Internet gaming disorder and tobacco use disorder share neural connectivity patterns between the subcortical and the motor network.

Internet gaming disorder (IGD) and tobacco use disorder (TUD) are globally common, non-substance-related disorders and substance-related disorders worldwide, respectively. Recognizing the commonalities between IGD and TUD will deepen understanding of the underlying mechanisms of addictive behavior and excessive online gaming. Using node strength, 141 resting-state data were collected in this study to compute network homogeneity. The participants included participants with IGD (PIGD: n = 34, male = 29, age: 15-25 years), participants with TUD (PTUD: n = 33, male = 33, age: 19-42 years), and matched healthy controls (control-for-IGD: n = 41, male = 38, age: 17-32 years; control-for-TUD: n = 33, age: 21-27 years). PIGD and PTUD exhibited common enhanced node strength between the subcortical and motor networks. Additionally, a common enhanced resting-state functional connectivity (RSFC) was found between the right thalamus and right postcentral gyrus in PIGD and PTUD. Node strength and RSFC were used to distinguish PIGD and PTUD from their respective healthy controls. Interestingly, models trained on PIGD versus controls could classify PTUD versus controls and vice versa, suggesting that these disorders share common neurological patterns. Enhanced connectivity may indicate a greater association between rewards and behaviors, inducing addiction behaviors without flexible and complex regulation. This study discovered that the connectivity between the subcortical and motor networks is a potential biological target for developing addiction treatment in the future.

Bulleyaconitine A is a sensitive substrate and competitive inhibitor of CYP3A4: One of the possible explanations for clinical adverse reactions.

Bulleyaconitine A (BLA), a toxic Aconitum alkaloid, is a potent analgesic that is clinically applied to treat rheumatoid arthritis, osteoarthritis and lumbosacral pain. BLA-related adverse reactions occur frequently, but whether the underlying mechanism is related to its metabolic interplay with drug-metabolizing enzymes remains unclear. This study aimed to elucidate the metabolic characteristics of BLA and its affinity action and mechanism to drug-metabolizing enzymes to reveal whether BLA-related adverse reactions are modulated by enzymes. After incubation with human liver microsomes and recombinant human cytochrome P450 enzymes, we found that BLA was predominantly metabolized by CYP3A, in which CYP3A4 had an almost absolute advantage. In vitro, the CYP3A4 inhibitor ketoconazole noticeably suppressed the metabolism of BLA. In vivo, the AUC0-∞ values, cardiotoxicity and neurotoxicity of BLA in Cyp3a-inhibited mice were all obviously enhanced (P < 0.05) compared to those in normal mice. In the enzyme kinetics study, BLA was found to be a sensitive substrate of CYP3A4, and its characteristics were consistent with substrate inhibition (Km = 39.36 ± 10.47 µmol/L, Ks = 83.42 ± 19.65 µmol/L). BLA was further identified to be a competitive inhibitor of CYP3A4 with Ki = 53.64 µmol/L, since the intrinsic clearance (CLint) of midazolam, a selective CYP3A4 substrate, decreased significantly (P < 0.05) when incubated with BLA together in mouse liver microsomes. Overall, BLA is a sensitive substrate and competitive inhibitor of CYP3A4, and clinical adverse reactions of BLA may mechanistically related to the CYP3A4-mediated drug-drug interactions.

Brain morphology, harm avoidance, and the severity of excessive internet use.

As the previous studies have mainly focused on the reward system and the corresponding brain regions, the relationship between brain morphology and excessive internet use (EIU) were not clear; the purpose of the study was to investigate if the brain regions other than the reward system were associated with EIU. Data were acquired from 131 excessive internet users. Psychological measures included internet use, life quality, personality, mental illness symptoms, impulsivity, and thought suppression. The brain was scanned with 3T magnetic resonance imaging (MRI) and six types of brain morphological indexes were calculated. Lasso regression methods were used to select the predictors. Stepwise linear regression methods were used to build the models and verify the model. The variables remaining in the model were left precentral (curve), left superior temporal (surface area), right cuneus (folding index), right rostral anterior cingulate (folding index), and harm avoidance. The independent variable was the EIU score of the worst week in the past year. The study found that the brain morphological indexes other than the reward system, including the left precentral (curve), the left superior temporal (surface area), the right cuneus (folding index), and the right rostral anterior cingulate (folding index), can predict the severity of EIU, suggesting an extensive change in the brain. In this study, a whole-brain data analysis was conducted and it was concluded that the changes in certain brain regions were more predictive than the reward system and psychological measures or more important for EIU.

Laboratory Predictors of COVID-19 Pneumonia in Patients with Mild to Moderate Symptoms.

OBJECTIVE: This research aims to develop a laboratory model that can accurately distinguish pneumonia from nonpneumonia in patients with COVID-19 and to identify potential protective factors against lung infection. METHODS: We recruited 50 patients diagnosed with COVID-19 infection with or without pneumonia. We selected candidate predictors through group comparison and punitive least absolute shrinkage and selection operator (LASSO) analysis. A stepwise logistic regression model was used to distinguish patients with and without pneumonia. Finally, we used a decision-tree method and randomly selected 50% of the patients 1000 times from the same specimen to verify the effectiveness of the model. RESULTS: We found that the percentage of eosinophils, a high-fluorescence-reticulocyte ratio, and creatinine had better discriminatory power than other factors. Age and underlying diseases were not significant for discrimination. The model correctly discriminated 77.1% of patients. In the final validation step, we observed that the model had an overall predictive rate of 81.3%. CONCLUSION: We developed a laboratory model for COVID-19 pneumonia in patients with mild to moderate symptoms. In the clinical setting, the model will be able to predict and differentiate pneumonia vs nonpneumonia before any lung computed tomography findings. In addition, the percentage of eosinophils, a high-fluorescence-reticulocyte ratio, and creatinine were considered protective factors against lung infection in patients without pneumonia.

Mdr1a, Bcrp and Mrp2 regulate the efficacy and toxicity of mesaconitine and hypaconitine by altering their tissue accumulation and in vivo residence.

Mesaconitine (MA) and hypaconitine (HA) are the main bioactive/toxic alkaloids of Aconitum carmichaelii Debx, and MDR1, BCRP and MRP2 are involved in their efflux in vitro. This study aimed to explore the effects of Mdr1a, Bcrp and Mrp2 on the efficacy/toxicity of MA and HA by using efflux transporter gene knockout mouse models. The analgesic and anti-inflammatory effects, neurotoxicity/cardiotoxicity, and pharmacokinetic profiles of MA and HA were studied. Compared to wild-type mice, the analgesic effects of MA or HA were significantly enhanced in Mdr1a--/-, Bcrp1-/- and Mrp2-/- mice, and the anti-inflammatory effects notably increased in Bcrp1-/- and Mrp2-/- mice. Compared to wild-type mice, Mdr1a-/-, Bcrp1-/- and Mrp2-/- mice suffered from severe karyopyknosis and edema in the brain after MA or HA treatment. Meanwhile, significant arrhythmia appeared, and the heart rate and RR-interval were greatly altered in Mdr1a-/-, Bcrp1-/- and Mrp2-/- mice. Additionally, obvious disorder of cardiomyocytes were observed, and the CK and cTnT (indicators of heart injury) levels were greatly enhanced in efflux transporter gene knockout mice. The brain levels of MA and HA were markedly increased in Mdr1a-/-, Bcrp1-/- and Mrp2-/- mice, and the heart levels of MA and HA enhanced greatly in Mdr1a-/- mice. The MRT0-t values of MA and HA were remarkably enhanced in most efflux transporter gene knockout mice. In conclusion, Mdr1a, Bcrp and Mrp2 were all involved in regulating the efficacy/toxicity of MA and HA by altering their tissue accumulation and in vivo residence. Among the three efflux transporters, Mdr1a had a superior regulatory effect.