Comparison of the Plasma Metabolome Profiles Between the Internal Thoracic Artery and Ascending Aorta in Patients Undergoing Coronary Artery Bypass Graft Surgery Using Gas Chromatography Time-of-Flight Mass Spectrometry.

BackgroundThe left internal thoracic artery (LITA) has been used as the first conduit of choice in coronary artery bypass grafting (CABG) because of excellent long-term patency and outcomes. However, no studies have examined substances other than nitric oxide that could be beneficial for the bypass conduit, native coronary artery or ischemic myocardium. This study was conducted to evaluate differences in metabolic profiles between the LITA and ascending aorta using gas chromatography-time of flight-mass spectrometry (GC-TOF-MS).MethodsTwenty patients who underwent CABG using the LITA were prospectively enrolled. Plasma samples were collected simultaneously from the LITA and ascending aorta. GC-TOF-MS based untargeted metabolomic analyses were performed and a 2-step volcano plot analysis was used to identify distinguishable markers from two plasma metabolome profiles. Semi-quantitative and quantitative analyses were performed using GC-TOF-MS and enzyme-linked immunosorbent assay, respectively, after selecting target metabolites based on the metabolite set enrichment analysis.ResultsInitial volcano plot analysis demonstrated 5 possible markers among 851 peaks detected. The final analysis demonstrated that the L-cysteine peak was significantly higher in the LITA than in the ascending aorta (fold change = 1.86). The concentrations of intermediate metabolites such as L-cysteine, L-methionine and L-cystine in the 'cysteine and methionine metabolism pathway' were significantly higher in the LITA than in the ascending aorta (2.0-, 1.4- and 1.2-fold, respectively). Quantitative analysis showed that the concentration of hydrogen sulfide (H₂S) was significantly higher in the LITA.ConclusionThe plasma metabolome profiles of the LITA and ascending aorta were different, particularly higher plasma concentrations of L-cysteine and H₂S in the LITA

Make Prompts Adaptable: Bayesian Modeling for Vision-Language Prompt Learning with Data-Dependent Prior

Recent Vision-Language Pretrained (VLP) models have become the backbone for many downstream tasks, but they are utilized as frozen model without learning. Prompt learning is a method to improve the pre-trained VLP model by adding a learnable context vector to the inputs of the text encoder. In a few-shot learning scenario of the downstream task, MLE training can lead the context vector to over-fit dominant image features in the training data. This overfitting can potentially harm the generalization ability, especially in the presence of a distribution shift between the training and test dataset. This paper presents a Bayesian-based framework of prompt learning, which could alleviate the overfitting issues on few-shot learning application and increase the adaptability of prompts on unseen instances. Specifically, modeling data-dependent prior enhances the adaptability of text features for both seen and unseen image features without the trade-off of performance between them. Based on the Bayesian framework, we utilize the Wasserstein Gradient Flow in the estimation of our target posterior distribution, which enables our prompt to be flexible in capturing the complex modes of image features. We demonstrate the effectiveness of our method on benchmark datasets for several experiments by showing statistically significant improvements on performance compared to existing methods. The code is available at https://github.com/youngjae-cho/APP.Comment: Accepted to AAAI-202

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimers disease animal model

Alzheimers disease (AD) is the most common neurodegenerative disease characterized by memory loss and the presence of amyloid plaques and neurofibrillary tangles in the patients brains. In this study, we investigated the alterations in metabolite profiles of the hippocampal tissues from 6, 8, and 12 month-old wild-type (WT) and 5xfamiliar AD (5xFAD) mice, an AD mouse model harboring 5 early-onset familiar AD mutations, which shows memory loss from approximately 5 months of age, by exploiting the untargeted metabolomics profiling. We found that nicotinamide and adenosine monophosphate levels have been significantly decreased while lysophosphatidylcholine (LysoPC) (16:0), LysoPC (18:0), and lysophosphatidylethanolamine (LysoPE) (16:0) levels have been significantly increased in the hippocampi from 5xFAD mice at 8 months or 12 months of age, compared to those from age-matched wild-type mice. In the present study, we focused on the role of nicotinamide and examined if replenishment of nicotinamide exerts attenuating effects on the reduction in dendritic spine density in hippocampal primary neurons from 5xFAD mice. Treatment with nicotinamide attenuated the deficits in spine density in the hippocampal primary neurons derived from 5xFAD mice, indicating a potential role of nicotinamide in the pathogenesis of AD. Taken together, these findings suggest that the decreased hippocampal nicotinamide level could be linked with AD pathogenesis and be a useful therapeutic target for AD.This study was financially supported by the National Research Foundation of Korea (NRF) grant, funded by the Korean Government (2016R1A2B4012232) and also partly supported by Seoul National University Bundang Hospital Research Fund, South Korea (02–2013-015). HJ.K. received a scholarship from the BK21-Plus Education Program provided by the National Research Foundation of Korea

Elevated matrix metalloproteinase-9 in patients with systemic sclerosis

Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of cancer, autoimmune disease, and various pathologic conditions characterized by excessive fibrosis. In this study, we investigated the expression of MMP-9 and its clinical significance in systemic sclerosis (SSc). The patients (n = 42) with SSc had higher concentrations of MMP-9 and of tissue inhibitor of metalloproteinase-1 (TIMP-1) and a higher ratio of MMP-9 to TIMP-1 in sera than healthy controls (n = 32). Serum MMP-9 concentrations were significantly higher in the diffuse type (n = 23) than the limited type of SSc (n = 19). Serum concentrations of MMP-9 correlated well with the degree of skin involvement, as determined by the Rodnan score and with serum concentrations of transforming growth factor β. Moreover, dermal fibroblasts from patients with SSc produced more MMP-9 than those from healthy controls when they were stimulated with IL-1β, tumor necrosis factor α, or transforming growth factor β. Such an increase in MMP-9 production was partially blocked by treatment with cyclosporin A. In summary, the serum MMP-9 concentrations were elevated in SSc patients and correlated well with skin scores. The increased MMP-9 concentrations may be attributable to overproduction by dermal fibroblasts in SSc. These findings suggest that the enhanced production of MMP-9 may contribute to fibrogenic remodeling during the progression of skin sclerosis in SSc

Endogenous metabolic markers for predicting the activity of dihydropyrimidine dehydrogenase

Five-fluorouracil (5-FU) is a chemotherapeutic agent that is mainly metabolized by the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). The DPD enzyme activity deficiency involves a wide range of severities. Previous studies have demonstrated the effect of a DPYD single nucleotide polymorphism on 5-FU efficacy and highlighted the importance of studying such genes for cancer treatment. Common polymorphisms of DPYD in European ancestry populations are less frequently present in Koreans. DPD is also responsible for the conversion of endogenous uracil (U) into dihydrouracil (DHU). We quantified U and DHU in plasma samples of healthy male Korean subjects, and samples were classified into two groups based on DHU/U ratio. The calculated DHU/U ratios ranged from 0.52 to 7.12, and the two groups were classified into the 10th percentile and 90th percentile for untargeted metabolomics analysis using liquid chromatography-quantitative time-of-flight-mass spectrometry. A total of 4440 compounds were detected and filtered out based on a coefficient of variation below 30%. Our results revealed that six metabolites differed significantly between the high activity group and low activity group (false discovery rate q-value \u3c 0.05). Uridine was significantly higher in the low DPD activity group and is a precursor of U involved in pyrimidine metabolism; therefore, we speculated that DPD deficiency can influence uridine levels in plasma. Furthermore, the cutoff values for detecting DPD deficient patients from previous studies were unsuitable for Koreans. Our metabolomics approach is the first study that reported the DHU/U ratio distribution in healthy Korean subjects and identified a new biomarker of DPD deficiency

Impact of vancomycin-induced changes in the intestinal microbiota on the pharmacokinetics of simvastatin

The pharmacokinetic (PK) properties of drugs are affected in several ways by interactions with microbiota. The aim of this study was to investigate the effects of oral vancomycin on the gut microbiota and, consequently, on the PKs of simvastatin. An open-label, single arm, sequential crossover study was conducted in six healthy Korean male subjects. After 6 days on a control diet, simvastatin 40 mg was orally administered to the subjects before and after 1 week of oral vancomycin treatment. Blood samples for PK analysis and fecal samples for metagenomic and metabolomic analyses were collected. After vancomycin treatment, the richness of microbiota considerably decreased, and the composition was altered. In particular, the relative abundance of Bacteroidetes decreased, whereas that of proteobacteria increased. In addition, changes in fecal metabolites, including D-glucuronic acid, were observed. However, systemic exposure of simvastatin was not changed whereas that of hydroxysimvastatin showed a tendency to increase. The relationship between the change of PKs of simvastatin and the change of gut microbiota and fecal metabolites were not clearly observed

Accidental intradural injection during attempted epidural block -A case report-

Several cases of accidental subdural injection have been reported, but only few of them are known to be accidental intradural injection during epidural block. Therefore we would like to report our experience of accidental intradural injection. A 68-year-old female was referred to our pain clinic due to severe metastatic spinal pain. We performed a diagnostic epidural injection at T9/10 interspace under the C-arm guided X-ray view. Unlike the usual process of block, onset was delayed and sensory dermatomes were irregular range. We found out a dense collection of localized radio-opaque contrast media on the reviewed X-ray findings. These are characteristic of intradural injection and clearly different from the narrow wispy bands of contrast in the subdural space

Changes in the gut microbiome influence the hypoglycemic effect of metformin through the altered metabolism of branched-chain and nonessential amino acids

AIMS: Although metformin has been reported to affect the gut microbiome, the mechanism has not been fully determined. We explained the potential underlying mechanisms of metformin through a multiomics approach. METHODS: An open-label and single-arm clinical trial involving 20 healthy Korean was conducted. Serum glucose and insulin concentrations were measured, and stool samples were collected to analyze the microbiome. Untargeted metabolomic profiling of plasma, urine, and stool samples was performed by GC-TOF-MS. Network analysis was applied to infer the mechanism of the hypoglycemic effect of metformin. RESULTS: The relative abundances of Escherichia, Romboutsia, Intestinibacter, and Clostridium were changed by metformin treatment. Additionally, the relative abundances of metabolites, including carbohydrates, amino acids, and fatty acids, were changed. These changes were correlated with energy metabolism, gluconeogenesis, and branched-chain amino acid metabolism, which are major metabolic pathways related to the hypoglycemic effect. CONCLUSIONS: We observed that specific changes in metabolites may affect hypoglycemic effects through both pathways related to AMPK activation and microbial changes. Energy metabolism was mainly related to hypoglycemic effects. In particular, branched-chain amino acid metabolism and gluconeogenesis were related to microbial metabolites. Our results will help uncover the potential underlying mechanisms of metformin through AMPK and the microbiome