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Aims Methods Results Conclusions Hydroxychloroquine (HCQ) is recommended for the long‐term treatment of rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. Given the complex process of HCQ metabolism and individual physiological differences, the metabolic profile of HCQ after long‐term administration is unknown. This study aimed to establish a population pharmacokinetic model for long‐term HCQ treatment in patients with rheumatic diseases and to identify the factors influencing HCQ metabolism.This study included 274 HCQ whole‐blood trough concentration data points from 203 patients with rheumatic diseases, all of whom had taken HCQ for more than 6 months, with a median duration of 36 months. A nonlinear mixed‐effects model was derived to establish a population pharmacokinetic model, and potential influencing factors were investigated. Different covariates were used to simulate the optimal dose.The final model describing the HCQ blood concentration–time profile was a compartmental model with first‐order absorption. The estimated values for apparent clearance and volume of distribution were 16.4 L/h and 1220 L, respectively. The clearance of HCQ gradually increased with increasing dosing regimens and weight gain. Monte Carlo simulations were used to determine the optimal dosage regimens for patients with different body weights and drug durations. The simulation results revealed that an initial dose of 5 mg/kg was appropriate.We developed a population pharmacokinetic model for long‐term HCQ therapy in patients with rheumatic diseases. HCQ clearance from whole blood increased progressively with increasing duration of drug administration. [ABSTRACT FROM AUTHOR]

What is Known and Objective. Voriconazole (VRC) increases the blood concentration of Tacrolimus (TAC). However, the patterns of changes in TAC trough concentration (TAC C0) and dose-adjustment regimens after VRC discontinuation have not been reported. We aimed to explore the changing pattern of TAC C0 after VRC discontinuation and provide strategies for TAC dose adjustment and blood concentration monitoring in renal transplant recipients. Methods. The clinical data of 46 renal transplant patients pre- and during VRC medication and VRC discontinuation were retrospectively recorded, including doses and concentrations 0 of TAC and VRC; biochemical indicators such as liver and kidney function; and CYP3A5, CYP3A4, and CYP2C19 gene types. Results and Discussion. After discontinuing VRC for 2–4 days, 81% of the patients returned to their initial TAC dose, although TAC C0 and TAC dose-adjusted trough concentration (C/D) were 2.43-fold and 3.35-fold higher, respectively, than pre-VRC administration. After 5–7 days, TAC C0 and C/D gradually recovered. TAC C/D was significantly higher after VRC discontinuation when the VRC trough concentration (VRC C0) was greater than 2.43 mg/L; CYP3A5, CYP3A4, and CYP2C19 genotypes and the administration of erythromycin did not affect the change in TAC C/D. What is New and Conclusion. TAC C/D remains elevated 2–4 days after discontinuing VRC compared to pre-VRC administration, with gradual recovery observed 5–7 days after VRC discontinuation. To avoid excessive blood TAC C0 , the initial TAC dose should not be immediately reinstated upon VRC discontinuation for 2–4 days. VRC C0 are a critical factor influencing the change in TAC C/D ratio after VRC discontinuation. [ABSTRACT FROM AUTHOR]

Background: Diffusion tensor imaging (DTI) studies have demonstrated white matter (WM) abnormalities in patients with temporal lobe epilepsy (TLE). However, alterations in the topological properties of the WM structural network in patients with TLE remain unclear. Graph theoretical analysis provides a new perspective for evaluating the connectivity of WM structural networks. Methods: DTI was used to map the structural networks of 18 patients with TLE (10 males and 8 females) and 29 (17 males and 12 females) age‐ and gender‐matched normal controls (NC). Graph theory was used to analyze the whole‐brain networks and their topological properties between the two groups. Finally, partial correlation analyses were performed on the weighted network properties and clinical characteristics, namely, duration of epilepsy, verbal intelligence quotient (IQ), and performance IQ. Results: Patients with TLE exhibited reduced global efficiency and increased characteristic path length. A total of 31 regions with nodal efficiency alterations were detected in the fractional anisotropy_ weighted network of the patients. Communication hubs, such as the middle temporal gyrus, right inferior temporal gyrus, left calcarine, and right superior parietal gyrus, were also differently distributed in the patients compared with the NC. Several node regions showed close relationships with duration of epilepsy, verbal IQ, and performance IQ. Conclusions: Our results demonstrate the disruption of the WM structural network in TLE patients. This study may contribute to the further understanding of the pathological mechanism of TLE. [ABSTRACT FROM AUTHOR]

Background and Purpose: Understanding the pathogenesis of temporal lobe epilepsy (TLE) is essential for its diagnosis and treatment. The study aimed to explore regional homogeneity (ReHo) and changes in effective connectivity (EC) between brain regions in TLE patients, hoping to discover potential abnormalities in certain brain regions in TLE patients. Methods: Resting‐state functional magnetic resonance data were collected from 23 TLE patients and 32 normal controls (NC). ReHo was used as a feature of multivariate pattern analysis (MVPA) to explore the ability of its alterations in identifying TLE. Based on the results of the MVPA, certain brain regions were selected as seed points to further explore alterations in EC between brain regions using Granger causality analysis. Results: MVPA results showed that the classification accuracy for the TLE and NC groups was 87.27%, and the right posterior cerebellum lobe, right lingual gyrus (LING_R), right cuneus (CUN_R), and left superior temporal gyrus (STG_L) provided significant contributions. Moreover, the EC from STG_L to right fusiform gyrus (FFG_R) and LING_R and the EC from CUN_R to the right occipital superior gyrus (SOG_R) and right occipital middle gyrus (MOG_R) were altered compared to the NC group. Conclusion: The MVPA results indicated that ReHo abnormalities in brain regions may be an important feature in the identification of TLE. The enhanced EC from STG_L to FFG_R and LING_R indicates a shift in language processing to the right hemisphere, and the weakened EC from SOG_R and MOG_R to CUN_R may reveal an underlying mechanism of TLE. [ABSTRACT FROM AUTHOR]

Antibiosis and resource competition are major drivers shaping the assembly, diversity and functioning of microbial communities. While it is recognized that competition is sensitive to environmental conditions, it is unclear to what extent this mediated by the availability of different carbon resources.Here, we used a model laboratory system to directly test this by exploring how carbon resource richness and identity shape resource competition and antibiosis between plant probiotic Bacillus amyloliquefaciens and phytopathogenic Ralstonia solanacearum bacteria. We found that while sugars typically promoted B. amyloliquefaciens growth, organic and amino acids increased the production of both bacillaene and macrolactin antibiotics and the direct inhibition of R. solanacearum. In contrast, when multiple different carbon resources were available, B. amyloliquefaciens could efficiently grow and produce antibiotics at the same time.Together, these results suggest that high carbon resource richness allows concurrent expression of growth‐ and antibiosis‐related traits, potentially altering bacterial competitive dynamics and plant growth promotion in microbial communities. A plain language summary is available for this article. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND AND PURPOSE This study aims to investigate the regional changes in the early onset of blindness using the deformation-based morphometry (DBM) method. METHODS A total of 15 early blindness and 30 gender- and age-matched sighted control subjects were recruited for the study. Statistically significant changes in regional volume were analyzed using DBM through HAMMER registration. Using this technique, changes in regional tissue volume can be detected on the basis of the deformation field derived from the warping subject to the template image. A voxelwise estimation of the morphological differences between the two groups can be acquired after applying a threshold ( P < .001, uncorrected) to the statistic maps. RESULTS Regions with enlarged volume in the brains of blind subjects are mainly localized in the left associated visual cortex, posterior cingulated cortex, and cerebellum, whereas volume reductions are primarily localized in the left early visual cortex. CONCLUSIONS DBM is an effective method for detecting entire brain structural changes in blindness. Visual deprivation actually alters the local structural organization during the early critical periods of neurodevelopment. Volume increases outside the occipital lobe detected with DBM may suggest compensatory adaptations. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND AND PURPOSE Small animal neuroimaging using magnetic resonance microscopy (MRM) has evolved significantly from understanding of imaging physics to widely use today as an important tool in computational neuroanatomy, while how to get optimal inhomogeneity correction for inhomogeneous mouse brain MRM has been given less attention. METHODS This present study investigates the ability of fine-tuning the nonparametric nonuniform intensity normalization (N3) technique to get optimal inhomogeneity correction of mouse brain MRM. Six mice were scanned on a 7-T scanner with a phased array surface coil of four elements. The N3 parameters such as stopping criteria, maximum iterations, down-sampling ratio, full width at half maximum, spline distance, and brain mask have been tuned to get optimal correction result. We used coefficient of variation of the white matter and joint variation to ascertain quantitatively the correction. The data were analyzed by two-way repeated measures analysis of variance and Bonferroni post hoc test. RESULTS The quantitative outcomes show that brain mask and spline distance have a significant influence on correcting performance. CONCLUSIONS The present study demonstrates the benefit of reducing the spline distance values to 25 and tighter mask. The finding can help researches to enhance precision in studies where mouse MRM need further registration or segmentation. [ABSTRACT FROM AUTHOR]

Small animal magnetic resonance microscopy (MRM) has been widely used today in computational neuroanatomy. Accurate identification of brain tissue in a mouse MRM is a critical fundamental step in neuroimaging processing, which is given less attention. This study presents an automatic skull-stripping technique based on template models and histogram analysis. Results were evaluated by calculating the Jaccard similarity index (JSI) and boundary concordance ratio (BCR) between the automatically segmented and manually traced brain volumes. Results demonstrate that this technique accurately extracts the brain volume (mean JSI = 97.1%, BC = 94.4%). The brain extraction method presented in this study will greatly facilitate analysis of neuroimaging studies of rodent animals in neurodegenerative diseases. Microsc. Res. Tech. 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

As a transmembrane chemokine, CXCL16 has been detected in various tissues and organs under normal and pathological conditions, it also plays an important role in macrophages/dendritic cells (DC) and T cell interactions and trafficking during inflammation and immune responses. LysoPtdOH, a bioactive lipid mediator has been indicated to regulate DC and epithelial functions during wound healing and inflammation responses. However, the direct link of CXCL16 expression with lysoPtdOH has not been established. Using monocyte-derived macrophages/DC (MoDC), we investigated the roles of lysoPtdOH in CXCL16 production and cell surface presentation. We found that macrophages/MoDC constitutively express and secrete CXCL16, lysoPtdOH significantly enhanced CXCL16 protein production stimulated with lipopolysaccharide (LPS) by more than twofold, which was reflected by increased mRNA transcription by 64-fold. Production of CXCL16 increased by lysoPtdOH and LPS from macrophages was inhibited around 70% by Pertussis toxin (Gi/o specific inhibitor), exoC3 (Rho specific inhibitor), and pyrrolidine dithiocarbamate (the NF-κB-dependent pathway inhibitor) separately. LysoPtdOH treatment increased macrophages’ chemotactic activity to activated T cells. The soluble form of CXCL16 produced by macrophages/MoDC was functionally chemoattractive to T cells. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to obtain antitumour molecules targeting to activate PKM2 through adequate computational methods combined with biological activity experiments. Methods: The structure‐based virtual screening was utilized to screen effective activator targeting PKM2 from ZINC database. Molecular dynamics simulations were performed to evaluate the stability of the small molecule‐binding PKM2 complex systems. Then, cell survival experiments, glutaraldehyde crosslinking reaction, western blot, and qPCR experiments were used to detect the effects of top hits on various cancer cells and the targeting specificity of PKM2. Results: Two small molecules in 1,5‐2H‐pyrrole‐dione were obtained after virtual screening. In vitro experiments demonstrated that ZINC08383544 specifically activated PKM2 and affected the expression of upstream and downstream genes of PKM2 during glycolysis, leading to the inhibition of tumour cell growth. These results indicate that ZINC08383544 conforms to the characteristics of PKM2 activator and is potential to be a novel PKM2 activator as antitumour drug. Discussion: This work proves that ZINC08383544 promotes the formation of PKM2 tetramer, effectively blocks PKM2 nuclear translocation, and inhibits the growth of tumour, and ZINC08383544 may be a novel activator of PKM2. This work may provide a good choice of drug or molecular fragments for the antitumour strategy targeting PKM2. Screening of targeted drugs by combination of virtual screening and bioactivity experiments is a rapid method for drug discovery. [ABSTRACT FROM AUTHOR]