OBJECTIVE To explore the potential mechanism of ketamine-induced cognitive impairment in mice based on metabolomics. METHODS Male C57BL/6 mice were randomly divided into control group and ketamine group （25 mg/kg）， with 12 mice in each group. Each group of mice was intraperitoneally injected with normal saline or corresponding drugs， 4 times a day， for 10 consecutive days. On the last 2 days of drug administration， the cognitive behavior was evaluated by Y maze and novel object recognition test， and the histopathological changes in the prefrontal cortex （PFC） were observed. Ultra-high performance liquid chromatography-tandem mass spectrometry technology was used to analyze the changes of metabolites in PFC， screen for differential metabolites， and perform pathway enrichment analysis. RESULTS Compared with the control group， the morphology of PFC neurons in the ketamine group of mice was inconsistent. There were cavities around the nucleus， and the number of deeply stained cells increased. The mean optical density value of the Nissl staining positive area was significantly reduced， and the alternation rate and discrimination index were significantly reduced （P＜0.05 or P＜0.01）. In the PFC tissue samples of mice of the two groups， there were a total of 114 differential metabolites， including 73 up-regulated and 41 down-regulated metabolites， including glutamine， succinic acid， ketoglutarate， and choline， etc. The differential metabolites mentioned above were mainly enriched in metabolism of alanine， aspartate and glutamate， metabolism of arginine and proline， γ aminobutyric acid synapses， pyrimidine metabolism， cholinergic synapses pathways， etc. CONCLUSIONS Ketamine can induce cognitive impairment in mice. Its neurotoxicity is related to abnormal synaptic transmission and energy metabolism， and neuroimmune regulation disorders.

Humans ; Consanguinity ; Exome Sequencing ; Mutation/genetics* ; Sequence Analysis, DNA ; Ciliary Motility Disorders ; Axonemal Dyneins/genetics*

Objective:To analyze the clinical characteristics, prognosis and gene mutation in patients with dilated cardiomyopathy (DCM) in Keshan disease area of Sichuan Province, and to explore the risk factors for all-cause death in DCM patients.Methods:In June 2016, 55 DCM patients diagnosed at the local disease prevention and control center through clinical manifestations, electrocardiogram examination, and echocardiography were selected as the survey subjects in Mianning County, Liangshan Yi Autonomous Prefecture, and Renhe District, Panzhihua City, Keshan disease areas of Sichuan Province. Baseline clinical data were analyzed and long-term follow-up was conducted. The follow-up period ended June 15, 2021, with the endpoint of all-cause death. Univariate Cox regression was used to analyze the influencing factors of all-cause death in patients, and Kaplan-Meier (K-M) survival curve was used to analyze the survival time of patients. At the same time, peripheral venous blood was collected from 27 DCM patients. After separating white blood cells, DNA was extracted, and whole exome sequencing was performed to screen potential pathogenic genes.Results:Among the 55 DCM patients, 40 were males and 15 were females. The age was (54.09 ± 12.38) years old. The heart function classification of New York Heart Association (NYHA) was mainly grade Ⅱ and Ⅲ, accounting for 94.55% (52/55). The follow-up time for 55 DCM patients was (7.02 ± 2.96) years, and 17 patients experienced all-cause death, accounting for 30.91% (17/55), including 15 males and 2 females. Compared with the survival group, the death group had a lower incidence of syncope (χ 2 = 6.57, P = 0.010), but higher rates of bilateral lower limb edema (χ 2 = 6.43, P = 0.017), pulmonary congestion (χ 2 = 7.61, P = 0.006), intraventricular conduction block (χ 2 = 6.41, P = 0.011), and angiotensin-converting enzyme inhibitor (ACEI) use (χ 2 = 6.57, P = 0.010), as well as increased left ventricular diameter ( t = 2.36, P = 0.022). Univariate Cox regression analysis showed that bilateral lower limb edema [hazard ratio ( HR) = 4.61, P = 0.042] and intraventricular conduction block ( HR = 3.20, P = 0.019) were risk factors for all-cause death of DCM patients. The results of K-M survival curve analysis showed that patients with bilateral lower limb edema and intraventricular conduction block had higher all-cause death rates (log-rank χ 2 = 5.02, 6.24, P = 0.025, 0.012). Whole exome sequencing results showed that 4 patients were detected to carry pathogenic or suspected pathogenic gene mutations, with a positive rate of 14.81% (4/27), involving three genes: β-myosin heavy chain 7 (MYH7), calreticulin 3 (CALR3), and gelsolin (GSN). Conclusions:The all-cause death rate of DCM patients in the Keshan disease area of Sichuan Province is relatively high. Dead patients are prone to bilateral lower limb edema, pulmonary congestion, and intraventricular conduction block, as well as increased left ventricular diameter. Bilateral lower limb edema and intraventricular conduction block are independent predictive risk factors for all-cause death in DCM patients. MYH7, CALR3 and GSN are involved in the pathogenesis of DCM.

Objective:To screen interleukin(IL)-1β secretion-related membrane transporters by macrophage experiment in vitro and conventional knockout mice.Methods:THP-1 cell line was differentiated to obtain human THP-1-derived macrophages,and the primary macrophages were obtained from human peripheral blood.FVB wild-type mice with the same sex and age were used as the controls of MRP1 knockout mice.The macrophages in abdominal cavity and bone marrow of mice were cultivated.The cells were treated with ABCC1/MRP1,ABCG2/BCRP,ABCB1/P-gp,OATP1B1,and MATE transporter inhibitors,then stimulated by lipopolysaccharide and adenosine triphosphate.The secretion level of IL-iβ was detected by ELISA,Western blot,and immunofluorescence.Results:After inhibiting ABCC1/MRP1 transporter,the secretion of IL-1β decreased significantly,while inhibition of the other 4 transporters had no effect.In animal experiment,the level of IL-1 β secreted by macrophages in bone marrow of MRP1 knockout mice was significantly lower than control group(P＜0.05).Conclusion:ABCC1/MRP1 transporter is a newly discovered IL-1β secretion pathway,which is expected to become a new target for solving clinical problems such as cytokine release syndrome.

Purpose: Numerous studies have produced conflicting findings regarding the efficacy of statins in prostate cancer treatment. Our objective was to examine the correlation between statin usage and clinical outcomes in Taiwanese men with de novo metastatic prostate cancer. Materials and Methods: We identified patients diagnosed with de novo metastatic prostate cancer from the Chang Gung Research Database spanning the years 2007 to 2020. To minimize confounding bias, we employed the inverse probability of treatment weighting (IPTW) method. Clinical outcomes were assessed using IPTW-adjusted Kaplan-Meier curves. Multivariate Cox proportional hazard regression analysis was utilized to evaluate the association between mortality and clinical factors. Results: The study cohort comprised 1,716 statin users and 276 non-users. Patients who used statins exhibited a longer median overall survival (85.4 months compared to 58.2 months; p=0.001) and cancer-specific survival (112.6 months compared to 75.7 months; p<0.001) compared to non-users. The median time to the development of castration-resistant status was similar between statin users and non-users (p=0.069). Multivariable Cox proportional hazards regression analysis, after IPTW adjustment, demonstrated that statin use was associated with improved overall survival. Conclusions Our study indicates that the use of statins following a de novo metastatic prostate cancer diagnosis enhances survival outcomes. However, statins did not appear to delay the onset of castration-resistant status. Further large-scale and long-term studies are warranted to investigate the biological effects of statins in men with prostate cancer.

Hyperplasia of mammary glands is a benign breast disease with disordered breast structure. Nowadays, the incidence rate of breast hyperplasia in women is increasing year by year, and the etiology is related to the imbalance of estrogen and progesterone in the body. The symptoms include breast pain, breast nodules, or nipple discharge, which can develop into breast cancer in the context of psychological pressure. Therefore, it is timely and effectively necessary for people to treat the symptoms. At present, traditional Chinese medicine(TCM) often treats breast hyperplasia by oral drug, external application, acupuncture, moxibustion, and massage, while western medicine often uses hormone therapy or surgery. TCM can regulate hormone levels to treat breast hyperplasia. Acupuncture, moxibustion, and other methods can stimulate acupoints to reduce breast lumps. However, since TCM is easy to produce hepatorenal toxicity after long-term use and simple external treatment is slow to take effect, rapid and effective treatment is difficult to be achieved. Although western medicine can inhibit the disease, it is easy to produce toxic and side effects if taken for a long time. In addition, surgery can only remove the focus and the recurrence rate is high. Some studies have found that the combination of oral and external use of TCM compounds has a significant effect, with mild toxic and side effects, few adverse reactions, and a low recurrence rate. Based on the relevant literature in recent years, this article reviewed the combination of oral and external treatment of TCM in the treatment of hyperplasia of mammary glands, discussed the effectiveness, clinical evaluation indexes, and mechanism, and pointed out the existing shortcomings to explore a comprehensive therapy worthy of clinical application.
Female ; Humans ; Mammary Glands, Human ; Medicine, Chinese Traditional ; Hyperplasia ; Acupuncture Therapy ; Breast Neoplasms ; Drug-Related Side Effects and Adverse Reactions ; Estrogens

Objective:To investigate the intervention effects and influencing factors of family management intervention on parents' disease management ability, family function of children with coronary artery lesions in Kawasaki disease.Methods:This was a quasi experimental study. Conveniently, 88 parents of children with Kawasaki disease coronary artery lesions from the Children's Hospital of Chongqing Medical University from March 2020 to June 2021 were selected for the study, and they were divided into the control group and the intervention group according to the order of the first consultation with 44 cases in each group. In the control group, conventional care and health education were used, while in the intervention group, a 6-month family management intervention was implemented on the basis of the control group. Family Management Measure (FaMM), Family Assessment Device (FAD) were used to assess the parents' disease management ability, family function before and after the intervention, respectively.Results:A total of 88 study subjects completed the pre-intervention survey in this study, and a total of 79 study subjects were surveyed when they returned to the hospital for review at the end of 6 months of intervention, including 40 in the intervention group and 39 in the control group, with a missed rate of 10.23% (9/88). There was no significant difference in the score of FAD, FaMM, Kawasaki disease knowledge questionnaire before the intervention between the two groups ( P>0.05). The scores of FAD in the intervention group was (21.58 ± 4.60) points, which was lower than that in the control group (24.62 ± 5.28) points, and the difference was statistically significant ( t=2.73, P <0.05). The scores of FaMM in the intervention group was (46.83 ± 6.02) points, which was higher than that in the control group (42.72 ± 6.09) points, and the differences was statistically significant ( t=-3.01, P <0.05). The age of the child, and whether the child was an only child were the influencing factors of the difference in disease management ability, and the difference in the family function of the parents of the child, respectively (all P<0.05). Conclusions:Family management intervention can improve the disease management ability of the parents of children with coronary artery lesion, improve family function. In the future, targeted interventions can be conducted according to different ages of children, and different family members' composition in order to obtain better intervention effects.

Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.
Humans ; Male ; Animals ; Mice ; Semen/metabolism* ; Dyneins/metabolism* ; Cilia/metabolism* ; Mutation ; Ciliary Motility Disorders/genetics*

Paeonia veitchii and P. lactiflora are both original plants of the famous Chinese medicinal drug Paeoniae Radix Rubra in the Chinese Pharmacopoeia. They have important medicinal value and great potential in the flower market. The selection of stable and reliable reference genes is a necessary prerequisite for molecular research on P. veitchii. In this study, two reference genes, Actin and GAPDH, were selected as candidate genes from the transcriptome data of P. veitchii. The expression levels of the two candidate genes in different tissues(phloem, xylem, stem, leaf, petiole, and ovary) and different growth stages(bud stage, flowering stage, and dormant stage) of P. veitchii were detected using real-time fluorescence quantitative technology(qRT-PCR). Then, the stability of the expression of the two reference genes was comprehensively analyzed using geNorm, NormFinder, BestKeeper, ΔCT, and RefFinder. The results showed that the expression patterns of Actin and GAPDH were stable in different tissues and growth stages of P. veitchii. Furthermore, the expression levels of eight genes(Pv-TPS01, Pv-TPS02, Pv-CYP01, Pv-CYP02, Pv-CYP03, Pv-BAHD01, Pv-UGT01, and Pv-UGT02) in different tissues were further detected based on the transcriptome data of P. veitchii. The results showed that when Actin and GAPDH were used as reference genes, the expression trends of the eight genes in different tissues of P. veitchii were consistent, validating the reliability of Actin and GAPDH as reference genes for P. veitchii. In conclusion, this study finds that Actin and GAPDH can be used as reference genes for studying gene expression levels in different tissues and growth stages of P. veitchii.
Real-Time Polymerase Chain Reaction/methods* ; Paeonia/genetics* ; Actins/genetics* ; Reproducibility of Results ; Transcriptome ; Glyceraldehyde-3-Phosphate Dehydrogenases/genetics* ; Reference Standards ; Gene Expression Profiling/methods*

Objective: To elucidate the clinical features of patients with refractory juvenile dermatomyositis (JDM), and to explore the efficacy and safety of tofacitinib in the treatment of refractory JDM. Methods: A total of 75 JDM patients admitted to the Department of Rheumatology and Immunology in Shenzhen Children's Hospital from January 2012 to January 2021 were retrospectively analyzed, and to analyze the clinical manifestations, efficacy and safety of tofacitinib in the treatment of refractory JDM. Patients were divided into refractory group with using of glucocorticoids in combination with two or more anti-rheumatic drugs for treatment, and the presence of disease activity or steroid dependence after a one-year follow-up. The non-refractory group is defined as clinical symptoms disappeared, laboratory indicators were normal, and clinical remission was achieved after initial treatment, and the clinical manifestations and laboratory indexes of the two groups were compared. The Mann-Whitney U test, Fisher's precision probability test was used for intergroup comparison. Binary Logistic multivariate regression analysis was used to identify risk factors for refractory JDM. Results: Among the 75 children with JDM, 41 were males and 34 were females with a age of onset of 5.3 (2.3, 7.8) years. The refractory group consisted of 27 cases with a age of onset of 4.4 (1.5, 6.8) years, while the non-refractory group consisted of 48 cases with a age of onset of 5.9 (2.5, 8.0) years. Compared with 48 cases in the non-refractory group, the proportion of interstitial lesions and calcinosis in the refractory group was higher than that in the non-refractory group (6 cases (22%) vs. 2 cases (4%), 8 cases (30%) vs. 4 cases (8%), both P<0.05). Binary Logistic regression analysis showed that observation group were more likely to be associated with to interstitial lung disease (OR=6.57, 95%CI 1.22-35.31, P=0.028) and calcinosis (OR=4.63, 95%CI 1.24-17.25, P=0.022). Among the 27 patients in the refractory group, 22 cases were treated with tofacitinib, after treatment with tofacitinib, 15 of 19 cases (86%) children with rashes showed improvement, and 6 cases (27%) with myositis evaluation table score less than 48 score both were improved, 3 of 6 cases (27%) had calcinosis were relieved, and 2 cases (9%) had glucocorticoid-dependence children were successfully weaned off. During the tofacitinib treatment, there was no increase in recurrent infection, blood lipids, liver enzymes, and creatinine were all normal in the 22 cases. Conclusions: Children with JDM with calcinosis and interstitial lung disease are more likely to develop refractory JDM. Tofacitinib is safe and effective for refractory JDM.
Child ; Female ; Male ; Humans ; Dermatomyositis/drug therapy* ; Retrospective Studies ; Risk Factors ; Calcinosis ; Glucocorticoids/therapeutic use*