), which was closer to that of fossil fuel combustion. The contributions of fossil fuel emissions, biomass combustion, and mixed sources to BC sources were 67.5%, 4.9% and 27.6%, respectively.

Cost-Effectiveness Analysis of Direct Oral Anticoagulants Versus Vitamin K Antagonists for Venous Thromboembolism in China.

Background: The drug therapy of venous thromboembolism (VTE) presents a significant economic burden to the health-care system in low- and middle-income countries. To understand which anticoagulation therapy is most cost-effective for clinical decision-making , the cost-effectiveness of apixaban (API) versus rivaroxaban (RIV), dabigatran (DAB), and low molecular weight heparin (LMWH), followed by vitamin K antagonist (VKA), in the treatment of VTE in China was assessed. Methods: To access the quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs), a long-term cost-effectiveness analysis was constructed using a Markov model with 5 health states. The Markov model was developed using patient data collected from the Xijing Hospital from January 1, 2016 to January 1, 2021. The time horizon was set at 30 years, and a 6-month cycle length was used in the model. Costs and ICERs were reported in 2020 U.S. dollars. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were used to test the uncertainties. A Chinese health-care system perspective was used. Results: In the base case, the data of 231 VTE patients were calculated in the base case analysis retrospectively. The RIV group resulted in a mean VTE attributable to 95% effective treatment. API, DAB, and VKA have a negative ICER (-187017.543, -284,674.922, and -9,283.339, respectively) and were absolutely dominated. The Markov model results confirmed this observation. The ICER of the API and RIV was negative (-216176.977), which belongs to the absolute inferiority scheme, and the ICER value of the DAB and VKA versus RIV was positive (110,577.872 and 836,846.343). Since the ICER of DAB and VKA exceeds the threshold, RIV therapy was likely to be the best choice for the treatment of VTE within the acceptable threshold range. The results of the sensitivity analysis revealed that the model output varied mostly with the cost in the DAB on-treatment therapy. In a probabilistic sensitivity analysis of 1,000 patients for 30 years, RIV has 100% probability of being cost-effective compared with other regimens when the WTP is $10973 per QALY. When WTP exceeded $148,000, DAB was more cost-effective than RIV. Conclusions: Compared with LMWH + VKA and API, the results proved that RIV may be the most cost-effective treatment for VTE patients in China. Our findings could be helpful for physicians in clinical decision-making to select the appropriate treatment option for VTE.

Comparison of Monopolar Electrosurgical Conization and the Loop Electrosurgical Excision Procedure in the Management of High-Grade Squamous Intraepithelial Lesion.

Objectives: To compare the performance and outcomes of monopolar electrosurgical conization (MESC) or the loop electrosurgical excision procedure (LEEP) in the treatment of high-grade squamous intraepithelial lesion (HSIL). Methods: This retrospective study included 554 patients diagnosed with HSIL through biopsy. The study used either LEEP or MESC for cervical conization. Additionally, the medical records of these patients, including the basic information, status of the excision margin, cone depth, cone width, fragmentation, complication, and the results of a 6-month follow-up after conization, were reviewed. Results: Compared to MESC, LEEP had a significantly higher rate of positive endocervical margin (3.77 vs. 8.65%; p = 0.018), burn injury of the margin (4.90 vs. 10.38%; p = 0.016) and a lower rate of adequate cone depth (83.40 vs. 89.62%; p = 0.034). In addition, LEEP was significantly more likely to cause fragmentation (p = 0.000). There was, however, no significant difference in the rate of abnormal cervical cytology and positive high-risk HPV (hrHPV) between these two groups, 6 months after cervical conization. Conclusion: Both LEEP and MESC appeared to be equally effective in the clinical treatment of HSIL. Nonetheless, MESC resulted in a better pathological outcome with regard to the status of the margin, tissue fragmentation, and cone depth.

Dichotomous impact of affinity on the function of T cell engaging bispecific antibodies.

BACKGROUND: Bispecific T cell engagers represent the majority of bispecific antibodies (BsAbs) entering the clinic to treat metastatic cancer. The ability to apply these agents safely and efficaciously in the clinic, particularly for solid tumors, has been challenging. Many preclinical studies have evaluated parameters related to the activity of T cell engaging BsAbs, but many questions remain. MAIN BODY: This study investigates the impact of affinity of T cell engaging BsAbs with regards to potency, efficacy, and induction of immunomodulatory receptors/ligands using HER-2/CD3 BsAbs as a model system. We show that an IgG BsAb can be as efficacious as a smaller BsAb format both in vitro and in vivo. We uncover a dichotomous relationship between tumor-associated antigen (TAA) affinity and CD3 affinity requirements for cells that express high versus low levels of TAA. HER-2 affinity directly correlated with the CD3 engager lysis potency of HER-2/CD3 BsAbs when HER-2 receptor numbers are high (~200 K/cell), while the CD3 affinity did not impact potency until its binding affinity was extremely low (<600 nM). When HER-2 receptor numbers were lower (~20 K/cell), both HER-2 and CD3 affinity impacted potency. The high affinity anti-HER-2/low CD3 affinity BsAb also demonstrated lower cytokine induction levels in vivo and a dosing paradigm atypical of extremely high potency T cell engaging BsAbs reaching peak efficacy at doses >3 mg/kg. This data confirms that low CD3 affinity provides an opportunity for improved safety and dosing for T cell engaging BsAbs. T cell redirection also led to upregulation of Programmed cell death 1 (PD-1) and 4-1BB, but not CTLA-4 on T cells, and to Programmed death-ligand 1 (PD-L1) upregulation on HER-2HI SKOV3 tumor cells, but not on HER-2LO OVCAR3 tumor cells. Using this information, we combined anti-PD-1 or anti-4-1BB monoclonal antibodies with the HER-2/CD3 BsAb in vivo and demonstrated significantly increased efficacy against HER-2HI SKOV3 tumors via both combinations. CONCLUSIONS: Overall, these studies provide an informational dive into the optimization process of CD3 engaging BsAbs for solid tumors indicating that a reduced affinity for CD3 may enable a better therapeutic index with a greater selectivity for the target tumor and a reduced cytokine release syndrome. These studies also provide an additional argument for combining T cell checkpoint inhibition and co-stimulation to achieve optimal efficacy.

Modified bluing treatment to produce nickel-cobalt-iron spinel oxide with promoted oxygen-evolving performance.

A rapid modified bluing treatment approach was proposed for the facile synthesis of a ternary NiCoFe spinel oxide catalyst. Benefitted from the synergy of multi-elements, the enriched high-valence species and good structural stability, highly efficient and durable oxygen-evolving performance was achieved, offering an economic route for the batch preparation of advanced electrocatalysts.

Effects and mechanism of epigallocatechin-3-gallate on apoptosis and mTOR/AKT/GSK-3ß pathway in substantia nigra neurons in Parkinson rats.

The aim of this study is to investigate the protective effect of epigallocatechin-3-gallate (EGCG) on apoptosis and mTOR/AKT/GSK-3ß pathway in substantia nigra neurons in 6-dopamine-induced Parkinson rats. A total of 30 healthy male SD rats were randomly divided into control group, the Parkinson model group, and Parkinson model+EGCG treatment group. The model and EGCG groups were injected into the right striatum with 6-OHDA to establish the Parkinson model, and the control group was injected with saline only. The EGCG group was intragastrically administered with EGCG 50 mg/kg daily for 4 weeks. The rats' turns, speed, and left forelimb usage; neuron apoptosis by TUNEL; and the α-synuclein protein expression in substantia nigra by immunohistochemical staining were studied. Western blotting was used to detect the relative protein (mTOR, AKT and GSK-3ß) expressions. Compared with the model group, the EGCG group significantly reduced the rotation speed; increased the left forelimb usage (P<0.01); reduced the neuron apoptosis (P<0.01); decreased α-synuclein expression (P<0.01); and decreased the mTOR, AKT, and GSK-3ß protein expressions (P<0.01). EGCG can reduce neuron cell apoptosis in substantia nigra neurons in 6-OHDA-induced Parkinson rats. The mechanism might be related to mTOR/AKT/GSK-3ß activation.

A Nano-Sized [MnII 18 ] Metallamacrocycle as a Building Unit to Construct Stable Metal-Organic Frameworks: Effective Gas Adsorption and Magnetic Properties.

A stable hex-type metal-organic framework (MOF, WMOF-1) was constructed by nano-sized [MnII 18 ] metallamacrocycle secondary building unit, being the one with the highest nuclearity of manganese wheel-like node in the microporous MOF. WMOF-1 displays an effective gas adsorption and the antiferromagnetic behavior.

A Microfluidic Fluorescent Flow Cytometry Capable of Quantifying Cell Sizes and Numbers of Specific Cytosolic Proteins.

This study presents a microfluidics based cytometry capable of characterizing cell sizes and counting numbers of specific cytosolic proteins where cells were first bound by antibodies labelled with fluorescence and then aspirated into a constriction microchannel in which fluorescent levels were measured. These raw fluorescent pulses were further divided into a rising domain, a stable domain and a declining domain. In addition, antibody solutions with labelled fluorescence were aspirated through the constriction microchannel, yielding curves to translate raw fluorescent levels to protein concentrations. By using key parameters of three domains as well as the calibration curves, cell diameters and the absolute number of ß-actins at the single-cell level were quantified as 14.2 ± 1.7 µm and 9.62 ± 4.29 × 105 (A549, ncell = 14 242), 13.0 ± 2.0 µm and 6.46 ± 3.34 × 105 (Hep G2, ncell = 35 932), 13.8 ± 1.9 µm and 1.58 ± 0.90 × 106 (MCF 10 A, ncell = 16 650), and 12.7 ± 1.5 µm and 1.09 ± 0.49 × 106 (HeLa, ncell = 26 246). This platform could be further adopted to measure numbers of various cytosolic proteins, providing key insights in proteomics at the single-cell level.

A microfluidic flow cytometer enabling absolute quantification of single-cell intracellular proteins.

Quantification of single-cell proteomics provides key insights into cellular heterogeneity while conventional flow cytometry cannot provide absolute quantification of intracellular proteins of single cells due to the lack of calibration approaches. This paper presents a constriction channel (with a cross sectional area smaller than cells) based microfluidic flow cytometer, capable of collecting copy numbers of specific intracellular proteins. In this platform, single cells stained with fluorescence labelled antibodies were forced to squeeze through the constriction channel with the fluorescence intensities quantified and since cells fully filled the constriction channel during the squeezing process, solutions with fluorescence labelled antibodies were flushed into the constriction channel to obtain calibration curves. By combining raw fluorescence data and calibration curves, absolute quantification of intracellular proteins was realized. As a demonstration, copy numbers of beta-actin of single tumour cells were quantified to be 0.90 ± 0.30 µM (A549, ncell = 14 228), 2.34 ± 0.70 µM (MCF 10A, ncell = 2455), and 0.98 ± 0.65 µM (Hep G2, ncell = 6945). The travelling time for individual cells was quantified to be roughly 10 ms and thus a throughput of 100 cells per s can be achieved. This microfluidic system can be used to quantify the copy numbers of intracellular proteins in a high-throughput manner, which may function as an enabling technique in the field of single-cell proteomics.

Mechanistic investigation inspired "on water" reaction for hydrobromic acid-catalyzed Friedel-Crafts-type reaction of ß-naphthol and formaldehyde.

The mechanism of the HBr-catalyzed Friedel-Crafts-type reaction between ß-naphthol and HCHO was investigated by DFT to improve this reaction. The HBr-H2 O co-catalyzed the preferential pathway undergoes the concerted nucleophilic addition and hydrogen shift, stepwise followed by H2 O elimination and the CC bond formation. The origin of the high catalytic activity of HBr is ascribed to CH···Br- and OH···Br- interactions, which suggest that the active species is Br- . Moreover, water molecules efficiently assist in improving the activity of Br- . The computational results show that solvent polarity profoundly affects the activation barriers. To our delight, the activation barrier of the rate-determining step for the favored pathway in water is comparable (0.6 kcal/mol difference) with that in acetonitrile. The experimental observation further confirmed our results and demonstrated that the title reaction can be successfully achieved "on water." Therefore, we open a new efficient and green strategy for the synthesis of biphenol derivatives. © 2017 Wiley Periodicals, Inc.

Synergistic antinociceptive effects of alfentanil and propofol in the formalin test.

The present study was conducted to determine the combined analgesic effect of alfentanil and propofol in the formalin test. Diluted formalin was injected into the dorsal surface of the right hind paw in rats. Nociceptive behavior was determined by counting the number of flinches of the injected paw for 1 h after injection; a reduction in formalin­induced flinching was interpreted as an antinociceptive effect. Isobolographic analysis was used to determine the type of antinociceptive interaction (additivity, antagonism or synergism). Extracellular signal­regulated kinase (ERK) and c­fos protein levels were also detected by western blot analysis to determine the potential mechanisms of the synergistic effect. Alfentanil, propofol or an alfentanil­propofol combination had an antinociceptive effect in the formalin test. The median effective dose (ED50), value of the individual drug was also obtained. The derived theoretical ED50 for the antinociceptive effect (4.36 mg/kg) was different from the observed experimental ED50 value (2.51 mg/kg). The interaction between alfentanil and propofol that produced the antinociceptive effect was synergistic according to isobolographic analysis. Furthermore, the combination of alfentanil and propofol treatments may produce synergistically antinociceptive effects by inhibiting the phosphorylation of ERK1/2 and decreasing the expression of c­fos in the spinal cord. These results demonstrated that combined treatment, with alfentanil and propofol, produced synergistic antinociceptive effects in the formalin test and may have therapeutic potential for the treatment of acute pain.

Modeling and mapping of cadmium in soils based on qualitative and quantitative auxiliary variables in a cadmium contaminated area.

The aim of this study was to measure the improvement in mapping accuracy of spatial distribution of Cd in soils by using geostatistical methods combined with auxiliary factors, especially qualitative variables. Significant correlations between Cd content and correlation environment variables that are easy to obtain (such as topographic factors, distance to residential area, land use types and soil types) were analyzed systematically and quantitatively. Based on 398 samples collected from a Cd contaminated area (Hunan Province, China), we estimated the spatial distribution of Cd in soils by using spatial interpolation models, including ordinary kriging (OK), and regression kriging (RK) with each auxiliary variable, all quantitative variables (RKWQ) and all auxiliary variables (RKWA). Results showed that mapping with RK was more consistent with the sampling data of the spatial distribution of Cd in the study area than mapping with OK. The performance indicators (smaller mean error, mean absolute error, root mean squared error values and higher relative improvement of RK than OK) indicated that the introduction of auxiliary variables can improve the prediction accuracy of Cd in soils for which the spatial structure could not be well captured by point-based observation (nugget to sill ratio=0.76) and strong relationships existed between variables to be predicted and auxiliary variables. The comparison of RKWA with RKWQ further indicated that the introduction of qualitative variables improved the prediction accuracy, and even weakened the effects of quantitative factors. Furthermore, the significantly different relative improvement with similar R2 and varying spatial dependence showed that a reasonable choice of auxiliary variables and analysis of spatial structure of regression residuals are equally important to ensure accurate predictions.

Synergistic analgesic effect of propofol-alfentanil combination through detecting the inhibition of cAMP signal pathway.

OBJECTIVE: The study aims to investigate the possible mechanism of the synergistic analgesic effect of propofol-alfentanil combination. METHODS: The synergistic analgesic effects of propofol-alfentanil combination in Sprague-Dawley (SD) rats were analysed through the von Frey test. Then, we examined the activity of phospholipase C (PLC) and the intracellular levels of Ca(2+) and adenosine 3', 5'cyclic monophosphate (cAMP) in primary neuronal cells of fetal SD rats. We detected the intracellular Ca(2+) concentration by fluorescence and flow cytometry. The PLC activity of the primary neuronal cells was assayed using the EnzChek(®) Direct Phospholipase C Assay Kit. The cAMP content of the cells was assayed using the cAMP Direct Immunoassay Kit (Fluorometric). KEY FINDINGS: Both propofol and alfentanil treatments depressed cAMP levels and PLC activity, but propofol-alfentanil combination decreased these parameters to a greater extent than alfentanil treatment alone. Propofol and alfentanil both inhibited Ca(2+) channel, but propofol-alfentanil combination suppressed this channel to a greater extent than alfentanil treatment alone. Fluorescent image analysis revealed that both propofol and alfentanil reduced the intracellular levels of Ca(2+) , and propofol-alfentanil combination showed weaker signals than alfentanil alone. Propofol-alfentanil combination significantly reduced intracellular Ca(2+) level, cAMP level and PLC activity. CONCLUSION: Propofol and alfentanil exert synergistic analgesic effects through the adenylyl cyclase pathway.