A case of neonatal tsutsugamushi disease diagnosed with the aid of rickettsial macrogenomic detection.

BACKGROUND: Tsutsugamushi, also known as bush typhus, is a naturally occurring disease caused by Orientia tsutsugamushi. We reported a case of vertical mother-to-newborn transmission of Orientia tsutsugamushi infection in a newborn from Yunnan (China). CASE PRESENTATION: Decreased fetal movements were observed at 39 weeks of gestation. After birth, the newborn (female) had recurrent fever, shortness of breath, and bruising around the mouth and extremities. At 5 h 58 min of age, the newborn was admitted for fever, shortness of breath and generalized rash. The liver was palpable 3 cm below the costal margin, and the limbs showed pitting edema. There was subcutaneous bleeding. Investigations suggested heavy infection, myocardial damage, decreased platelets. Treatment with cefotaxime and ampicillin failed. The mother was hospitalized at 29 weeks of gestation with a fever for 4 consecutive days, and an ulcerated crust was found in the popliteal fossa. Due to this pregnancy history, A diagnosis of Orientia tsutsugamushi infection was suspected in our index case and confirmed by macrogenomic testing and she was treated with vancomycin and meropenem, and later azithromycin for 1 week. The newborn was discharged in good general condition, gradually normalizing body temperature, and decreasing rash and jaundice. There were no abnormalities on subsequent blood macrogenomic tests for the baby. And one month later she showed good mental health, sleep, and food intake and no fever, rash, or jaundice. CONCLUSION: Determining the cause of symptoms is the key to treating diseases, especially the rare diseases that can be misdiagnosed. SUITABLE FOR PEOPLE WITH: Infectious Diseases; Neonatology; Obstetrics.

ToxMPNN: A deep learning model for small molecule toxicity prediction.

Machine learning (ML) has shown a great promise in predicting toxicity of small molecules. However, the availability of data for such predictions is often limited. Because of the unsatisfactory performance of models trained on a single toxicity endpoint, we collected toxic small molecules with multiple toxicity endpoints from previous study. The dataset comprises 27 toxic endpoints categorized into seven toxicity classes, namely, carcinogenicity and mutagenicity, acute oral toxicity, respiratory toxicity, irritation and corrosion, cardiotoxicity, CYP450, and endocrine disruption. In addition, a binary classification Common-Toxicity task was added based on the aforementioned dataset. To improve the performance of the models, we added marketed drugs as negative samples. This study presents a toxicity predictive model, ToxMPNN, based on the message passing neural network (MPNN) architecture, aiming to predict the toxicity of small molecules. The results demonstrate that ToxMPNN outperforms other models in capturing toxic features within the molecular structure, resulting in more precise predictions with the ROC_AUC testing score of 0.886 for the Toxicity_drug dataset. Furthermore, it was observed that adding marketed drugs as negative samples not only improves the predictive performance of the binary classification Common-Toxicity task but also enhances the stability of the model prediction. It shows that the graph-based deep learning (DL) algorithms in this study can be used as a trustworthy and effective tool to assess small molecule toxicity in the development of new drugs.

Cardiotoxicity of (-)-borneol, (+)-borneol, and isoborneol in zebrafish embryos is associated with Na+ /K+ -ATPase and Ca2+ -ATPase inhibition.

Borneol is an example of traditional Chinese medicine widely used in Asia. There are different isomers of chiral borneol in the market, but its toxicity and effects need further study. In this study, we used zebrafish embryos to examine the effects of exposure to three isomers of borneol [(-)-borneol, (+)-borneol, and isoborneol] on heart development and the association with Na+ /K+ -ATPase from 4 h post-fertilization (4 hpf). The results showed that the three isomers of borneol increased mortality and decreased hatching rate when the zebrafish embryo developed to 72 hpf. All three isomers of borneol (0.01-1.0 mM) significantly reduced heart rate from 48 to 120 hpf and reduced the expression of genes related to Ca2+ -ATPase (cacna1ab and cacna1da) and Na+ /K+ -ATPase (atp1b2b, atp1a3b, and atp1a2). At the same time, the three isomers of borneol significantly reduced the activities of Ca2+ -ATPase and Na+ /K+ -ATPase at 0.1 to 1.0 mM. (+)-Borneol caused the most significant reduction (p < 0.05), followed by isoborneol and (-)-borneol. Na+ /K+ -ATPase was mainly expressed in otic vesicles and protonephridium. All three isomers of borneol reduced Na+ /K+ -ATPase mRNA expression, but isoborneol was the most significant (p < 0.01). Our results indicated that (+)-borneol was the least toxic of the three isomers while the isoborneol showed the most substantial toxic effect, closely related to effects on Na+ /K+ -ATPase.

Pseudoephedrine hydrochloride causes hyperactivity in zebrafish via modulation of the serotonin pathway.

This study aimed to explore behavioral changes of embryonic and larval zebrafish caused by pseudoephedrine hydrochloride (PSE) and its underlying mechanism. Zebrafish embryos were exposed to 0.5 µM, 2 µM, and 8 µM PSE at 4 h post-fertilization (4 hpf) or 22-23 hpf. Mortality, hatching rate, coiling frequency, heart rate, behavior changes, and related gene expression were observed at different developmental stages. PSE below 8 µM did not affect zebrafish mortality, hatching rate, and heart rate compared with the control group. For embryos, PSE caused an increase at 16-32 hpf in zebrafish coiling frequency which could be rescued by serotonin antagonist WAY100635. Similarly, PSE caused an increase in the swimming distance of zebrafish larvae at 120 hpf. PSE also elevated the expression of serotonin (5-HT)-related genes 5-htr1ab and tph2 and dopamine-related gene dbh. Behavioral changes in zebrafish embryos and larvae caused by PSE may be closely associated with increased expression of 5-HT and dopamine-related genes. This may be reflected that the behavioral changes in zebrafish are a possible PSE monitoring indicator.

Identification of Potential Molecular Targets and Active Ingredients of Mingmu Dihuang Pill for the Treatment of Diabetic Retinopathy Based on Network Pharmacology.

Objective: Mingmu Dihuang Pill (MMDHP) is a traditional Chinese formula that has shown remarkable improvements of dry eyes, tearing, and blurry vision; however, the mechanisms underlying MMDHP treatment for diabetic retinopathy have not been fully understood. This study is aimed at identifying the molecular targets and active ingredients of MMDHP for the treatment of diabetic retinopathy based on network pharmacology. Methods: All active ingredients of MMDHP were retrieved from TCMSP and BATMAN-TCM databases, and the targets of active ingredients of MMDHP were predicted on the SwissTargetPrediction website. Diabetic retinopathy-related target sets were retrieved from GeneCards and OMIM databases, and the intersecting targets between targets of active ingredients of MMDHP and potential therapeutic targets of diabetic retinopathy were collected to generate the traditional Chinese medicine-ingredient-target-diabetic retinopathy network and to create the protein-protein interaction network. In addition, GO terms and KEGG pathway enrichment analyses were performed to identify the potential pathways, and molecular docking was employed to verify the binding of active ingredients of MMDHP to key targets of diabetic retinopathy. Results: Network pharmacology predicted 183 active ingredients and 904 targets from MMDHP, and 203 targets were intersected with the therapeutic targets of diabetic retinopathy. The top 10 hub targets included PIK3RA, TP53, SRC, JUN, HRAS, AKT1, VEGFA, EGFR, ESR1, and PI3KCA. GO terms and KEGG pathway enrichment analyses identified AGE-RAGE, PI3K-AKT, and Rap1 signaling pathways as major pathways involved in MMDHP treatment for diabetic retinopathy. Molecular docking confirmed a good binding affinity of active ingredients of MMDHP, including luteolin, acacetin, naringenin, and alisol B, with AKT1, SRC, and VEGFA as the three key targets of diabetic retinopathy. Conclusion: MMDHP may be effective for the treatment of diabetic retinopathy through active ingredients luteolin, acacetin, naringenin, and alisol B via AKT1, SRC, and VEGFA in AGE-RAGE, PI3K-AKT, and Rap1 signaling pathways.

Validation of the watch-type HUAWEI WATCH D oscillometric wrist blood pressure monitor in adult Chinese.

OBJECTIVE: The aim of this study was to evaluate the accuracy of the watch-type automated oscillometric wrist blood pressure (BP) monitor HUAWEI WATCH D in the general population according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard. METHOD: Subjects were recruited to fulfill the age, sex, BP and cuff distributions of the AAMI/ESH/ISO Universal Standard in the general population using the same arm sequential BP measurement method. Two cuffs of the test device were used for wrist circumference of 13-16 cm (medium) and 16-20 cm (large), respectively. RESULTS: One-hundred and nine subjects were recruited and 85 were analyzed. For validation criterion 1, the mean ± SD of the differences between the test device and reference BP readings was -1.4 ± 6.47/-0.2 ± 5.85 mmHg (systolic/diastolic). For criterion 2, the SD of the average BP differences between the test device and reference BP per subject was 5.66/5.48 mmHg (systolic/diastolic). CONCLUSION: The HUAWEI WATCH D watch-type wrist BP monitor fulfilled all the requirements of the AAMI/ESH/ISO Universal Standard in the general population and can be recommended for self-measurement.

Effects of Vitexin, a Natural Flavonoid Glycoside, on the Proliferation, Invasion, and Apoptosis of Human U251 Glioblastoma Cells.

Glioblastoma is a highly aggressive brain tumor characterized by high recurrence and poor prognosis. Vitexin has shown activities against esophageal, liver, lung, colorectal, and ovarian cancers; however, there is little knowledge on the activity of vitexin against glioblastoma. This study was therefore designed with aims to examine the effects of vitexin on proliferation, invasion, and apoptosis of human U251 glioblastoma cells and explore the underlying molecular mechanisms using mRNA sequencing and molecular docking. Vitexin was found to inhibit cell proliferation, colony formation, and invasion and promote apoptosis in U251 cells. mRNA sequencing identified 499 differentially expressed genes in vitexin-treated U251 cells relative to controls, including 154 upregulated genes and 345 downregulated genes. Gene ontology (GO) term enrichment analysis revealed that the upregulated genes were most significantly enriched in intrinsic apoptotic signaling pathway and the downregulated genes were most significantly enriched in positive regulation of cell development and positive regulation of locomotion relating to biological processes, endoplasmic reticulum lumen and side of membrane relating to cellular components, and receptor ligand activity and receptor regulator activity relating to molecular functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the upregulated genes were involved in the pathways of transcriptional misregulation in cancer and the downregulated genes were involved in FoxO and JAK/STAT signaling pathways. Western blotting assay revealed that vitexin treatment resulted in reduced p-JAK1, p-JAK3, and p-STAT3 protein expression in U251 cells relative to untreated controls, and molecular docking predicted that vitexin had docking scores of -8.8, -10.8, and -10.5 kJ/mol with STAT3, JAK1, and JAK2, respectively. The results of the present study demonstrate that vitexin inhibits the proliferation and invasion and induces the apoptosis of glioblastoma U251 cells through suppressing the JAK/STAT3 signaling pathway, and vitexin may be a promising potential agent for the chemotherapy of glioblastoma.

Developmental disorders caused by cefixime in the otic vesicles of zebrafish embryos or larvae.

To explore the developmental toxicity of cefixime (CE) in the developmental disorder and toxicity mechanism of CE on otic vesicles, zebrafish embryos were used as an animal model. The results showed that CE increased mortality in a dose-dependent manner and decreased the hatching rate of zebrafish larva at 96 hpf. Interestingly, CE significantly reduced the area of the saccule and utricle, as well as the area of otic vesicles in zebrafish larvae (p < 0.001). Fibroblast growth factor 8a (Fgf8a) inhibitors and bone morphogenetic protein (BMP) inhibitors caused similar morphological changes. CE decreased the lateral hair cells of zebrafish larvae in a dose-dependent manner. Furthermore, CE caused the downregulation of cartilage and bone-related genes and Na+/K+-ATPase-related genes of zebrafish larvae at 72 hpf and 120 hpf according to RT-qPCR. A comparison with the control group revealed that 100 µg/mL CE also caused a decrease in Na+/K+-ATPase activity (p < 0.01). In addition, antibody staining verified that CE inhibited the expression of Na+/K+-ATPase in the otic vesicles and the nephridium of zebrafish larvae. The data obtained in this study suggested that CE has significant ototoxicity during embryonic development of zebrafish, which is closely related to Na+/K+-ATPase and the regulation of the Fgf8a/BMP signaling pathways. The effects and toxicity of CE on ear development in other animal models need to be further explored.

Repeatability and reproducibility of a double-pass optical quality analysis device.

PURPOSE: To evaluate the repeatability and reproducibility of a double-pass instrument (OQASII, Visiomereics SL, Spain), which objectively measures overall optical quality of the human eyes. METHODS: The right eye of 119 healthy subjects with best corrected visual acuity of 20/25 or better was included in this prospective, comparative, observational study. Two separate tests with OQASII were conducted sequentially on the same day by two different examiners. A week later, the first examiner conducted the third measurement. All subjects underwent three consecutive tests during each session. The repeatability and reproducibility of the modulation transfer function cut off frequency (MTF cutoff), the Strehl ratio, the OQAS values (OVs) at contrasts of 100%, 20% and 9%, and the objective scatter index (OSI) were analyzed. RESULTS: For MTF cutoff, Strehl ratio, OV100%, OV20%, OV9%, and OSI, the mean values were 39.32±9.75cpd, 0.22±0.06, 1.31±0.33, 1.33±0.39, 1.33±0.41, 0.60±0.42, respectively. Repeatability and reproducibility were good with a very low coefficient of variation and high interclass correlation coefficients (>0.88) for all parameters. Bland-Altman plots showed good correlation with 95% limits of agreement ranged from -6.04 to 6.78cpd, -0.05 to 0.05, -0.20 to 0.23, -0.29 to 0.32, -0.40 to 0.42, -0.23 to 0.21 in inter-observer, and -6.56 to 7.42cpd, -0.06 to 0.06, -0.22 to 0.24, -0.30 to 0.32, -0.35 to 0.34, -0.24 to 0.23 in inter-visit, respectively. CONCLUSION: The OQASII system yields excellent repeatability and good reproducibility for objective measurements of overall optical quality in clinic.