Pharmacokinetics and Safety of Intramuscular Injectable Benzathine Penicillin G in Japanese Healthy Participants.

An intramuscular (IM) suspension of benzathine penicillin G (BPG) has been used as first-line therapy for the treatment of syphilis worldwide since its approval in the 1950s. However, there are limited reports about the pharmacokinetics of BPG. A Phase 1 study was conducted on eight Japanese healthy participants to investigate the pharmacokinetics (samples collected predose to 648 h post-dose) and safety of 2.4 million units of BPG after a single IM injection. Following administration, penicillin G, the active moiety of BPG, was absorbed slowly from the injection site with a median time to Cmax (tmax) of 48 h post-dose. After the achievement of Cmax, concentrations of penicillin G declined slowly in a monophasic fashion with a mean apparent terminal half-life of 189 h. Geometric mean AUCinf and Cmax were 50770 ng•h/mL and 259 ng/mL, respectively. Median time (range) above the well-accepted therapeutic concentration (18 ng/mL) for syphilis treatment was 561 h (439-608 h [18-25 days]), which reached and exceeded the necessary duration of 7-10 days for syphilis treatment. Two participants were underdosed with residual drug left in the syringe due to the high viscosity of the drug product. Only one (12.5%) participant reported a mild adverse event of nasopharyngitis, which was considered not related to the study treatment. The study results supported BPG approval in Japan as an option for syphilis treatment.

MRI-guided cell membrane-camouflaged bimetallic coordination nanoplatform for combined tumor phototherapy.

Nanotechnology for tumor diagnosis and optical therapy has attracted widespread interest due to its low toxicity and convenience but is severely limited due to uncontrollable tumor targeting. In this work, homologous cancer cell membrane-camouflaged multifunctional hybrid metal coordination nanoparticles (DRu/Gd@CM) were prepared for MRI-guided photodynamic therapy (PDT) and photothermal therapy (PTT) of tumors. Bimetallic coordination nanoparticles are composed of three functional modules: dopamine, Ru(dcbpy)3Cl2 and GdCl3, which are connected through 1,4-Bis[(1H-imidazole-1-yl)methyl]benzene (BIX). Their morphology can be easily controlled by adjusting the ratio of precursors. Optimistically, the intrinsic properties of the precursors, including the photothermal properties of polydopamine (PDA), the magnetic resonance (MR) response of Gd3+, and the singlet oxygen generation of Ru(dcbpy)3Cl2, are well preserved in the hybrid metal nanoparticles. Furthermore, the targeting of homologous cancer cell membranes enables these coordinated nanoparticles to precisely target tumor cells. The MR imaging capabilities and the combination of PDT and PTT were demonstrated in in vitro experiments. In addition, in vivo experiments indicated that the nanoplatform showed excellent tumor accumulation and therapeutic effects on mice with subcutaneous tumors, and could effectively eliminate tumors within 14 days. Therefore, it expanded the new horizon for the preparation of modular nanoplatform and imaging-guided optical therapy of tumors.

Rapid visual detection of sulfur dioxide residues in food using acid-sensitive CdTe quantum dots-loaded alginate hydrogel beads.

Acid-sensitive CdTe quantum dots-loaded alginate hydrogel (CdTe QDs-AH) beads were designed for the visual detection of SO2 residues. As proof of concept, two types of CdTe QDs were selected as model probes and embedded in AH beads. The entire test was performed within 25 min in a modified double-layer test tube with one bead fixed above the sample solution. Adding citric acid and heating at 70 ℃ for 20 min transformed the sulfites in the solution into SO2 gas, which then quenched the fluorescence of the CdTe QDs-AH beads. Using this assay, qualitative, naked-eye detection of SO2 residues was achieved in the concentration range of 25-300 ppm, as well as precise quantification was possible based on the difference in the average fluorescence brightness of the beads before and after the reaction. Five food types were successfully analysed using this method, which is simpler and more economical than existing methods, and does not require complex pretreatment.

Radiomic profiling for insular diffuse glioma stratification with distinct biologic pathway activities.

Current literature emphasizes surgical complexities and customized resection for managing insular gliomas; however, radiogenomic investigations into prognostic radiomic traits remain limited. We aimed to develop and validate a radiomic model using multiparametric magnetic resonance imaging (MRI) for prognostic prediction and to reveal the underlying biological mechanisms. Radiomic features from preoperative MRI were utilized to develop and validate a radiomic risk signature (RRS) for insular gliomas, validated through paired MRI and RNA-seq data (N = 39), to identify core pathways underlying the RRS and individual prognostic radiomic features. An 18-feature-based RRS was established for overall survival (OS) prediction. Gene set enrichment analysis (GSEA) and weighted gene coexpression network analysis (WGCNA) were used to identify intersectional pathways. In total, 364 patients with insular gliomas (training set, N = 295; validation set, N = 69) were enrolled. RRS was significantly associated with insular glioma OS (log-rank p = 0.00058; HR = 3.595, 95% CI:1.636-7.898) in the validation set. The radiomic-pathological-clinical model (R-P-CM) displayed enhanced reliability and accuracy in prognostic prediction. The radiogenomic analysis revealed 322 intersectional pathways through GSEA and WGCNA fusion; 13 prognostic radiomic features were significantly correlated with these intersectional pathways. The RRS demonstrated independent predictive value for insular glioma prognosis compared with established clinical and pathological profiles. The biological basis for prognostic radiomic indicators includes immune, proliferative, migratory, metabolic, and cellular biological function-related pathways.

De novo aging-related NADPH diaphorase positive megaloneurites in the sacral spinal cord of aged dogs.

We investigated aging-related changes in nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) in the spinal cord of aged dogs. At all levels of the spinal cord examined, NADPH-d activities were observed in neurons and fibers in the superficial dorsal horn (DH), dorsal gray commissure (DGC) and around the central canal (CC). A significant number of NADPH-d positive macro-diameter fibers, termed megaloneurites, were discovered in the sacral spinal cord (S1-S3) segments of aged dogs. The distribution of megaloneurites was characterized from the dorsal root entry zone (DREZ) into the superficial dorsal horn, along the lateral collateral pathway (LCP) to the region of sacral parasympathetic nucleus (SPN), DGC and around the CC, but not in the cervical, thoracic and lumbar segments. Double staining of NADPH-d histochemistry and immunofluorescence showed that NADPH-d positive megaloneurites co-localized with vasoactive intestinal peptide (VIP) immunoreactivity. We believed that megaloneurites may in part represent visceral afferent projections to the SPN and/or DGC. The NADPH-d megaloneurites in the aged sacral spinal cord indicated some anomalous changes in the neurites, which might account for a disturbance in the aging pathway of the autonomic and sensory nerve in the pelvic visceral organs.

Added value of zoomed-echo-planar imaging diffusion-weighted imaging for evaluation of periampullary carcinomas.

BACKGROUND: To assess the image quality feasibility and diagnostic value of zoomed diffusion-weighted imaging (z-EPI DWI) using echo-planar imaging (EPI) compared with conventional DWI (c-EPI DWI) in patients with periampullary disease. METHODS: Thirty-six patients with periampullary carcinomas and fifteen with benign periampullary disease were included in this study. All the subjects underwent MR cholangiopancreatography (MRCP), c-EPI DWI, and z-EPI DWI. Two radiologists independently assessed image quality of the two image sets, including overall image quality and lesion conspicuity. In addition, signal intensity and ADC measurements of DWIs in the periampullary lesions were conducted. Diagnostic accuracies of the combined image sets of MRCP and z-EPI DWI were compared with those of a combined set of MRCP and c-EPI DWI. RESULTS: z-EPI DWI showed significantly better image quality scores (anatomic structure visualization, 2.94 ± 0.24; overall image quality, 2.96 ± 0.17) compared to that with c-EPI DWI (anatomic structure visualization, 2.02 ± 0.22; overall image quality, 2.04 ± 0.24) (both P < 0.01). For all the periampullary malignant lesions and small lesions (≤ 20 mm), there was better delineation of lesion conspicuity and the lesion margin, as well as diagnostic confidence with z-EPI DWI (all P < 0.05). The rate of periampullary malignancy's hyperintense signal on z-EPI DWI was increased to 91.7% (33/36) compared to c-EPI DWI (69.4% (25/36)) (P = 0.023). For all malignant lesions and small lesions, the diagnostic accuracy scores were increased using the MRCP and z-EPI DWI combined set, compared to the MRCP and c-EPI DWI combined set (P < 0.05). Diagnostic accuracy for detection and differentiation of malignant lesions from benign lesions significantly improved for the MRCP and z-EPI DWI combined set compared with MRCP and c-EPI DWI combined set (P < 0.05). There were no significant differences between c-EPI DWI and z-EPI DWI in the ADC values of periampullary malignant and benign lesions (P > 0.05). CONCLUSIONS: z-EPI DWI has an advantage that could lead to remarkable image quality improvements and enhanced lesion visualization of periampullary carcinomas. z-EPI DWI was superior to c-EPI DWI for detecting, delineating, and diagnosing the lesions, particularly for small challenging lesions.

Associations between dysbiosis gut microbiota and changes of neurotransmitters and short-chain fatty acids in valproic acid model rats.

Introduction: The microbiota-gut-brain axis plays an important role in the pathophysiology of autism spectrum disorder, but its specific mechanisms remain unclear. This study aimed to explore the associations of changes in neurotransmitters and short-chain fatty acids with alterations in gut microbiota in valproic acid model rats. Methods: The autism model rats were established by prenatal exposure to valproic acid (VPA). The Morris water maze test, open field test, and three-chamber test were conducted to assess the behaviors of rats. 16S rRNA gene sequences extracted from fecal samples were used to assess the gut microbial composition. Gas and liquid chromatography-mass spectroscopy was used to identify short-chain fatty acids in fecal samples and neurotransmitters in the prefrontal cortex (PFC). Results: The results showed that 28 bacterial taxa between valproic acid model rats and control rats were identified, and the most differential bacterial taxa in valproic acid model rats and control rats belonged to metagenomic species and Lactobacillus intestinalis. Acetic acid, butyric acid, valeric acid, isobutyric acid, and isovaleric acid were significantly decreased in the valproic acid model rats compared to those in control rats. Five neurotransmitters (threonine, kynurenine, tryptophan, 5-hydroxyindoleacetic acid, denoted as 5-HIAA, and betaine aldehyde chloride, denoted as BAC) were significantly decreased, whereas betaine was increased in the prefrontal cortex of valproic acid model rats compared to control rats. A variety of neurotransmitters (≥4) were correlated with Pseudomonas, Collisella, and Streptococcus at the genus level, and they were also related to the decrease of short-chain fatty acids. Discussion: According to this study, we can preliminarily infer that gut microbiota or their metabolic productions (such as SCFAs) may influence central neurotransmitter metabolism through related pathways of the gut-brain axis. These results provide microbial and short-chain fatty acid (SCFA) frameworks for understanding the role of the microbiota-gut-brain axis in autism spectrum disorder and shed new light on autism spectrum disorder treatment.

A survey study on early detection of young children with disabilities in urban and rural areas of China.

AIM: This study aimed to understand how children and families access early intervention in China. BACKGROUND: Timely identification and high-quality intervention is expected to prevent and reduce the occurrence and severity of chronic functional impairment for children with disability and is of great significance to individuals and the society. The current study recruited 1129 caregivers of children with disabilities from rural and urban areas of China were recruited to participate in a survey. RESULTS: (a) The first concern about development was raised, usually by the parents, when a child with disabilities was 26 months of age, (b) developmental screening took place 4 months after the first concern and diagnostic evaluation happened 7 months after, (c) the types of early intervention programme varied across urban and rural areas and (d) child and family factors were found associating with age of detection. CONCLUSIONS: Findings highlight the concerningly late age of children being identified for early intervention and disparities in services between urban and rural areas in China. Implications are provided for practitioners, policy makers and future research.

The association of coagulation indicators with in-hospital acute kidney injury and malignant events of patients with acute aortic dissection: a retrospective cohort study.

Background: Acute kidney injury (AKI) is a prevalent complication of acute aortic dissection (AAD) and is associated with poor outcomes. The onset of AAD may result in endothelial injury due to the formation of the false lumen, which can activate the coagulation pathway and lead to coagulation dysfunction. It serves as a valuable diagnostic and prognostic marker for AAD, but also plays a role in the pathological mechanisms underlying AKI. We aimed to investigate the potential value of coagulation indicators at admission for assessing in-hospital AKI and malignant events after AAD. Methods: We identified patients with AAD admitted to the First Affiliated Hospital of Shantou University Medical College from January 2015 to October 2020 and divided them into two groups according to coagulation function. Univariable and multivariable analyses were used to analyze the association between coagulation indicators and AKI and malignant events in patients with AAD. Chi-squared or Fisher exact test and receiver operating characteristic (ROC) curve analysis was conducted to assess the value of coagulation indicators in predicting in-hospital AKI and malignant events. Results: A total of 487 patients were enrolled in this study, including 309 cases with normal coagulation. After the multivariable adjustment, the incidence of in-hospital AKI in the abnormal coagulation group was significantly higher [model 1: 2.061 (1.214-3.501), P=0.007; model 2: 1.833 (1.058-3.177), P=0.031; model 3: 1.836 (1.048-3.216), P=0.034]. The incidence of malignant events was higher in the abnormal prothrombin time (PT) group [model 1: 4.283 (0.983-18.665), P=0.053; model 2: 7.342 (1.467-36.749), P=0.015; model 3: 6.996 (1.377-35.537), P=0.019]. Chi-squared and Fisher exact test showed that PT and abnormal coagulation score (ACS) were statistically different among the AKI groups and malignant event groups. Under ROC analysis, coagulation indicators were helpful to predict AKI (AUC =0.668; P<0.001). Conclusions: Our study confirmed the presence of coagulation dysfunction is associated with an increased risk of AKI and malignant events. It suggested the severity of coagulation dysfunction is positively correlated with the incidence of in-hospital AKI in AAD patients. These results highlight the importance of considering coagulation dysfunction as a potential mechanism underlying AKI and malignant events after AAD.

Bibliometric study of neuroinflammation in autism spectrum disorder.

Background: Neuroinflammation is closely associated with the occurrence and development of autism spectrum disorder (ASD). This study aims to describe the global development history and current status of neuroinflammation in ASD from 2004 to 2021 and reveal the research hotspots and frontiers to provide a reference for scholars in related fields to carry out further research. Methods: Journal articles on ASD and neuroinflammation-related research were obtained from the Web of Science Core Collection (WOSCC) database from its inception to 2021. Literature was analyzed visually by VOSviewer, CiteSpace, and R language, including publication analysis, author, institution, national/regional cooperative network analysis, and keyword analysis. We screened the most accumulatively cited 10 experimental papers in the field and the most cited 10 experimental papers in the last 2 years (2020 and 2021) for combing. Results: A total of 620 publications were included in this study, and the number of publications has increased in recent years. The United States (256, 41.29%) was the country with the largest number of publications. King Saud University (40, 6.45%) was the most published institution; Laila Al-Ayadhi Yousef was the most published researcher; the Brain Behavior and Immunity was the main journal for the study of neuroinflammation in autism, having published 22 related articles. Keyword co-occurrence analysis showed that short chain fatty acid, mast cells, and glial cells have been the focus of recent attention. Burst keywords show that gut microbiota and immune system are the future research trends. Conclusion: This bibliometric study describes the basic framework for the development in the field of neuroinflammation and ASD through an exploration of key indicators (countries, institutions, journals, authors, and keywords). We found that the key role of neuroinflammation in the development of ASD is attracting more and more researchers' attention. Future studies can investigate the changes in cytokines and glial cells and their related pathways in ASD neuroinflammation. Immunotherapy to inhibit neuroinflammation may be intensively studied as a direction for ASD treatment or intervention.

Reliability and validity of the East Asian children's version of mini-MACS in children with cerebral palsy.

Background: Mini-Manual Ability Classification System (Mini-MACS) was developed for children with cerebral palsy aged 1-4 years, but its validity and reliability in different cultures are unavailable yet. This study was to determine the reliability and validity of Mini-MACS in East Asian children with cerebral palsy and investigate the correlation between Mini-MACS and Gross Motor Function Classification System. Methods: One hundred and four East Asian children with cerebral palsy aged 12-48 months were classified by one of their parents, an occupational therapist, and a physical therapist with Mini-MACS. The results were analyzed for inter-rater reliability by using intraclass correlation coefficient (ICC). The Nine-hole Peg Test was used for the criterion-related validity analysis, and parents retested their children after 2 weeks to evaluate test-retest reliability. Gross Motor Function Classification System levels were also collected to investigate the correlation with Mini-MACS. Results: Good inter-rater reliability among the occupational therapist, physical therapist, and parents was found [ICC = 0.984 (95% confidence interval, CI, 0.976-0.989), 0.973 (95% CI 0.960-0.982), and 0.966 (95% CI 0.950-0.977), respectively; p < 0.01]. The test-retest reliability in parents was almost perfect [ICC = 0.985 (95% CI 0.977-0.990), p < 0.01]. Mini-MACS had consistency with the Nine-hole Peg Test (r = 0.582, 0.581, and 0.566, respectively; p < 0.01). A correlation was found between Gross Motor Function Classification System and Mini-MACS (r = 0.626, 0.596, and 0.598, respectively; p < 0.01). Conclusion: The Mini-MACS demonstrates evidence that it is a valid and reliable tool to classify manual ability in East Asian children with cerebral palsy and is also positively related to the Gross Motor Function Classification System.

Corrigendum: The evaluation of zoomed echo-planar diffusion-weighted magnetic resonance imaging with two-dimensional spatial-selective radiofrequency excitation pulses in patients with hilar cholangiocarcinoma.

[This corrects the article DOI: 10.3389/fonc.2022.816008.].

The Evaluation of Zoomed Echo-Planar Diffusion-Weighted Magnetic Resonance Imaging With Two-dimensional Spatial-Selective Radiofrequency Excitation Pulses in Patients With Hilar Cholangiocarcinoma.

Background: We aimed to investigate the feasibility and application of using the zoomed diffusion-weighted echo-planar imaging (z-EPI DWI) sequences for hilar cholangiocarcinoma assessment compared with conventional single-shot EPI diffusion-weighted imaging (c-EPI DWI). Methods: Both c-EPI DWI and z-EPI DWI were preoperatively performed in 16 patients with histopathologically-confirmed hilar cholangiocarcinoma. A two-dimensional spatial-selective radiofrequency (RF) pulse was applied to the z-EPI DWI using an echo-planar transmit trajectory. Anatomic structural visualization, lesion conspicuity, artifact presence and overall image quality were evaluated and compared between the two sequence images. The ratio of differences regarding hilar cholangiocarcinoma lesion sizes measured on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) were compared from both EPI techniques. The DW images for tumor involvement of the bile duct were reviewed based on histopathological examination of the surgical intraoperative evaluation. ADC measurements of DWIs in the hilar cholangiocarcinoma lesions were conducted. Results: The hepatic hilar region was better delineated by visualization of anatomical structures, lesion conspicuity and overall image quality using the z-EPI DWI and these analyses were compared with the c-EPI DWI method (all p<0.05). Better lesion delineation of bile duct walls and lumens was noted in four patients with z-EPI DWI compared with those of c-EPI DWI. No significant differences were noted between the two image datasets for artifacts (p=0.876). The ratio of differences regarding hilar cholangiocarcinoma lesion sizes was significantly lower (p= 0.018) on T2WI and DWI, as determined by the z-EPI DWI than that determined by the c-EPI method. The use of z-EPI DWI resulted in the accurate diagnosis of the Bismuth-Corlette classification of 15 tumors (15/16, 93.75%), whereas the use of c-EPI DWI resulted in correct diagnosis of 12 tumors (12/16, 75.00%). There were no significant differences between c-EPI DWI and z-EPI DWI in the ADC values of hilar cholangiocarcinoma lesions (p= 0.48). Conclusion: z-EPI DWI resulted in remarkable image quality improvements for hilar cholangiocarcinoma. The ability to detect and delineate lesions using z-EPI DWI was superior to that of c-EPI DWI.

Apparent Diffusion Coefficient Map-Based Radiomics Features for Differential Diagnosis of Pleomorphic Adenomas and Warthin Tumors From Malignant Tumors.

Purpose: The magnetic resonance imaging (MRI) findings may overlap due to the complex content of parotid gland tumors and the differentiation level of malignant tumor (MT); consequently, patients may undergo diagnostic lobectomy. This study assessed whether radiomics features could noninvasively stratify parotid gland tumors accurately based on apparent diffusion coefficient (ADC) maps. Methods: This study examined diffusion-weighted imaging (DWI) obtained with echo planar imaging sequences. Eighty-eight benign tumors (BTs) [54 pleomorphic adenomas (PAs) and 34 Warthin tumors (WTs)] and 42 MTs of the parotid gland were enrolled. Each case was randomly divided into training and testing cohorts at a ratio of 7:3 and then was compared with each other, respectively. ADC maps were digitally transferred to ITK SNAP (www.itksnap.org). The region of interest (ROI) was manually drawn around the whole tumor margin on each slice of ADC maps. After feature extraction, the Synthetic Minority Oversampling TEchnique (SMOTE) was used to remove the unbalance of the training dataset. Then, we applied the normalization process to the feature matrix. To reduce the similarity of each feature pair, we calculated the Pearson correlation coefficient (PCC) value of each feature pair and eliminated one of them if the PCC value was larger than 0.95. Then, recursive feature elimination (RFE) was used to process feature selection. After that, we used linear discriminant analysis (LDA) as the classifier. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of the ADC. Results: The LDA model based on 13, 8, 3, and 1 features can get the highest area under the ROC curve (AUC) in differentiating BT from MT, PA from WT, PA from MT, and WT from MT on the validation dataset, respectively. Accordingly, the AUC and the accuracy of the model on the testing set achieve 0.7637 and 73.17%, 0.925 and 92.31%, 0.8077 and 75.86%, and 0.5923 and 65.22%, respectively. Conclusion: The ADC-based radiomics features may be used to assist clinicians for differential diagnosis of PA and WT from MTs.

L-theanine protects rat kidney from D-galactose-induced injury via inhibition of the AGEs/RAGE signaling pathway.

As the irreversible products of the non-enzymatic reduction of sugars and the amino groups of proteins or peptides, advanced glycation end products (AGEs) are metabolized and excreted via the kidneys. However, if AGEs are not metabolized, they are deposited in the kidneys and bind to AGE receptors (RAGE), which can induce various pathological changes, including oxidative stress, apoptosis, and inflammation. This study used the D-galactose (DG)-induced rat model to explore the potential role and mechanism of L-theanine in inhibiting AGEs/RAGE-related signaling pathways in renal tissues. L-theanine increased the activities of glutathione peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) while downregulating the contents of malondialdehyde (MDA) and AGEs in renal tissues induced by DG (P < 0.05). By inhibiting the upregulation of RAGE protein expression attributed to AGEs accumulation (P < 0.05), L-theanine downregulated phosphorylated nuclear factor (p-NF-κB (p65)), Bax, and cleaved-caspase-3 expression and increased Bcl-2 protein expression (P < 0.05), thereby alleviating the oxidative stress damage and reducing the inflammation and cell injury induced by DG. In addition, the Congo red staining section of renal tissue also showed that the natural product L-theanine can protect against AGEs-induced renal damage in DG-induced rat model.

Differentiation of Diffuse Infiltration Pattern in Multiple Myeloma From Hyperplastic Hematopoietic Bone Marrow: Qualitative and Quantitative Analysis Using Whole-Body MRI.

BACKGROUND: The visual assessment used for diffuse infiltration of multiple myeloma (MM) is inadequate. It can be difficult to differentiate MM from hyperplastic hematopoietic bone marrow (HHBM) because the MRI signal characteristics overlap. PURPOSE: To analyze the bone marrow diffuse signal changes on whole-body MRI caused by MM and HHBM. STUDY TYPE: Retrospective. SUBJECTS: Thirty Four patients with MM (21 men and 13 women), 22 patients with HHBM (9 men and 13 women), and 15 healthy controls (9 men and 6 women). FIELD STRENGTH/SEQUENCE: A 3.0 T MRI; diffusion-weighted whole-body imaging with background body signal suppression (DWIBS), modified Dixon T1 fast field echo, and T2 STIR. ASSESSMENT: Three radiologists analyzed the whole-body MRI alone and in combination with apparent diffusion coefficient (ADC) and fat fraction (FF) with qualitative and quantitative analysis. Normalized T1 and T2 signal intensities (nT1 and nT2) and signal-to-noise ratio (SNR) were obtained. STATISTICAL TESTS: Kruskal-Wallis and chi-square tests. RESULTS: The MM group had significantly higher ADC and significantly lower FF than HHBM and control groups. There was no significant difference in nT1, nT2 or SNR between MM and HHBM (P = 0.932, P = 0.097, and P = 0.110, respectively). Receiver operating characteristic (ROC) analysis using ADC and FF cut-off values of 0.47 × 10-3  mm2 /sec and 20.63%, respectively. The AUC was 0.866 for ADC and 0.886 for FF. The quantitative analysis yielded better specificity (observer 1: 81.8% vs. 27.3%; observer 2: 68.2% vs. 22.7%; and observer 3: 72.7% vs. 18.2%) and a higher diagnostic accuracy (observer 1: 82.1% vs. 51.8%; observer 2: 80.4% vs. 50.0%; observer 3: 76.8% vs. 44.6%) than the qualitative analysis. DATA CONCLUSION: Whole-body MRI combined with DWIBS and mDIXON could be used to differentiate between MM and HHBM. Combining the quantitative ADC and FF with the whole-body MRI improved the specificity and accuracy in differentiating these conditions. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Evaluation of Diffuse Bone Marrow Infiltration Pattern in Monoclonal Plasma Cell Diseases by Quantitative Whole-body Magnetic Resonance Imaging.

RATIONALE AND OBJECTIVES: To analyze diffuse infiltration pattern in monoclonal plasma cell diseases by diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) and quantitative chemical-shift encoded MRI. MATERIALS AND METHODS: Ninety-nine patients with monoclonal plasma cell diseases and 15 healthy control subjects were retrospectively analyzed. All patients underwent whole-body MRI (including DWIBS and mDIXON Quant) and were divided into three groups: monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM). Apparent diffusion coefficient (ADC), fat fraction (FF), and T2* values for each group were calculated then analyzed by one-way ANOVA and receiver operating characteristic curve. Correlations of ADC, FF, and T2* with clinical indices were analyzed with Spearman correlation test. RESULTS: The ADC and T2* values of MM were significantly higher than those of the healthy control, MGUS and SMM (ADC: p = 0.003, p = 0.003, and p = 0.042; T2*: all with p < 0.001). The FF values of MM were significantly lower than those of the healthy control, MGUS and SMM (p < 0.001, p < 0.001 and p = 0.034). The ADC, FF, and T2* thresholds for recognizing MM and MGUS+SMM were 0.51 × 10-3 mm2/s, 31.14%, and 10.53 ms, respectively. The ADC, FF, and T2* values were identified to be significantly associated with bone marrow plasma cells and hemoglobin in patients (all with p < 0.001). CONCLUSION: ADC, FF, and T2* were significantly correlated with clinical indices related to monoclonal plasma cell diseases. MM with the diffuse infiltration pattern can be distinguished more objectively from MGUS and SMM by quantitative functional MRI parameters.

L-Theanine Regulates the Abundance of Amino Acid Transporters in Mice Duodenum and Jejunum via the mTOR Signaling Pathway.

The intestine is a key organ for the absorption of amino acids. L-theanine (LTA) is a structural analog of glutamine and a characteristic non-protein amino acid found in tea (Camellia sinensis) that regulates lipid and protein metabolism. The present study explored the role of LTA in intestinal amino acid absorption, protein synthesis, and its mechanisms. Overall, our findings suggest that LTA supplementation not only affects serum alkaline phosphatase (AKP), total protein (TP), and urea nitrogen (BUN) levels, but it also upregulates the mRNA and protein expression of amino acid transporters (EAAT3, EAAT1, 4F2hc, y+LAT1, CAT1, ASCT2, and B0AT1), and activates the mTOR signaling pathway. The downstream S6 and S6K1 proteins are regulated, and the expression of amino acid transporters is regulated. These findings suggest that LTA increases intestinal AA absorption, promotes protein metabolism, and increases nitrogen utilization by upregulating AAT expression, activating the mTOR signaling pathway, and phosphorylating the mTOR downstream proteins S6 and S6K1.

Assessment of the Utility of Physiologically-based Pharmacokinetic Model for prediction of Pharmacokinetics in Chinese and Japanese Populations.

The objective for the present analyses was to evaluate the utility of physiologically-based pharmacokinetic (PBPK) modeling for prediction of the pharmacokinetics (PK) in Chinese and Japanese populations with a panel of Pfizer internal compounds. Twelve compounds from Pfizer internal development pipeline with available Westerner PK data and available PK data in at least one of the subpopulations of Japanese and Chinese populations were identified and included in the current analysis. These selected compounds represent various elimination pathways across different therapeutic areas. The Simcyp® PBPK simulator was used to develop and verify the PBPK models of individual compounds. The developed models for these compounds were verified by using the clinical PK data in Westerners. The verified PBPK models were further used to predict the PK of these compounds in Chinese and Japanese populations and the predicted PK parameters were compared with the observed PK parameters. Ten of the 12 compounds had PK data in Chinese, and all the 12 compounds had PK data in Japanese. In general, the PBPK models performed well in predicting PK in Chinese and Japanese, with 8 of 10 drugs in Chinese and 7 of 12 drugs in Japanese has AAFE values less than 1.25-fold. PBPK-guided predictions of the relative PK difference were successful for 75% and 50%, respectively, between Chinese and Western and between Japanese and Western of the tested drugs using 0.8-1.25 as criteria. In conclusion, well verified PBPK models developed using data from Westerners can be used to predict the PK in Chinese and Japanese populations.

Role of Epigallocatechin Gallate in Glucose, Lipid, and Protein Metabolism and L-Theanine in the Metabolism-Regulatory Effects of Epigallocatechin Gallate.

Epigallocatechin gallate (EGCG) and L-theanine (LTA) are important bioactive components in tea that have shown promising effects on nutrient metabolism. However, whether EGCG alone or combined with LTA can regulate the glucose, lipid, and protein metabolism of healthy rats remains unclear. Therefore, we treated healthy rats with EGCG or the combination of EGCG and LTA (EGCG+LTA) to investigate the effects of EGCG on nutrient metabolism and the role of LTA in the metabolism-regulatory effects of EGCG. The results showed that compared with the control group, EGCG activated insulin and AMP-activated protein kinase (AMPK) signals, thus regulating glucose, lipid, and protein metabolism. Compared with EGCG, EGCG+LTA enhanced hepatic and muscle glycogen levels and suppressed phosphorylation of AMPK, glycogen synthase 2, mammalian target of rapamycin, and ribosomal protein S6 kinase. In addition, EGCG+LTA inhibited the expression of liver kinase B1, insulin receptor and insulin receptor substrate, and promoted the phosphorylation level of acetyl-CoA carboxylase. Furthermore, both EGCG and EGCG+LTA were harmless for young rats. In conclusion, EGCG activated AMPK and insulin pathways, thereby promoting glycolysis, glycogen, and protein synthesis and inhibiting fatty acid (FA) and cholesterol synthesis. However, LTA cooperated with EGCG to promote glycogen metabolism and suppressed the effect EGCG on FA and protein synthesis via AMPK signals.