Mechanisms of brain damage caused by inorganic fluoride using proteomics-based techniques / 环境与职业医学

Background Chronic excessive exposure to fluoride can cause damage to the central nervous system and a certain degree of learning and memory impairment. However, the associated mechanism is not yet clear and further exploration is needed. Objective Using 4D unlabelled quantitative proteomics techniques to explore differentially expressed proteins and their potential mechanisms of action in chronic excessive fluoride exposure induced brain injury. Methods Twenty-four SPF-grade adult SD rats, half male and half male, were selected and divided into a control group and a fluoride group by random number table method, with 12 rats in each group. Among them, the control group drank tap water (fluorine content<1 mg·L−1), the fluoride group drank sodium fluoride solution (fluorine content 10 mg·L−1), and both groups were fed with ordinary mouse feed (fluoride content<0.6 mg·kg−1). After 180 d of feeding, the SD rats were weighed, and then part of the brain tissue was sampled for pathological examination by hematoxylin-eosin (HE) staining and Nissl staining. The rest of the brain tissue was frozen and stored at −80 ℃. Three brain tissue samples from each group were randomly selected for proteomics detection. Differentially expressed proteins were screened and subcellular localization analysis was performed, followed by Gene Ontology (GO) function analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, cluster analysis, and protein-protein interaction analysis. Finally, Western blotting was used to detect the expression levels of key proteins extracted from the brain tissue samples. Results After 180 d of feeding, the average weight of the rats in the fluoride group was significantly lower than that in the control group (P<0.05). The brain tissue stained with HE showed no significant morphological changes in the cerebral cortex of the fluoride treated rats, and neuron loss, irregular arrangement of neurons, eosinophilic changes, and cell body pyknosis were observed in the hippocampus. The Nissl staining results showed that the staining of neurons in the cerebral cortex and hippocampus of rats exposed to fluoride decreased (Nissl bodies decreased). The proteomics results showed that a total of 6927 proteins were identified. After screening, 206 differentially expressed proteins were obtained between the control group and the fluoride group, including 96 up-regulated proteins and 110 down-regulated proteins. The differential proteins were mainly located in cytoplasm (30.6%), nucleus (27.2%), mitochondria (13.6%), plasma membrane (13.6%), and extracellular domain (11.7%). The GO analysis results showed that differentially expressed proteins mainly participated in biological processes such as iron ion transport, regulation of dopamine neuron differentiation, and negative regulation of respiratory burst in inflammatory response, exercised molecular functions such as ferrous binding, iron oxidase activity, and cytokine activity, and were located in the smooth endoplasmic reticulum membrane, fixed components of the membrane, chloride channel complexes, and other cellular components. The KEGG significantly enriched pathways included biosynthesis of secondary metabolites, carbon metabolism, and microbial metabolism in diverse environments. The results of differential protein-protein interaction analysis showed that the highest connectivity was found in glucose-6-phosphate isomerase (Gpi). The expression level of Gpi in the brain tissue of the rats in the fluoride group was lower than that in the control group by Western blotting (P<0.05). Conclusion Multiple differentially expressed proteins are present in the brain tissue of rats with chronic fluorosis, and their functions are related to biosynthesis of secondary metabolites, carbon metabolism, and microbial metabolism in diverse environments; Gpi may be involved in cerebral neurological damage caused by chronic overdose fluoride exposure.

Analysis of HIV-1 subtypes and pretreatment drug resistance in newly reported HIV/AIDS cases in Hangzhou, 2020-2022 / 中华微生物学和免疫学杂志

Objective:To analyze the HIV-1 subtypes and drug resistance among newly reported HIV/AIDS cases before antiretroviral therapy (ART) in Hangzhou.Methods:Blood samples were collected from newly diagnosed HIV-1/AIDS cases not receiving ART in Hangzhou from 2020 to 2022. HIV-1 pol gene was amplified and then sequenced. A phylogenetic tree was construct using MEGA7.0 software to analyse the HIV-1 subtypes, The sequences were submitted to the Stanford University drug resistance database to identify drug resistance mutation sites and drug sensitivity. Results:A total of 2 700 sequences were obtained. Twelve subtypes were identified, and the predominant subtypes were CRF07_BC (46.8%, 1 263/2 700) and CRF01_AE (34.6%, 933/2 700). The overall drug resistance rate before ART was 8.1% (220/2 700) and the resistance rates to protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were 2.8% (75/2 700), 1.3% (36/2 700) and 4.4% (119/2 700), respectively. Among the 220 drug-resistant cases, mutations conferring resistance to PIs (Q58E), NRTIs (M184V/I) and NNRTIs (K103N/S and E138A/G/K/Q) were detected in 47 (21.4%), 13 (5.9%), 42 (19.1%) and 41 (18.6%) patients, respectively.Conclusions:HIV-1 genotypes were highly complex in newly reported HIV/AIDS cases in Hangzhou from 2020 to 2022. There were cases showing moderate or high resistance to backbone drugs before ART, indicating that HIV-1 monitoring should be strengthened to avoid treatment failure and reduce the spread of drug-resistant strains.

Prognostic value of diffusion kurtosis imaging histogram based nomogram model for cervical cancer / 中华放射肿瘤学杂志

Objective:To analyze the prognostic value of nomogram model for cervical cancer based on the imaging features of diffusion kurtosis imaging (DKI) histogram.Methods:The DKI and clinical data of 272 patients with cervical cancer who were admitted to Affiliated Hospital of Guangdong Medical University from March 2015 to February 2022 were collected and retrospectively analyzed. All patients were randomly divided into the training group ( n=190) and validation group ( n=82) at a ratio of 7 vs. 3. The parameters of DKI histogram were obtained by GE AW 4.2 MRI software. The best prognostic imaging features were screened by LASSO regression. The DKI radiomics score was calculated by linear combination. The independent risk factors of prognosis were identified by univariate and multivariate regression analyses, and a nomogram model was constructed. The model discrimination was assessed by the area under the receiver operating characteristic (ROC) curve (AUC). The internal consistency of the model was evaluated by the calibration map. Results:Adenocarcinoma ( HR=2.496, 95% CI=1.312-4.749, P=0.005), DKI score ( HR=24.087, 95% CI=6.062-95.711, P<0.001), depth of invasion ≥ 1/2 muscular layer ( HR=2.277, 95% CI=1.156-4.487, P=0.017) and neutrophil to lymphocyte ratio (NLR) ( HR=1.800, 95% CI=1.313-2.468, P<0.001) were the independent risk factors for prognosis of cervical cancer. The AUC of the nomogram model in the training and validation groups were 0.860 and 0.757, respectively. The calibration curve was well fitted with the 45° diagonal. The prediction results of long-term prognosis of this model were in good agreement with the actual situation. Conclusions:Adenocarcinoma, NLR, DKI score and depth of invasion ≥ 1/2 muscular layer are the independent risk factors for the prognosis of patients with cervical cancer. The constructed nomogram model could reliably predict the 3-year survival rate of patients with cervical cancer.

Exploring Methods of Constructing Harmonious Doctor-patient Relationship from the Perspective of Image Theory / 中国医学伦理学

The application of the image theory of psychology to the modern doctor-patient relationship offers a new perspective and method for alleviating tensions between doctors and patients. In the construction of a doctor-patient community, doctors and patients must empathize and build a consensus based on empathy. From the perspective of constructivism, it is recommended that patients actively complete the process of "meaning construction" of disease cognition through "collaboration" and "dialogue" with doctors, so as to achieve the goal of shared decision-making between doctors and patients. Constructing a harmonious doctor-patient relationship requires putting patients in the center to create patient persona, taking narrative medicine as a bridge to listen to doctor-patient stories, and using multimedia as a platform to medical knowledge.

Superiority of sugammadex in preventing postoperative pulmonary complications / 中华医学杂志(英文版)

BACKGROUND@#Postoperative pulmonary complications often lead to increased mortality and financial burden. Residual paralysis plays a critical role in postoperative pulmonary complications. This meta-analysis was performed to determine whether sugammadex overmatches neostigmine in reducing postoperative pulmonary complications.@*METHODS@#PubMed, Embase, Web of Science, Medline through Ovid, Cochrane Library, Wanfang, China National Knowledge Infrastructure, and Chinese BioMedical Literature Databases were searched from their inception to 24 June, 2021. Random effects models were used for all analyses. Cochrane risk of bias tool was used to assess the quality of RCTs, while Newcastle Ottawa Quality Assessment Scale was used to assess for the quality of cohort studies.@*RESULTS@#Seventeen studies were included in the meta-analysis. Pooled data from cohort studies showed reversing neuromuscular blocking with sugammadex had less risk of compound postoperative pulmonary complications (relative risk [RR]: 0.73; 95% confidence interval [CI]: 0.60-0.89; P  = 0.002; I2  = 81%), pneumonia (RR: 0.64; 95% CI: 0.48-0.86; I2  = 42%) and respiratory failure (RR: 0.48; 95% CI: 0.41-0.56; I2  = 0%). However, pooled data from RCTs did not show any difference between the two groups in pneumonia (RR: 0.58; 95% CI: 0.24-1.40; I2  = 0%) and no respiratory failure was reported in the included RCTs. The difference was not found between sugammadex and neostigmine about atelectasis in pooled data from either RCTs (RR: 0.85; 95% CI: 0.69-1.05; I2  = 0%) or cohort studies (RR: 1.01; 95% CI: 0.87-1.18; I2  = 0%).@*CONCLUSION@#The evidence of superiority of sugammadex was limited by the confounding factors in cohort studies and small scale of RCTs. Whether sugammadex precedes neostigmine in preventing pulmonary complications after surgery is still unknown. Well-designed RCTs with large scale are needed.@*REGISTRATION@#PROSPERO ( https://www.crd.york.ac.uk/PROSPERO/ ); CRD 42020191575.

Comparison of oxycodone and sufentanil in patient-controlled intravenous analgesia for postoperative patients: a meta-analysis of randomized controlled trials / 中华医学杂志(英文版)

BACKGROUND@#Managing acute postoperative pain is challenging for anesthesiologists, surgeons, and patients, leading to adverse events despite making significant progress. Patient-controlled intravenous analgesia (PCIA) is a recommended solution, where oxycodone has depicted unique advantages in recent years. However, controversy still exists in clinical practice and this study aimed to compare two drugs in PCIA.@*METHODS@#We performed a literature search in PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, Chinese National Knowledge Infrastructure, Wanfang, and VIP databases up to December 2020 to select specific randomized controlled trials (RCTs) comparing the efficacy of oxycodone with sufentanil in PCIA. The analgesic effect was the primary outcome and the secondary outcome included PCIA consumption, the Ramsay sedation scale, patients' satisfaction and side effects.@*RESULTS@#Fifteen RCTs were included in the meta-analysis. Compared with sufentanil, oxycodone showed lower Numerical Rating Scale scores (mean difference [MD] = -0.71, 95% confidence interval [CI]: -1.01 to -0.41; P < 0.001; I2 = 93%), demonstrated better relief from visceral pain (MD = -1.22, 95% CI: -1.58 to -0.85; P < 0.001; I2 = 90%), promoted a deeper sedative level as confirmed by the Ramsay Score (MD = 0.77, 95% CI: 0.35-1.19; P < 0.001; I2 = 97%), and resulted in fewer side effects (odds ratio [OR] = 0.46, 95% CI: 0.35-0.60; P < 0.001; I2 = 11%). There was no statistical difference in the degree of patients' satisfaction (OR = 1.13, 95% CI: 0.88-1.44; P = 0.33; I2 = 72%) and drug consumption (MD = -5.55, 95% CI: -14.18 to 3.08; P = 0.21; I2 = 93%).@*CONCLUSION@#Oxycodone improves postoperative analgesia and causes fewer adverse effects, and could be recommended for PCIA, especially after abdominal surgeries.@*REGISTRATION@#PROSPERO; https://www.crd.york.ac.uk/PROSPERO/; CRD42021229973.

Upregulation of IL-18 expression in blood CD4+ Th2 cells of patients with allergic rhinitis / 细胞与分子免疫学杂志

Objective To investigate the expressions of IL-18, IL-18 binding protein isoform a (IL-18BPa) and IL-18 receptor α (IL-18Rα) in blood CD4+ Th2 cells of patients with allergic rhinitis (AR) and the effects of allergens on their expressions. Methods Blood samples of AR patients and healthy control subjects (HCs) were collected. Peripheral blood mononuclear cells (PBMCs) and CD4+ T cells sorted by immunomagnetic beads were stimulated by crude extract of Artemisia sieversiana wild allergen (ASWE), Platanus pollen (PPE) and house dust mite extract (HDME). Flow cytometry was used to detect the expression of IL-18, IL-18BPa and IL-18Rα in CD4+ Th2 cells, and BioPlex was used to detect the level of plasma IL-4 and analyze its correlation with the proportion of IL-18+ Th2 cells. Results Compared with HCs, the proportion of IL-18+ cells was increased in Th2 cells of AR patients; MFI of IL-18 was increased, while that of IL-18Rα was decreased. Moreover, allergens induced IL-18 and IL-18Rα expression in sorted CD4+ Th2 cells of HCs and induced IL-18Rα in that of AR patients. Additionally, elevated plasma IL-4 level was found in AR patients, which was moderately correlated with the percentage of IL-18+ Th2 cells. Conclusion Allergens may be involved in the pathogenesis of AR by inducing expression of IL-18 in peripheral blood CD4+ Th2 cells.

Aplicación del modelo AREA en cuidados al paciente con enfermedad de Ebstein sometido a cirugía extracorpórea / Application of the AREA model in care for patients with Ebstein's disease undergoing extracorporeal surgery

Se presenta el caso de una mujer de 32 años ingresada tras intervención de plastia tricuspídea y Glenn bidireccional por enfermedad de Ebstein. Se realizó una valoración al ingreso según las 14 Necesidades de Henderson. El plan de cuidados (PC) se efectuó siguiendo el modelo AREA. Se creó una red de razonamiento que identifica la convergencia de la relación entre los diagnósticos NANDA para priorizar aquellos con mayor concentración de actividad. De estos diagnósticos se extrajeron objetivos NOC e intervenciones NIC con sus correspondientes actividades, y se analizó el resultado teniendo en cuenta la evolución de la paciente para replantear el PC. Los diagnósticos priorizados fueron “Limpieza ineficaz de las vías aéreas”, “Disminución del gasto cardiaco”, “Deterioro de la integridad cutánea”, “Deterioro de la movilidad física” y “Riesgo de infección”. Tras la reevaluación-reflexión se excluyeron “Limpieza ineficaz de las vías aéreas” y “Deterioro de la integridad cutánea” por haberse resuelto, se sustituyó la “Disminución del gasto cardiaco” por “Déficit de volumen de líquidos” que se ajustaba mejor y se incluyó el diagnóstico “Dolor agudo”. Tras modificar el PC, todos los indicadores alcanzaron la puntuación diana establecida no quedando ningún objetivo sin resolver.(AU)

IRAK2-NF-κB signaling promotes glycolysis-dependent tumor growth in pancreatic cancer.

BACKGROUND: Metabolic reprogramming has emerged as a core hallmark of cancer, and cancer metabolism has long been equated with aerobic glycolysis. Moreover, hypoxia and the hypovascular tumor microenvironment (TME) are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is imperative for tumor cell survival and proliferation. Here, we explored the impact of interleukin 1 receptor-associated kinase 2 (IRAK2) on the biological behavior of PDAC and investigated the underlying mechanism. METHODS: The expression pattern and clinical relevance of IRAK2 was determined in GEO, TCGA and Ren Ji datasets. Loss-of-function and gain-of-function studies were employed to investigate the cellular functions of IRAK2 in vitro and in vivo. Gene set enrichment analysis, Seahorse metabolic analysis, immunohistochemistry and Western blot were applied to reveal the underlying molecular mechanisms. RESULTS: We found that IRAK2 is highly expressed in PDAC patient samples and is related to a poor prognosis. IRAK2 knockdown led to a significant impairment of PDAC cell proliferation via an aberrant Warburg effect. Opposite results were obtained after exogenous IRAK2 overexpression. Mechanistically, we found that IRAK2 is critical for sustaining the activation of transcription factors such as those of the nuclear factor-κB (NF-κB) family, which have increasingly been recognized as crucial players in many steps of cancer initiation and progression. Treatment with maslinic acid (MA), a NF-κB inhibitor, markedly attenuated the aberrant oncological behavior of PDAC cells caused by IRAK2 overexpression. CONCLUSIONS: Our data reveal a role of IRAK2 in PDAC metabolic reprogramming. In addition, we obtained novel insights into how immune-related pathways affect PDAC progression and suggest that targeting IRAK2 may serve as a novel therapeutic approach for PDAC.

Factors related to false negative results of interferon-γ release test in patients with confirmed pulmonary tuberculosis / 中华临床感染病杂志

Objective:To analyze the influencing factors related to false-negative results of interferon-γ release assay (IGRA) QFT-GIT in patients with confirmed pulmonary tuberculosis.Methods:Clinical data of 389 patients with bacteriologically confirmed pulmonary tuberculosis who underwent QFT-GIT in Quzhou Hospital Affiliated to Wenzhou Medical University between January 1 and December 31 2020 were retrospectively analyzed. Univariate and multivariate logistic regression were used to analyze the influencing factors related to the false-negative results of QFT-GIT.Results:Among 389 confirmed patients, 347 cases had positive QFT-GIT results and 42 cases had negative results. Univariate analysis showed that the false-negative results of QFT-GIT were associated with low BMI, reduced CD4 + T lymphocyte count, decreased lymphocyte count, increased C-reactive protein, negative sputum smear, anemia, diabetes mellitus, malignant tumor and sepsis ( P<0.05 or P<0.01). Multivariate conditional logistic regression analysis showed that BMI <18.5 kg/m 2( OR=1.585, 95% CI 1.076-2.336), complicated with diabetes( OR=5.157, 95% CI 2.340-11.365), malignant tumors ( OR=5.596, 95% CI 2.048-15.295)and sepsis ( OR=4.141, 95% CI 1.042-16.459) were independent risk factors for the false-negative results of QFT-GIT ( P<0.05 or P<0.01). Conclusion:When the pulmonary tuberculosis patients are extreme emaciation, complicated with diabetes, malignant tumor or sepsis, the QFT-GIT results will be false negative.

Etiological identification and phylogenetic analysis of a clustered epidemic caused by norovirus on a patrol boat / 上海预防医学

ObjectiveTo determine the pathogen and phylogenetic characteristics of an uncommon outbreak of recombinant norovirus infection in Daishan County in February 2022. MethodsFluorescence quantitative PCR was used to detect the norovirus in the eight anal swabs collected in the outbreak. In the positive samples， reverse transcription PCR were used to amplify the norovirus. Norovirus sequences were characterized by MEGA7 and Simplot. ResultsNorovirus GⅠ was identified in all eight anal samples. It was further determined to be recombinant norovirus GⅠ.6 ［P11］， with the recombination site at the ORF1-ORF2 junction. The sequence had the highest nucleotide identity （98.75%） to a GⅠ.6［P11］ strain collected in 2018 （GenBank accession number MT357995）. ConclusionAccording to the etiological identification and phylogenetic analysis， this outbreak is confirmed to be caused by the uncommon recombinant norovirus GⅠ.6 ［P11］ in China.

Molecular transmission characteristics of HIV-1 in mountainous areas of southwest Zhejiang Province / 中华微生物学和免疫学杂志

Objective:To understand the molecular transmission characteristics of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome(AIDS) patients in the mountainous area of southwest Zhejiang Province(Lishui city).Methods:A total of 147 blood samples were collected from newly-diagnosed HIV-1 infected who received no antiviral therapy, and pol gene was amplified, followed by sequencing. MEGA6.0 software was used to construct phylogenetic tree and determine gene subtypes. HIVDB online was used to analyze drug resistance mutation, then the pairwise genetic distance(GD) was calculated and the opitimal threshold of GD was selected, finally the molecular transmission network was constructed by Cytoscape3.7.0 software. Chi-square or Fisher′s exact probability method was used for statistical analysis. Results:A total of 134 sequences were obtained successfully, and nine subtypes were detected. The dominant subtypes were CRF08_BC (34.33%, 46/134), CRF01_AE (29.85%, 40/134) and CRF07_BC (23.88%, 32/134). It also found that age, registered residence, education level and transmission route had significant differences in distribution of subtypes ( P<0.05). Nineteen drug resistance individuals were found, and the total drug resistance rate was 14.18% (19/134). The HIV-1 molecular transmission network was plotted based on 1.2% GD threshold. A total of 15 transmission clusters (cluster size ranging from 2 to 29) were found. The network access rate was 49.25% (66/134), mainly including male (75.76%, 50/66), heterosexual (81.82%, 54/66) and patientsrinfected with CRF08_ BC (50.00%, 33/66). A transmission cluster including two cases of female sex workers and seven cases of drug resistance was identified, in which the average age of the patients was 57.21 years old and the average degree value was 22.7, and the cases were mainly infected through heterosexual contact (96.55%, 28/29). The highest homology of the sequences in the cluster was in Yunnan. Conclusions:The HIV-1 subtypes were diverse in the mountainous area of southwest Zhejiang Province(Lishui city). Drug resistant transmission had reached a moderate epidemic level. There were molecular transmission clusters with the aggregation characteristics of elderly clients in specific regions. It was urgent to formulate and implement precise intervention strategies to curb the spread of HIV.

Effect of urokinase on inflammatory substances and thrombomodulin in rats with deep vein thrombosis / 中国医师杂志

Objective:To investigate the mechanism of urokinase on inflammatory substances and thrombomodulin (TM) in deep vein thrombosis (DVT) rats.Methods:A rat model of deep vein thrombosis was established. Thirty rats were randomly divided into sham group, DVT group and UK (urokinase) group. The rat model of deep venous thrombosis was established in DVT group and UK group. One day after operation, urokinase (20 000 U/kg) was injected into caudal vein in UK group once a day for 14 days; Sham group and DVT group were given the same volume of normal saline. The wet weight and the ratio of wet weight/length of thrombus were compared among the three groups; HE staining was used to detect the pathological changes of thrombus in the three groups; The plasma inflammatory factors interleukin-8 (IL-8) and tumor necrosis factor α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of TM in the three groups was detected by real-time fluorescence quantitativepolymerase chain reaction (qRT-PCR).Results:Compared with sham group, thrombosis was found in DVT group. The wet weight and wet weight/length ratio of thrombus in DVT group were significantly higher than those in sham group ( P<0.05); After urokinase intervention, the wet weight of thrombus in UK group was significantly lower than that in DVT group, and the wet weight/length ratio of thrombus was also significantly lower than that in DVT group ( P<0.05). Compared with sham group, DVT group had obvious thrombosis, granulation tissue covered around the tissue, obvious adhesion between blood vessels and tube wall, a large number of inflammatory cell infiltration around venous tissue and obvious destruction of valve structure; After urokinase intervention, the thrombus tissue of UK group was significantly improved. Compared with sham group, the concentration of IL-8 , TNF-α and sTM in DVT group were significantly increased ( P<0.05). After urokinase intervention, the IL-8, TNF-α and sTM concentration in UK group were significantly lower than those in DVT group ( P<0.05). qRT-PCR results showed that TM mRNA expression in DVT group was significantly higher than that in sham group ( P<0.05). The TM mRNA expression in UK group was significantly lower than that in DVT group ( P<0.05). Conclusions:Urokinase can inhibit the inflammatory factors and the expression of thrombomodulin in DVT.

Epidemic characteristics and genetic analysis of hemorrhagic fever with renal syndrome in an industrial park in Daishan County, Zhejiang Province / 中华地方病学杂志

Objective:To analyze the epidemic characteristics and virus gene sequence of hemorrhagic fever with renal syndrome (HFRS) in an industrial park in Daishan County, Zhejiang Province, and to provide clues and basis for local HFRS prevention and control.Methods:According to the case questionnaire in the "National Surveillance Program for Hemorrhagic Fever with Renal Syndrome", general and epidemiological investigation of HFRS cases was carried out in the epidemic-related industrial park. Serum samples of the cases, people and host animals in the same living environment were collected for hantavirus antibody or nucleic acid detection, the M, S gene amplification and sequence determination. MEGAX 10.1.8 software was used to construct the phylogenetic tree of M and S genes for virus genotyping and evolutionary analysis.Results:A total of 3 confirmed cases of HFRS were reported. They were all workers in the epidemic-related industrial park, male, who lived in the park for more than half a year and had no history of HFRS vaccination. There were no rodent-proof facilities in the industrial park's dormitories and canteens, and the living items were placed in a disorderly manner, the rodents and its excrement could be seen; a total of 38 host animals were captured in the same living environment with cases, all of which were Rattus norvegicus. The 3 reported cases of HFRS were all mild, with atypical clinical manifestations in the early stage of onset, mainly fever and fatigue. The serum specific antibodies of hantavirus IgG and IgM were positive (3/3), and the antibodies of people in the same living environment were negative (100.0%, 100/100). The serum samples of 2 reported cases of HFRS and 4 Rattus norvegicus were positive for nucleic acid, all of which were SEOV type hantavirus. The M gene segment homology of 6 positive serum samples was 100.0%, which was closely related to Rod/2012/QHD/4/Gc isolated from Hebei and RuianRn180 isolated from Ruian Zhejiang Province; the homology of S gene segment was 99.6% to 99.8%, which was closely related to JiangxiXinjianRn-09-2011, a strain isolated from Jiangxi Province. Conclusions:The HFRS epidemic in the industrial park is caused by the transmission of SEOV type hantavirus to humans via Rattus norvegicus; poor living environment, poor hygiene habits of personnel and lack of vaccination are all related to the incidence of HFRS; the main epidemic strains shows high homology and geographical aggregation.

The protective effect of ritonavir against Gynura japonica-induced liver injury in rats / 药学学报

Numerous in vitro studies have shown that most pyrrolizidine alkaloids (PAs) are hepatotoxic after being metabolically activated by cytochrome P450 (CYP) 3A4. However, the key role of CYP3A4 has not been confirmed in vivo. Therefore, the CYP3A4 chemical inhibitor ritonavir was employed in this work and the effect of ritonavir on Gynura japonica-induced liver injury in rats was investigated. All experiments were approved by the Animal Research Committee of Shanghai University of Traditional Chinese Medicine. Animal welfare and the animal experimental protocols were strictly consistent with related ethics regulations of Shanghai University of Traditional Chinese Medicine. Acute liver injury was induced by a single gavage of Gynura japonica extracts (GJE, 8 g·kg-1); rats in the protection group were gavaged with ritonavir (RIT, 30 mg·kg-1) 1 h before GJE treatment. The results show that RIT could significantly attenuate GJE-induced liver injury in rats. Rats in the protection group showed decreased serum activities for alanine aminotransferase and aspartate aminotransferase, as well as lower total bile acids. In addition, the infiltration of inflammatory cells, sinusoidal hemorrhage, and hepatic necrosis in GJE-treated rats were markedly attenuated in the protection group. The content of pyrrole-protein adducts (PPAs), a recommended biomarker for PA-induced hepatotoxicity in clinics, was determined at 10 min to 24 h after GJE treatment. The content of 13 bile acids was also quantified. RIT treatment reduced the content of PPAs in serum dramatically and restored the impaired bile acid homeostasis caused by GJE. These studies indicate that RIT attenuated Gynura japonica-induced liver injury in rats, which was closely related to the inhibition of the metabolic activation of PAs and the regulation of bile acid metabolism. These results provide a better understanding of the relationship between CYP3A4 and PA-induced toxicity. This work will also be helpful in developing effective treatments for PA-induced liver injury and making a reasonable evaluation of the safety of drugs containing PAs in clinic.

Evaluation of astigmatism-correcting efficiency and clinical effects after phacoemulsification with bifocal Toric intraocular lens implantation / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To assess the astigmatism-correcting efficiency and clinical effects of cataract phacoemulsification combined with bifocal Toric intraocular lens(IOL)implantation. METHODS: Retrospective analysis. The clinical data of 46 patients(46 eyes)with cataract complicated with regular corneal astigmatism by the treatment of cataract phacoemulsification and bifocal Toric IOL implantation in our hospital from August 2020 to September 2021 were included. The patients were followed up for 3mo after operation, and the changes of uncorrected distant visual acuity(UDVA), uncorrected near visual acuity(UNVA), best corrected distant visual acuity(BCDVA), best corrected near visual acuity(BCNVA)and astigmatism before and 1, 3mo after operation were evaluated. The IOL axial rotation was measured and calculated, and a questionnaire was conducted to investigate the necessity of using glasses at different distances and overall satisfaction.RESULTS:After operation at 1 and 3mo, there were significant differences in UDVA, BCDVA, UNVA and BCNVA compared with those before operation(all P&#x003C;0.001), and there was no significant difference in UDVA, BCDVA, UNVA and BCNVA at 1mo after operation and 3mo after operation(all P&#x003E;0.0167). At 3mo after operation, 46 eyes(100%)of UDVA reached 0.20(LogMAR), 40 eyes(87.0%)of UNVA reached 0.20(LogMAR). Astigmatism vector analysis showed that the mean preoperative corneal astigmatism in this group was 1.88±0.70D, and the centroid value was 0.61D@177°±1.93D, the mean residual astigmatism at 3mo postoperatively was 0.33±0.30D, and the centroid value was 0.03D@34°±0.45D. After operation at 3mo, the axial rotation of IOL was 3°(0°, 5°). Only 5 eyes(11%)required some degree of refractive correction for near or intermediate distances. 83%(38 eyes)were satisfied or very satisfied with the surgical results CONCLUSION: The implantation of bifocal Toric IOL during cataract surgery could effectively correct corneal regular astigmatism, improve uncorrected distance and near vision, and had high patient satisfaction.

Bear bile powder attenuates senecionine-induced hepatic sinusoidal obstruction syndrome in mice / 中国天然药物

Hepatic sinusoidal obstruction syndrome (HSOS) via exposure to pyrrolizidine alkaloids (PAs) is with high mortality and there is no effective treatment in clinics. Bear bile powder (BBP) is a famous traditional animal drug for curing a variety of hepatobiliary diseases such as cholestasis, inflammation, and fibrosis. Here, we aim to evaluate the protective effect of BBP against HSOS induced by senecionine, a highly hepatotoxic PA compound. Our results showed that BBP treatment protected mice from senecionine-induced HSOS dose-dependently, which was evident by improved liver histology including reduced infiltration of inflammatory cells and collagen positive cells, alleviated intrahepatic hemorrhage and hepatic sinusoidal endothelial cells, as well as decreased conventional serum liver function indicators. In addition, BBP treatment lowered matrix metalloproteinase 9 and pyrrole-protein adducts, two well-known markers positively associated with the severity of PA-induced HSOS. Further investigation showed that BBP treatment prevents the development of liver fibrosis by decreasing transforming growth factor beta and downstream fibrotic molecules. BBP treatment also alleviated senecionine-induced liver inflammation and lowered the pro-inflammatory cytokines, in which tauroursodeoxycholic acid played an important role. What's more, BBP treatment also decreased the accumulation of hydrophobic bile acids, such as cholic acid, taurocholic acid, glycocholic acid, as well. We concluded that BBP attenuates senecionine-induced HSOS in mice by repairing the bile acids homeostasis, preventing liver fibrosis, and alleviating liver inflammation. Our present study helps to pave the way to therapeutic approaches of the treatment of PA-induced liver injury in clinics.

Aberrant NF-κB activation in odontoblasts orchestrates inflammatory matrix degradation and mineral resorption / 国际口腔科学杂志·英文版

Inflammation-associated proteinase functions are key determinants of inflammatory stromal tissues deconstruction. As a specialized inflammatory pathological process, dental internal resorption (IR) includes both soft and hard tissues deconstruction within the dentin-pulp complex, which has been one of the main reasons for inflammatory tooth loss. Mechanisms of inflammatory matrix degradation and tissue resorption in IR are largely unclear. In this study, we used a combination of Cre-loxP reporter, flow cytometry, cell transplantation, and enzyme activities assay to mechanistically investigate the role of regenerative cells, odontoblasts (ODs), in inflammatory mineral resorption and matrices degradation. We report that inflamed ODs have strong capabilities of matrix degradation and tissue resorption. Traditionally, ODs are regarded as hard-tissue regenerative cells; however, our data unexpectedly present ODs as a crucial population that participates in IR-associated tissue deconstruction. Specifically, we uncovered that nuclear factor-kappa b (NF-κB) signaling orchestrated Tumor necrosis factor α (TNF-α)-induced matrix metalloproteinases (Mmps) and Cathepsin K (Ctsk) functions in ODs to enhance matrix degradation and tissue resorption. Furthermore, TNF-α increases Rankl/Opg ratio in ODs via NF-κB signaling by impairing Opg expression but increasing Rankl level, which utterly makes ODs cell line 17IIA11 (A11) become Trap+ and Ctsk+ multinucleated cells to perform resorptive actions. Blocking of NF-κB signaling significantly rescues matrix degradation and resorptive functions of inflamed ODs via repressing vital inflammatory proteinases Mmps and Ctsk. Utterly, via utilizing NF-κB specific small molecule inhibitors we satisfactorily attenuated inflammatory ODs-associated human dental IR in vivo. Our data reveal the underlying mechanisms of inflammatory matrix degradation and resorption via proteinase activities in IR-related pathological conditions.

Invasive Blood Pressure Measurement and In-hospital Mortality in Critically Ill Patients With Hypertension.

Background: Invasive blood pressure (IBP) measurement is common in the intensive care unit, although its association with in-hospital mortality in critically ill patients with hypertension is poorly understood. Methods and Results: A total of 11,732 critically ill patients with hypertension from the eICU-Collaborative Research Database (eICU-CRD) were enrolled. Patients were divided into 2 groups according to whether they received IBP. The primary outcome in this study was in-hospital mortality. Propensity score matching (PSM) and inverse probability of treatment weighing (IPTW) models were used to balance the confounding covariates. Multivariable logistic regression was used to evaluate the association between IBP measurement and hospital mortality. The IBP group had a higher in-hospital mortality rate than the no IBP group in the primary cohort [238 (8.7%) vs. 581 (6.5%), p < 0.001]. In the PSM cohort, the IBP group had a lower in-hospital mortality rate than the no IBP group [187 (8.0%) vs. 241 (10.3%), p = 0.006]. IBP measurement was associated with lower in-hospital mortality in the PSM cohort (odds ratio, 0.73, 95% confidence interval, 0.59-0.92) and in the IPTW cohort (odds ratio, 0.81, 95% confidence interval, 0.67-0.99). Sensitivity analyses showed similar results in the subgroups with high body mass index and no sepsis. Conclusions: In conclusion, IBP measurement was associated with lower in-hospital mortality in critically ill patients with hypertension, highlighting the importance of IBP measurement in the intensive care unit.

SF3B1 mutation in pancreatic cancer contributes to aerobic glycolysis and tumor growth through a PP2A-c-Myc axis.

Hot spot gene mutations in splicing factor 3b subunit 1 (SF3B1) are observed in many types of cancer and create abundant aberrant mRNA splicing, which is profoundly implicated in tumorigenesis. Here, we identified that the SF3B1 K700E (SF3B1K700E ) mutation is strongly associated with tumor growth in pancreatic ductal adenocarcinoma (PDAC). Knockdown of SF3B1 significantly retarded cell proliferation and tumor growth in a cell line (Panc05.04) with the SF3B1K700E mutation. However, SF3B1 knockdown had no notable effect on cell proliferation in two cell lines (BxPC3 and AsPC1) carrying wild-type SF3B1. Ectopic expression of SF3B1K700E but not SF3B1WT in SF3B1-knockout Panc05.04 cells largely restored the inhibitory role induced by SF3B1 knockdown. Introduction of the SF3B1K700E mutation in BxPC3 and AsPC1 cells also boosted cell proliferation. Gene set enrichment analysis demonstrated a close correlation between SF3B1 mutation and aerobic glycolysis. Functional analyses showed that the SF3B1K700E mutation promoted tumor glycolysis, as evidenced by glucose consumption, lactate release, and extracellular acidification rate. Mechanistically, the SF3B1 mutation promoted the aberrant splicing of PPP2R5A and led to the activation of the glycolytic regulator c-Myc via post-translational regulation. Pharmacological activation of PP2A with FTY-720 markedly compromised the growth advantage induced by the SF3B1K700E mutation in vitro and in vivo. Taken together, our data suggest a novel function for SF3B1 mutation in the Warburg effect, and this finding may offer a potential therapeutic strategy against PDAC with the SF3B1K700E mutation.