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Abstract

Venetoclax is the first oral Bcl-2 inhibitor with high affinity targeting tumor cell apoptosis mechanism. In this study we developed a simple, sensitive and reliable LC–MS/MS method to determine venetoclax in children's hemolytic or lipemic samples. The method utilized an electrospray ion source and operated in multiple reaction monitoring mode. Venetoclax-d8 was used as an internal standard. Plasma samples were precipitated by acetonitrile containing 10% dimethyl sulfoxide and were separated by a Hypersil GOLD column (2.1 mm × 150 mm, 5 μm). The mobile phase consisted of acetonitrile-2 mM ammonium acetate (30:70, v/v) containing 0.4% formic acid. The quantification for venetoclax and venetoclax-d8 were m/z 868.1 → 636.1, m/z 876.1 → 644.1, respectively. The linear range was 10–2,000 ng mL−1 for venetoclax. The matrix in normal plasma, hemolytic or lipemic plasma had no significant effect on the detection results. The specificity, recovery and stability also met the acceptance criteria of guiding principles for the validation of biological sample quantitative analysis presented in the Chinese Pharmacopoeia (2015). As a result, this method is particularly suitable for determining venetoclax in hemolytic or lipemic samples from children with acute myeloid leukemia. The method, with the application of monitoring drug concentrations in pediatric patients, was successful.

Open access

Abstract

Objectives

Understanding the neural mechanisms underlying Internet gaming disorder (IGD) is essential for the condition's diagnosis and treatment. Nevertheless, the pathological mechanisms of IGD remain elusive at present. Hence, we employed multi-voxel pattern analysis (MVPA) and spectral dynamic causal modeling (spDCM) to explore this issue.

Methods

Resting-state fMRI data were collected from 103 IGD subjects (male = 57) and 99 well-matched recreational game users (RGUs, male = 51). Regional homogeneity was calculated as the feature for MVPA based on the support vector machine (SVM) with leave-one- out cross-validation. Mean time series data extracted from the brain regions in accordance with the MVPA results were used for further spDCM analysis.

Results

Results display a high accuracy of 82.67% (sensitivity of 83.50% and specificity of 81.82%) in the classification of the two groups. The most discriminative brain regions that contributed to the classification were the bilateral parahippocampal gyrus (PG), right anterior cingulate cortex (ACC), and middle frontal gyrus (MFG). Significant correlations were found between addiction severity (IAT and DSM scores) and the ReHo values of the brain regions that contributed to the classification. Moreover, the results of spDCM showed that compared with RGU, IGD showed decreased effective connectivity from the left PG to the right MFG and from the right PG to the ACC and decreased self-connection in the right PG.

Conclusions

These results show that the weakening of the PG and its connection with the prefrontal cortex, including the ACC and MFG, may be an underlying mechanism of IGD.

Open access

Summary

A simple hydrolysis method has been developed for determination of phenylethanoid glycosides in Lamiophlomis rotata (L.R.). Different kinds of phenylethanoid glycosides were hydrolyzed in hydrochloric acid solution to produce corresponding phenethyl alcohols and cinnamic acids, mainly containing hydroxytyrosol, homovanillyl alcohol, 3,4-dimethoxyphenethyl alcohol, caffeic acid, fumalic acid and 3,4-dimethoxycinnamic acid. The six analytes could be determined simultaneously by high-performance liquid chromatography (HPLC). The effects of mobile phase, pH and concentration of running buffer, detection wavelength, flow rate and injection volume were also investigated. Under the optimum conditions, the six hydrolyzates could be perfectly separated within 45 min. The response was linear over four orders of magnitude with detection limits (S/N = 3) ranging from 1 × 10−8 to 1.5 × 10−4 mol L−1 for the analytes. The method has been successfully applied to the analysis of real sample Du-Yi-Wei capsule and Qi-Zheng-Yan-Tong patch, with satisfactory results.

Open access
Journal of Behavioral Addictions
Authors:
Wei-Ran Zhou
,
Min Wang
,
Hao-Hao Dong
,
Zhaojie Zhang
,
Xiaoxia Du
,
Marc N. Potenza
, and
Guang-Heng Dong

Abstract

Background

Internet gaming disorder (IGD) is a type of behavioral addiction characterized by poorly controlled and interfering patterns of game playing. Studies have suggested that the IGD is usually accompanied by increased desire or craving for gaming, suggesting that secondary rewards related to gaming may become more salient than those for primary rewards like food. However, this hypothesis has not been formally tested and potential neural mechanisms remain unclear.

Methods

This is a functional magnetic resonance imaging (fMRI) study. Twenty-one IGD subjects and 23 matched individuals with recreational game use (RGU) were scanned when exposed to gaming (secondary rewards), food (primary rewards) and neutral cues. Group-by-cue-type interaction analyses and subsequent within-group analyses for fMRI data were performed and seed-based functional connectivity (FC) analyses explored further potential neural features.

Results

IGD subjects’ subjective craving responses to gaming cues were higher than to food cues, while the opposite was observed in RGU subjects. Group-by-cue interaction effects implicated the precuneus and precuneus-caudate FC. Simple effect analysis showed that for IGD subjects, gaming-related cues elicited higher FC in precuneus-caudate relationships than did food-related cues. In the RGU subjects, the opposite was observed. Significant correlations were found between brain features and craving scores.

Conclusions

These results support the hypothesis regarding imbalances in sensitivities to different types of reward in IGD, and suggest neural mechanisms by which craving for gaming may make secondary rewards more salient than primary ones, thus promoting participation in addictive patterns of gaming.

Open access

Abstract

Background

Internet gaming disorder (IGD) is included in the DSM-5 as a provisional diagnosis. Whether IGD should be regarded as a disorder and, if so, how it should be defined and thresholded have generated considerable debate.

Methods

In the current study, machine learning was used, based on regional and interregional brain features. Resting-state data from 374 subjects (including 148 IGD subjects with DSM-5 scores ≥5 and 93 IGD subjects with DSM-5 scores ≥6) were collected, and multivariate pattern analysis (MVPA) was employed to classify IGD from recreational game use (RGU) subjects based on regional brain features (ReHo) and communication between brain regions (functional connectivity; FC). Permutation tests were used to assess classifier performance.

Results

The results demonstrated that when using DSM-5 scores ≥5 as the inclusion criteria for IGD subjects, MVPA could not differentiate IGD subjects from RGU, whether based on ReHo or FC features or by using different templates. MVPA could differentiate IGD subjects from RGU better than expected by chance when using DSM-5 scores ≥6 with both ReHo and FC features. The brain regions involved in the default mode network and executive control network and the cerebellum exhibited high discriminative power during classification.

Discussion

The current findings challenge the current IGD diagnostic criteria thresholding proposed in the DSM-5, suggesting that more stringent criteria may be needed for diagnosing IGD. The findings suggest that brain regions involved in the default mode network and executive control network relate importantly to the core criteria for IGD.

Open access

Abstract

Background

Although previous studies have revealed gender-related differences in executive function in internet gaming disorder (IGD), neural mechanisms underlying these processes remain unclear, especially in terms of brain networks.

Methods

Resting-state fMRI data were collected from 78 subjects with IGD (39 males, 20.8 ± 2.16 years old) and 72 with recreational game use (RGU) (39 males, 21.5 ± 2.56 years old). By utilizing graph theory, we calculated participation coefficients among brain network modules for all participants and analyzed the diagnostic-group-by-gender interactions. We further explored possible causal relationships between networks through spectral dynamic causal modeling (spDCM) to assess differences in between-network connections.

Results

Compared to males with RGU, males with IGD demonstrated reduced modular segregation of the frontal-parietal network (FPN). Male IGD subjects also showed increased connections between the FPN and cingulo-opercular network (CON); however, these differences were not found in female subjects. Further spDCM analysis indicated that the causal influence from CON to FPN in male IGD subjects was enhanced relative to that of RGU males, while this influence was relatively reduced in females with IGD.

Conclusions

These results suggest poor modular segmentation of the FPN and abnormal FPN/CON connections in males with IGD, suggesting a mechanism for male vulnerability to IGD. An increased “bottom-up” effect from the CON to FPN in male IGD subjects could reflect dysfunction between the brain networks. Different mechanisms may underlie in IGD, suggesting that different interventions may be optimal in males and females with IGD.

Open access

Molecularly imprinted polymers (MIPs) were synthesized by imprinting a new template—S(-)-1,1′-binaphthalene-2,2′-diamine (S-DABN) and applied as chiral stationary phases for chiral separation of DABN racemates by high-performance liquid chromatography (HPLC). The influence of some key factors on the chiral recognition ability of MIPs, such as the type of functional monomers and porogen and the molar ratio of template to monomer, was systematically investigated. The chromatographic conditions, such as mobile phase composition, sample loading, and flow rate, were also measured. The chiral separation for DABN racemates under the optimum chromatographic conditions by using MIP chiral stationary phase (CSP) of P3, prepared with the S-DABN/MAA ratio = 1/4 and used acetonitrile (2 mL) and chloroform (4 mL) as porogen, showed the highest separation factor (2.14). Frontal analysis was used to evaluate affinity to the target molecule of MIPs. The binding sites (B t) of MIPs and dissociation constant (K d) were estimated as 4.56 μmol g−1 and 1.40 mmol L−1, respectively. In comparison with the previous studies, this approach had the advantages, such as the higher separation factor, easy preparation, and cost-effectiveness, it not only has the value for research but also has a potential in industrial application.

Open access

Background and aims

Although studies have suggested that individuals with Internet gaming disorder (IGD) may have impairments in cognitive functioning, the nature of the relationship is unclear given that the information is typically derived from cross-sectional studies.

Methods

Individuals with active IGD (n = 154) and those individuals no longer meeting criteria (n = 29) after 1 year were examined longitudinally using functional magnetic resonance imaging during performance of cue-craving tasks. Subjective responses and neural correlates were contrasted at study onset and at 1 year.

Results

Subjects’ craving responses to gaming cues decreased significantly at 1 year relative to study onset. Decreased brain responses in the anterior cingulate cortex (ACC) and lentiform nucleus were observed at 1 year relative to onset. Significant positive correlations were observed between changes in brain activities in the lentiform nucleus and changes in self-reported cravings. Dynamic causal modeling analysis showed increased ACC–lentiform connectivity at 1 year relative to study onset.

Conclusions

After recovery from IGD, individuals appear less sensitive to gaming cues. This recovery may involve increased ACC-related control over lentiform-related motivations in the control over cravings. The extent to which cortical control over subcortical motivations may be targeted in treatments for IGD should be examined further.

Open access

Abstract

In this work, a simple and rapid high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to carry out the simultaneous measurement of busulfan (BU) and phenytoin (PHT) in the plasma of children. In this method, plasma sample could be prepared by one-step protein precipitation using 1 mL of methanol/water (1:1, v/v). After centrifugation (14,500 rpm, 5 min, 4 °C), 10 μL of the supernatant was injected into a Hypersil Gold C18 column (150 × 2.1 mm, 5 μm, Thermo Fisher Scientific) for separation by gradient elution. Quantification was carried out using multiple reactions monitoring (MRM) under positive scan mode. In the method verification, the calibration curves of BU and PHT showed satisfactory linearity (r > 0.99) at the concentration ranging from 0.02 to 20 μg mL−1. The accuracy and precision were tested at four concentration levels (including the LLOQ level) with the relative error (RE) ranging from −0.80% to 11.45% and coefficient of variation (CV) between 0.93% and 7.74%. There was no pronounced matrix effect to interfere with the quantitative analysis. Compared to determine BU and PHT using two individual methods, less pre-treatment process, labor and blood sample volume are required in this proposed method. Finally, this method was successfully applied to the therapeutic drug monitoring of BU and PHT for children underwent hematological stem cell transplantation.

Open access

Abstract

Nattokinase (NK) is effective in the prevention and treatment of cardiovascular disease. Cucumber is rich in nutrients with low sugar content and is safe for consumption. The aim of this study was to construct a therapeutic cucumber that can express NK, which can prevent and alleviate cardiovascular diseases by consumption. Because the Bitter fruit (Bt) gene contributes to bitter taste but has no obvious effect on the growth and development of cucumber, so the NK-producing cucumber was constructed by replacing the Bt gene with NK by using CRISPR/Cas9. The pZHY988-Cas9-sgRNA and pX6-LHA-U6-NK-T-RHA vectors were constructed and transformed into Agrobacterium tumefaciens EHA105, which was transformed into cucumber by floral dip method. The crude extract of NK-producing cucumber had significant thrombolytic activity in vitro. In addition, treatment with the crude extract significantly delayed thrombus tail appearance, and the thrombin time of mice was much longer than that of normal mice. The degrees of coagulation and blood viscosity as well as hemorheological properties improved significantly after crude extract treatment. These findings show that NK-producing cucumber can effectively alleviate thrombosis and improve blood biochemical parameters, providing a new direction for diet therapy against cardiovascular diseases.

Open access