Cardiogenic shock in a 28-year-old woman associated with sibutramine use.

A 28-year-old woman collapsed in her home, and her companion rushed to call emergency services. Upon arrival, a physician performed CPR and endotracheal intubation, successfully restoring her voluntary heart rhythm. However, while en route to the hospital, ventricular fibrillation recurred. Despite the restoration of her voluntary rhythm through electrical defibrillation, she remained in a comatose state, which eventually led to multiple organ failures. Family members revealed that she had a 2-month history of taking diet pills. Histological examination revealed cardiomyocyte necrosis, contraction band necrosis, interstitial hemorrhage, collagen deposition, interstitial fiber proliferation, and myofiber remodeling. Analysis of blood and urine using GC-MS and LC-MS detected sibutramine and its primary metabolites, M1 and M2, which were consistent with the composition of the medication she was taking. The deceased was in good health with no underlying heart disease. The above information confirmed that the cause of her death was sibutramine.

Double-Balanced Loss for Imbalanced Colorectal Lesion Classification.

Colorectal cancer has a high incidence rate in all countries around the world, and the survival rate of patients is improved by early detection. With the development of object detection technology based on deep learning, computer-aided diagnosis of colonoscopy medical images becomes a reality, which can effectively reduce the occurrence of missed diagnosis and misdiagnosis. In medical image recognition, the assumption that training samples follow independent identical distribution (IID) is the key to the high accuracy of deep learning. However, the classification of medical images is unbalanced in most cases. This paper proposes a new loss function named the double-balanced loss function for the deep learning model, to improve the impact of datasets on classification accuracy. It introduces the effects of sample size and sample difficulty to the loss calculation and deals with both sample size imbalance and sample difficulty imbalance. And it combines with deep learning to build the medical diagnosis model for colorectal cancer. Experimentally verified by three colorectal white-light endoscopic image datasets, the double-balanced loss function proposed in this paper has better performance on the imbalance classification problem of colorectal medical images.

SARS-CoV-2 in the pancreas and the impaired islet function in COVID-19 patients.

Diabetes mellitus (DM) is one of the most common underlying diseases that may aggravates COVID-19. In the present study, we explored islet function, the presence of SARS-CoV-2 and pathological changes in the pancreas of patients with COVID-19. Oral glucose tolerance tests (OGTTs) and the C-peptide release test demonstrated a decrease in glucose-stimulated C-peptide secretory capacity and an increase in HbA1c levels in patients with COVID-19. The prediabetic conditions appeared to be more significant in the severe group than in the moderate group. SARS-CoV-2 receptors (ACE2, CD147, TMPRSS2 and neuropilin-1) were expressed in pancreatic tissue. In addition to SARS-CoV-2 virus spike protein and virus RNA, coronavirus-like particles were present in the autophagolysosomes of pancreatic acinar cells of a patient with COVID-19. Furthermore, the expression and distribution of various proteins in pancreatic islets of patients with COVID-19 were altered. These data suggest that SARS-CoV-2 in the pancreas may directly or indirectly impair islet function.

White-Light Endoscopic Colorectal Lesion Detection Based on Improved YOLOv5.

As an effective tool for colorectal lesion detection, it is still difficult to avoid the phenomenon of missed and false detection when using white-light endoscopy. In order to improve the lesion detection rate of colorectal cancer patients, this paper proposes a real-time lesion diagnosis model (YOLOv5x-CG) based on YOLOv5 improvement. In this diagnostic model, colorectal lesions were subdivided into three categories: micropolyps, adenomas, and cancer. In the course of convolutional network training, Mosaic data enhancement strategy was used to improve the detection rate of small target polyps. At the same time, coordinate attention (CA) mechanism was introduced to take into account channel and location information in the network, so as to realize the effective extraction of three kinds of pathological features. The Ghost module was also used to generate more feature maps through linear processing, which reduces the stress of learning model parameters and speeds up detection. The experimental results show that the lesion diagnosis model proposed in this paper has a more rapid and accurate lesion detection ability, and the AP value of polyps, adenomas, and cancer is 0.923, 0.955, and 0.87, and mAP@50 is 0.916.

Biotransformation of Polyphenols in Apple Pomace Fermented by ß-Glucosidase-Producing Lactobacillus rhamnosus L08.

Apple pomace, the main by-product in apple processing, is a cheap source of bioactive compounds that could be used in the food industry. However, the value of this by-product is still far from being fully realized. In this study, 11 strains of Lactobacillus strains were assayed for ß-glucosidase activity, and only Lactobacillus rhamnosus L08 (L. rhamnosus L08) showed high cell-membrane associated ß-glucosidase activity. We then evaluated the effects of fermentation of apple pomace using the selected strain, focusing on the biotransformation of polyphenols and antioxidant capacity. We found that L. rhamnosus L08 fermentation significantly reduced the contents of quercitrin and phlorizin in apple pomace, while increasing the contents of quercetin and phloretin. The contents of gallic acid, epicatechin acid, caffeic acid, and ferulic acid were also increased in apple pomace after fermentation. In addition, the antioxidant activities of apple pomace were enhanced during fermentation, based on the bioconversion of phenolic profiles. Our results demonstrate that lactic acid bacteria fermentation is a promising approach to enhance the bioactivity of phenolic compounds in apple pomace. Moreover, this study demonstrates that, as a valuable processing by-product with bioactive components, apple pomace can be used in the food industry to provide economic benefits.

Application of Deep Learning for Early Screening of Colorectal Precancerous Lesions under White Light Endoscopy.

METHODS: We collected and sorted out the white light endoscopic images of some patients undergoing colonoscopy. The convolutional neural network model is used to detect whether the image contains lesions: CRC, colorectal adenoma (CRA), and colorectal polyps. The accuracy, sensitivity, and specificity rates are used as indicators to evaluate the model. Then, the instance segmentation model is used to locate and classify the lesions on the images containing lesions, and mAP (mean average precision), AP50, and AP75 are used to evaluate the performance of an instance segmentation model. RESULTS: In the process of detecting whether the image contains lesions, we compared ResNet50 with the other four models, that is, AlexNet, VGG19, ResNet18, and GoogLeNet. The result is that ResNet50 performs better than several other models. It scored an accuracy of 93.0%, a sensitivity of 94.3%, and a specificity of 90.6%. In the process of localization and classification of the lesion in images containing lesions by Mask R-CNN, its mAP, AP50, and AP75 were 0.676, 0.903, and 0.833, respectively. CONCLUSION: We developed and compared five models for the detection of lesions in white light endoscopic images. ResNet50 showed the optimal performance, and Mask R-CNN model could be used to locate and classify lesions in images containing lesions.

Biomonitoring of chlorinated polyfluoroalkyl ether sulfonic acid in the general population in central and eastern China: Occurrence and associations with age/sex.

Although chlorinated polyfluoroalkyl ether sulfonic acid (Cl-PFESA) has been reported to be widespread in different environmental matrices of China, its exposure data in the general Chinese population are very limited. In the present study, the serum-to-whole-blood ratio was first assessed for 6:2 Cl-PFESA (mean/median: 2.07/1.82) based on its paired concentrations (n = 36), which allows a comparison in different blood matrices. The exposure levels of Cl-PFESAs in the general population were investigated by collecting blood samples (n = 1516) from residents of seven cities in central and eastern China. 6:2 Cl-PFESA was observed as the third-highest contributing polyfluoroalkyl substance (PFAS) (8.69%), with the median concentration at 2.18 ng/mL, indicating its importance for assessing the human exposure risks of PFASs. The regional difference between 6:2 Cl-PFESA and perfluorooctane sulfonate (PFOS) can be explained by their use pattern in China. Overall, similar to PFOS, 6:2 Cl-PFESA displays significantly increasing levels with increasing age for both males and females, with significantly higher levels in males. However, a significant sex dependence was found for 6:2 Cl-PFESA in one specific age group (41-60), while there was no significance in the other groups although males display higher levels than females. Our study provides robust data regarding human exposure to 6:2 Cl-PFESA in the general population in central and eastern China.

Mild changes in the mucosal microbiome during terminal ileum inflammation.

Patients with inflammation in the terminal ileum have high morbidity. In genetically susceptible hosts, chronic intestinal inflammation targeting the resident intestinal microbiota develops, but the microbial signature of the terminal ileum is poorly studied. To improve understanding of the mechanisms underlying the high prevalence of terminal ileum inflammation, we used 16S rRNA sequencing to analyse the mucosa-associated microbiota of the terminal ileum under intestinal homeostasis and inflammation conditions. Mucosal biopsy is the most commonly used sampling technique for assessing microbial communities associated with the intestinal mucosa. Thirty patients (15 with terminal ileum inflammation and 15 controls) underwent colonoscopy and biopsies were taken from the terminal ileum. Diagnosis depended on a combination of endoscopic and histological factors. To determine the composition and diversity of the microbiota, the 16S rRNA was analysed, and a variety of bioinformatics analyses were performed. Among the patients, composition analysis showed that the most abundant phyla identified in the terminal ileum samples were Fusobacteria, Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria. At the phylum level, the relative proportion of Bacteroidetes was lower in patients with inflammation than in control patients. In addition, there was an increase in the abundance of the phyla Proteobacteria and Lentisphaerae in patients with inflammation. The abundances of the dominant microbes in the terminal ileum were not significantly different between patients in an inflammatory state and controls. These results confirm that partial dysbiosis of the intestinal mucosa-associated microbiota composition is associated with terminal ileum inflammation.

Pathological changes in the lungs and lymphatic organs of 12 COVID-19 autopsy cases.

Systematic autopsy and comprehensive pathological analyses of COVID-19 decedents should provide insights into the disease characteristics and facilitate the development of novel therapeutics. In this study, we report the autopsy findings from the lungs and lymphatic organs of 12 COVID-19 decedents-findings that evaluated histopathological changes, immune cell signature and inflammatory factor expression in the lungs, spleen and lymph nodes. Here we show that the major pulmonary alterations included diffuse alveolar damage, interstitial fibrosis and exudative inflammation featured with extensive serous and fibrin exudates, macrophage infiltration and abundant production of inflammatory factors (IL-6, IP-10, TNFα and IL-1ß). The spleen and hilar lymph nodes contained lesions with tissue structure disruption and immune cell dysregulation, including lymphopenia and macrophage accumulation. These findings provide pathological evidence that links injuries of the lungs and lymphatic organs with the fatal systematic respiratory and immune malfunction in critically ill COVID-19 patients.

Dihydroartemisinin inhibits the growth and invasion of gastric cancer cells by regulating cyclin D1-CDK4-Rb signaling.

BACKGROUND: Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has a broad range of biological properties, including antitumor activity. However, the mechanisms by which DHA affects the tumorigenesis of gastric carcinoma (GC) are poorly understood. MATERIAL AND METHODS: The targets of DHA were identified by network pharmacology, and the association of CDK4 with clinicopathological characteristics and prognosis in patients with GC was analyzed by using TCGA data. CCK8, Transwell and flow cytometric analyses, as well as a tumor xenograft model, were used to assess the effects of DHA on the growth and migration of GC cells. qRT-PCR and Western blot analyses were used to determine the effects of DHA on the cyclin D1-CDK4-Rb signaling pathway. RESULTS: We identified 13 DHA targets and measured their expression of whichCDK4 expression levels were substantially higher in GC tissues than those in adjacent normal tissues, and high CDK4 expression acted as an independent prognostic factor of poor survival in patients with GC. DHA suppressed cell proliferation, migration and invasion in vitro and in vivo and induced G1 phase cell cycle arrest in a dose-dependent manner by regulating cyclin D1-CDK4-Rb signaling. CONCLUSIONS: DHA inhibits the tumorigenesis and invasion of GC by regulating cyclin D1-CDK4-Rb signaling and may provide therapeutic strategies for the treatment of GC.

Long-term effects of methamphetamine exposure in adolescent mice on the future ovarian reserve in adulthood.

Currently, there is an increasing prevalence of adolescent exposure to methamphetamine (MA). However, there is a paucity of information concerning the long-term impact of early exposure to MA upon female fertility and ovarian reserve. The aim of this study was to investigate the effect of long-term MA exposure in adolescents on their ovarian reserve in adulthood. Adolescent mice received intraperitoneal injections of MA (5mg/kg, three times per week) or saline from the 21st postnatal day for an 8 week period. Morphological, histological, biochemical, hormonal and ethological parameters were evaluated. An impaired ovarian reserve and vitality was found in the group treated with MA, manifesting in morphological-apparent mitochondrial damage, an activated apoptosis pathway in the ovarian tissue, a downward expression of ovarian anti-Mullerian hormone (AMH), a decreased number of primordial and growing follicles, an increased number of atretic follicles, and a depressed secretion of AMH, estradiol and progesterone from granulosa cells. However, no significant difference was noticed regarding the estrous cycle, the mating ability and the fertility outcome in the reproductive age of the mice after a period of non-medication. The present results confirmed that a long term exposure to methamphetamine in adolescent mice does have an adverse impact on their ovarian reserve, which indicates that such an early abuse of MA might influence the fertility lifespan of the female mouse.

Silencing of MAP4K4 by short hairpin RNA suppresses proliferation, induces G1 cell cycle arrest and induces apoptosis in gastric cancer cells.

Gastric cancer (GC) is the second most common cause of cancer­associated mortality worldwide. Previous studies suggest that mitogen­activated protein kinase kinase kinase kinase isoform 4 (MAP4K4) is involved in cancer cell growth, apoptosis and migration. In the present study, bioinformatics analysis and reverse transcription­quantitative polymerase chain reaction were performed to determine if MAP4K4 was overexpressed in GC. The knockdown of MAP4K4 by RNA interference in GC cells markedly inhibited cell proliferation, which may be mediated by cell cycle arrest in the G1 phase. The silencing of MAP4K4 also induced cell apoptosis by increasing the ratio of Bax/Bcl­2. In addition, Notch signaling was markedly reduced by MAP4K4 silencing. The results of the present study suggested that inhibition of MAP4K4 may be a therapeutic strategy for GC.

Effect of RTKN on progression and metastasis of colon cancer in vitro.

Like many epithelial-derived cancers, colon cancer results from a multistep tumorigenic process. However, the detailed mechanisms involved in colon cancer formations are poorly characterized. In the present study, we investigated the role of RTKN in colon cancer and explored underlying mechanisms. The results showed that RTKN expression was significantly increased in colon cancer tissues when compared with the adjacent tissues of patients in Shanghai People's hospital and in TCGA independent dataset. Furthermore, silencing of RTKN inhibited cell proliferation, migration, invasion, and arrested cell cycle at G1 phase in LOVO cells. Bioinformatics analysis demonstrated that DNA replication and cell cycle were involved in the regulation of RTKN. MCM2/3/5, CDK1/2 and PCNA expression had a direct relationship with the reduction of RTKN. RTKN could affect the proliferation and metastasis of colon cancer by reducing expression of MCM2/3/5, CDK1/2 and PCNA, suggesting that RTKN was a potential target for treating colon cancer.

Ponicidin induces apoptosis via JAK2 and STAT3 signaling pathways in gastric carcinoma.

Ponicidin has a variety of biological effects such as immunoregulatory and anti-inflammatory functions as well as anti-viral functions especially in the upper respiratory tract infection. This study was aimed to elucidate the antitumor effect of ponicidin in gastric carcinoma MKN28 cells and the possible molecular mechanism involved. Cell viability was measured by the Cell Count Kit-8 (CCK8). Cell apoptosis was assessed by flow cytometry as well as cell cycle and reactive oxygen species (ROS) analysis. Western blot analysis was used to detect the active form of caspase-3 as well as Bax and B-cell lymphoma-2 (Bcl-2) expressions after cells were treated with different concentrations of ponicidin. The results revealed that ponicidin could inhibit the growth of MKN28 cells significantly in both a time- and dose-dependent manner. The cell cycle was blocked and ROS generation was increased after the cells were treated with ponicidin. Bcl-2 expression was down-regulated remarkably while Bax expression and the active form of caspase-3 were increased after apoptosis occurred. We therefore conclude that ponicidin exhibited significant growth inhibition of gastric carcinoma cell line MKN28 and induced apoptosis of MKN28 cells via the signaling pathway regulated by Janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3). Ponicidin may serve as a potential therapeutic agent for gastric carcinoma.

Expression profiling of microRNAs in hippocampus of rats following traumatic brain injury.

The changes of microRNA expression in rat hippocampus after traumatic brain injury (TBI) were explored. Adult SD rats received a single controlled cortical impact injury, and the ipsilateral hippocampus was harvested for the subsequent microarray assay at three time points after TBI: 1st day, 3rd day and 5th day, respectively. We characterized the microRNA expression profile in rat hippocampus using the microRNA microarray analysis, and further verified microarray results of miR-142-3p and miR-221 using quantitative real-time PCR. Totally 205 microRNAs were identified and up-/down-regulated more than 1.5 times. There were significant changes in 17 microRNAs at all three time points post-TBI. The quantitative real-time PCR results of miR-142-3p and miR-221 indicated good consistency with the results of the microarray method. MicroRNAs altered at different time points post-TBI. MiR-142-3p and miR-221 may be used as potentially biological markers for TBI assessment in forensic practice.

Traumatic brain injury dysregulates microRNAs to modulate cell signaling in rat hippocampus.

Traumatic brain injury (TBI) is a common cause for cognitive and communication problems, but the molecular and cellular mechanisms are not well understood. Epigenetic modifications, such as microRNA (miRNA) dysregulation, may underlie altered gene expression in the brain, especially hippocampus that plays a major role in spatial learning and memory and is vulnerable to TBI. To advance our understanding of miRNA in pathophysiological processes of TBI, we carried out a time-course microarray analysis of microRNA expression profile in rat ipsilateral hippocampus and examined histological changes, apoptosis and synapse ultrastructure of hippocampus post moderate TBI. We found that 10 out of 156 reliably detected miRNAs were significantly and consistently altered from one hour to seven days after injury. Bioinformatic and gene ontology analyses revealed 107 putative target genes, as well as several biological processes that might be initiated by those dysregulated miRNAs. Among those differentially expressed microRNAs, miR-144, miR-153 and miR-340-5p were confirmed to be elevated at all five time points after TBI by quantitative RT-PCR. Western blots showed three of the predicated target proteins, calcium/calmodulin-dependent serine protein kinase (CASK), nuclear factor erythroid 2-related factor 2 (NRF2) and alpha-synuclein (SNCA), were concurrently down- regulated, suggesting that miR-144, miR-153 and miR-340-5p may play important roles collaboratively in the pathogenesis of TBI-induced cognitive and memory impairments. These microRNAs might serve as potential targets for progress assessment and intervention against TBI to mitigate secondary damage to the brain.

Roles of 3,4-methylenedioxymethamphetamine (MDMA)-induced alteration of connexin43 and intracellular Ca(2+) oscillation in its cardiotoxicity.

UNLABELLED: Although it is well known that 3,4-methylenedioxymethamphetamine (MDMA) can cause various cardiovascular abnormalities and even sudden death from cardiac arrhythmia, whether it has any effect on myocardial gap junctions, which might be one of the targets mediating MDMA-induced cardiotoxicity, remains unclear. OBJECTIVE: To test the hypothesis that MDMA may affect the myocardial gap junction protein connexin43 (Cx43) and induce cardiac dysrhythmia. METHOD: (1) In vivo study: adult rats were treated with a single dose MDMA administration (20mg/kg, i.p.). Electrocardiogram detection and immunohistochemical analysis were performed to evaluate cardiac function and expression of Cx43, respectively; (2) in vitro study: cultured ventricular myocytes of neonatal rats were treated with MDMA (10, 100, 1000µmol/L) for 1h. Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) were performed to investigate the total Cx43 mRNA expression. Immunofluorescent analysis was used to evaluate the amount of junctional Cx43. The phosphorylation status of Cx43 at site Ser368 and intracellular Ca(2+) oscillation were also studied. RESULTS: Obvious changes in electrocardiographic patterns were found in rats following MDMA administration. They were characterized by prolonged QRS duration associated with increased amplitude of QRS complex. The heart rates in treated rats were significantly decreased compared to the rats in the control group. The immunohistochemical findings revealed a significant decrease in Cx43 expression. The in vitro study also showed a marked decline in total Cx43 protein associated with reduction of Cx43 mRNA, whereas the phosphorylated Cx43 at Ser368 was increased. Decrease of junctional Cx43 was found correlated with reduction in N-cadherin induced by high concentration of MDMA. Additionally, confocal microscopy findings revealed alteration of intracellular calcium oscillation patterns characterized by high frequency and increasing influx Ca(2+). CONCLUSIONS: MDMA reduces expression of cardiac gap junction protein Cx43. The increase of phosphorylation status of Cx43 at Ser368 induced by MDMA is attributed, at least in part, to the Ca(2+)-dependent regulation of protein kinase C (PKC) activity. Our findings provide first evidence of MDMA-mediated changes in those cardiac gap junctions that may underlie MDMA-induced cardiac arrhythmia.