A Nomogram Based on Conventional and Contrast-Enhanced Ultrasound for Pre-operative Prediction of Nipple-Areola Complex Involvement in Breast Cancer: A Prospective Study.

OBJECTIVE: Accurately predicting nipple-areola complex (NAC) involvement in breast cancer is essential for identifying eligible patients for a nipple-sparing mastectomy. This study was aimed at developing a pre-operative nomogram for NAC involvement in breast cancer using conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS). METHODS: All patients with primary breast cancer confirmed by pre-operative biopsy underwent US and CEUS examinations. Post-operative pathology was used as the gold standard in assessing NAC involvement. Lasso regression was used to select the predictors most associated with NAC involvement. A nomogram was constructed to calculate the diagnostic efficacy. The data were internally verified with 500 bootstrapped replications, and a calibration curve was generated to validate the predictive capability. RESULTS: Seventy-six patients with primary breast cancer were included in this study, which included 16 patients (21.1%) with NAC involvement and 60 patients (78.9%) without NAC involvement. Among the 23 features of US and CEUS, Lasso regression selected one US feature and two CEUS features, namely, ductal echo extending from the lesion, ductal enhancement extending to the nipple and focal nipple enhancement. A nomogram was constructed, and the results revealed that the area under the curve, sensitivity, specificity and accuracy were 0.891, 81.3%, 86.7% and 85.5%, respectively. The calibration curve exhibited good consistency between the predicted probability and the actual probability. CONCLUSION: The nomogram developed based on US and CEUS had good performance in predicting NAC involvement in breast cancer before surgery, which may facilitate the selection of suitable patients for NAC preservation with greater oncological safety.

Effect of the Holistic Nursing Model of Responsibility System on the Mental State of Elderly Patients with Limb Fractures Fixed by Splints in the Emergency Department.

Objective: To explore the effect of the overall nursing mode of responsibility system on the psychological state of elderly patients with limb fractures fixed by splints. Methods: This study selected 150 elderly patients who received emergency treatment of a limb fracture fixed by a traditional Chinese medicine splint in our hospital from May 2018 to June 2021 as the research subjects. They were divided into a control group and an observation group, with 75 cases in each group. The control group was intervened by traditional nursing mode, and the research group was intervened by responsible overall nursing mode. The quality of nursing work was observed and compared with the nursing staff's work quality and satisfaction, patients' psychological states and satisfaction, and the risk of clinical adverse events. Results: After management, the quality of nursing work in the two groups was significantly improved. Compared with before management, the scores of basic nursing measures, nursing of critical patients, ward environment management, disinfection and isolation, rescue drugs and instruments, and nursing document management in the observation group were significantly higher than those in the control group (P < 0.05). After management, the work quality and satisfaction of nurses in the two groups were significantly higher than those before management. The SERVQUAL scale score and satisfaction score in the observation group were significantly higher than those in the control group (P < 0.05). The scores of HAMA and HAMD in the observation group were significantly lower than those in the control group (P < 0.05). The overall satisfaction of nursing in the observation group was 96.00%, which was significantly higher than the 80.00% in the control group (P < 0.05). The incidence of adverse events in the observation group was 8.00%, which was significantly lower than 17.33% in the control group (P < 0.05). Conclusion: Giving elderly patients with limb fracture emergencies treated with splint fixation using traditional Chinese medicine the overall nursing mode management and responsibility system can give the elderly patients comprehensive and systematic clinical nursing, increase their trust and compliance with nursing work, improve the patient's psychological state, improve clinical satisfaction, and achieve the ideal doctor-patient relationship, which is worthy of clinical application.

Family Functioning and Intraindividual Reaction Time Variability Interactively Predict Children's Externalizing Problems.

Family functioning including family adaptability and family cohesion, and intraindividual reaction time variability (IIV) which serves as an index of attentional control has been found to relate to children's externalizing problems. However, it remains unknown whether family functioning interacts with children's IIV to predict their externalizing problems based on the diathesis-stress model. The present study examined this concern. Participants included 168 (Mage = 7.35 years, SD = 0.48; 48% boys) and 155 (Mage = 8.32 years, SD = 0.45; 49% boys) children at the first (T1) and second (after one year, T2) measurements, respectively. At T1, a flanker task was used to assess children's IIV. Mothers reported family functioning using the Chinese version of the Family Adaptability and Cohesion Scales, and children's externalizing problems using the Chinese version of the Child Behavior Checklist. At T2, mothers reported children's externalizing problems again. Results indicated that family functioning negatively and IIV positively correlated with children's externalizing problems. Furthermore, family functioning interacted with children's IIV to predict their externalizing problems concurrently and longitudinally. Specifically, low family functioning combined with greater IIV predicted prospective externalizing problems. Findings suggested that better attentional control (indexed by lower IIV) may buffer the negative effect of poor family functioning.

Study of nonsynchronous online teaching of regional anatomy for international students integrated with medical humanities and local culture during COVID-19 pandemic.

PURPOSE: The COVID-19 pandemic imposed unexpected disruptions to anatomical educational practice, the teaching of regional anatomy for international students which has changed to an online format and faces various challenges. The challenges include creating online education homogeneous/equivalent to offline education, introducing local culture to international students, and educating students in medical humanities and ethics. METHODS: To address these problems, the teaching staff integrated medical humanities and local culture into nonsynchronous online teaching of regional anatomy. RESULTS: The nonsynchronous online teaching with interpreted videos of dissections does not significantly affect the experimental and total scores of regional anatomy courses for international students. Integrating medical humanities and local culture into this teaching model is appreciated by them and also has a good teaching effect. CONCLUSION: Students not only gained professional knowledge but also obtained enhanced exposure to local culture and professional spirit from this regional anatomy education.

Synthesis and biological evaluation of cholic acid-conjugated oxaliplatin as a new prodrug for liver cancer.

A cholic acid-conjugated oxaliplatin, LLC-202, is developed as a novel prodrug for liver cancer. The conjugate is obtained by using 3-NH2-cyclobutane-1,1-dicarboxylate as a linker between the oxaliplatin analogue and cholic acid moiety and cholic acid is strongly bonded to the linker via an amide bond. Pharmacokinetic experiment shows that LLC-202 is mainly distributed and accumulated in the liver after intravenous administration to Sprague-Dawley rats, revealing the liver-targeting profile. Compared to oxaliplatin, LLC-202 is more easily taken up by human liver cancer cells than normal human liver cells. LLC-202 exhibits higher in vitro anticancer activity and higher efficacy comparable to oxaliplatin in treating primary hepatocellular carcinoma in C57BL/6 mice. It can significantly prolong the survival time of tumor-bearing mice by inducing apoptosis and inhibiting proliferation of cancer cells. In addition, LLC-202 shows less cytotoxicity toward normal human liver cells than oxaliplatin. Its acute toxicity in healthy Kunming (KM) mice after i.v. administration is comparable to oxaliplatin. Histopathological examination reveals that the main toxicity of LLC-202 in mice is the depression of bone marrow hematopoietic cells. The results suggest that LLC-202 has great potential for further development as a new prodrug specific for liver cancer.

Deep learning-enabled pelvic ultrasound images for accurate diagnosis of ovarian cancer in China: a retrospective, multicentre, diagnostic study.

BACKGROUND: Ultrasound is a critical non-invasive test for preoperative diagnosis of ovarian cancer. Deep learning is making advances in image-recognition tasks; therefore, we aimed to develop a deep convolutional neural network (DCNN) model that automates evaluation of ultrasound images and to facilitate a more accurate diagnosis of ovarian cancer than existing methods. METHODS: In this retrospective, multicentre, diagnostic study, we collected pelvic ultrasound images from ten hospitals across China between September 2003, and May 2019. We included consecutive adult patients (aged ≥18 years) with adnexal lesions in ultrasonography and healthy controls and excluded duplicated cases and patients without adnexa or pathological diagnosis. For DCNN model development, patients were assigned to the training dataset (34 488 images of 3755 patients with ovarian cancer, 541 442 images of 101 777 controls). For model validation, patients were assigned to the internal validation dataset (3031 images of 266 patients with ovarian cancer, 5385 images of 602 with benign adnexal lesions), external validation datasets 1 (486 images of 67 with ovarian cancer, 933 images of 268 with benign adnexal lesions), and 2 (1253 images of 166 with ovarian cancer, 5257 images of 723 benign adnexal lesions). Using these datasets, we assessed the diagnostic value of DCNN, compared DCNN with 35 radiologists, and explored whether DCNN could augment the diagnostic accuracy of six radiologists. Pathological diagnosis was the reference standard. FINDINGS: For DCNN to detect ovarian cancer, AUC was 0·911 (95% CI 0·886-0·936) in the internal dataset, 0·870 (95% CI 0·822-0·918) in external validation dataset 1, and 0·831 (95% CI 0·793-0·869) in external validation dataset 2. The DCNN model was more accurate than radiologists at detecting ovarian cancer in the internal dataset (88·8% vs 85·7%) and external validation dataset 1 (86·9% vs 81·1%). Accuracy and sensitivity of diagnosis increased more after DCNN-assisted diagnosis than assessment by radiologists alone (87·6% [85·0-90·2] vs 78·3% [72·1-84·5], p<0·0001; 82·7% [78·5-86·9] vs 70·4% [59·1-81·7], p<0·0001). The average accuracy of DCNN-assisted evaluations for six radiologists reached 0·876 and were significantly augmented when they were DCNN-assisted (p<0·05). INTERPRETATION: The performance of DCNN-enabled ultrasound exceeded the average diagnostic level of radiologists matched the level of expert ultrasound image readers, and augmented radiologists' accuracy. However, these observations warrant further investigations in prospective studies or randomised clinical trials. FUNDING: National Key Basic Research Program of China, National Sci-Tech Support Projects, and National Natural Science Foundation of China.

Antitumor Activity of α-Linolenic Acid-Paclitaxel Conjugate Nanoparticles: In vitro and in vivo.

PURPOSE: Small molecule modified antitumor drug conjugate nanoparticles have the advantages of high drug loading, simple synthesis and preparation, and better biocompatibility. Due to the large demand for exogenous α-linolenic acid (ALA) by tumor cells, we synthesized α-linolenic acid-paclitaxel conjugate (ALA-PTX) and prepared α-linolenic acid-paclitaxel conjugate nanoparticles (ALA-PTX NPs), in order to obtain better tumor cellular uptake and antitumor activity in vitro and in vivo. METHODS: We synthesized and characterized ALA-PTX, and then prepared and characterized ALA-PTX NPs. The cellular uptake, uptake pathways, intracellular behavior, in vitro and in vivo antitumor activity of ALA-PTX NPs were evaluated. RESULTS: The size of ALA-PTX NPs was approximately 110.7±1.7 nm. The drug loading was approximately 90% (w/w) with CrEL-free and organic solvent-free characteristics. The cellular uptake of ALA-PTX NPs was significantly higher than that of PTX injection by MCF-7, MCF-7/ADR and HepG2 cells. In these three cell lines, the cellular uptake of ALA-PTX NPs at 6h was approximately 1.5-2.6 times higher than that of PTX injection. ALA-PTX NPs were ingested through clathrin-mediated endocytosis, then transferred to lysosomes, and could dissolve in cells to play an antitumor activity. The in vitro and in vivo antitumor activity of ALA-PTX NPs was confirmed in MCF-7/ADR and HepG2 cell models and tumor-bearing nude mouse models. CONCLUSION: ALA-PTX NPs developed in our study could provide a new method for the preparation of nano-delivery systems suitable for antitumor therapy that could increase tumor cellular uptake and enhance antitumor activity.

Pharmacokinetics and tissue distribution in rats of a novel anticancer platinum compound LLC-1903.

LLC-1903, a novel anticancer compound, was synthesized by optimizing the structure, which was derived from altering the leaving group of lobaplatin. It has an excellent in vitro anti-cancer activity, high water solubility, high stability in solution and low in vivo toxicity according to our former study.The plasma pharmacokinetics (PK) and tissue distribution of LLC-1903 and lobaplatin in rats were determined after intravenous administration of a single dose (0.06 mmol/kg body weight). Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the concentration of platinum (Pt) in plasma and tissue samples.Most PK parameters of the Pt in LLC-1903 showed a significant difference from those of lobaplatin. The plasma level of LLC-1903 is only half of that of lobaplatin (p < 0.01) which could be the direct result of faster drug clearance. The tissue distribution showed that both LLC-1903 and lobaplatin were mainly found in the liver and kidney, and less in other organs. At four time points (0.083, 0.5, 1 and 4 h) after administration, the tissue concentrations of LLC-1903 were almost always significantly higher than those of lobaplatin (p < 0.05 or p < 0.01).

RANK/RANKL Acts as a Protective Factor by Targeting Cholangiocytes in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the highly selective autoimmune injury of small intrahepatic bile ducts. Studies reported that the cholangiocytes from PBC patients expressed significantly higher levels of both receptor activator of nuclear factor-kappa B (RANK) and its ligand RANKL. However, the accurate role of RANK/RANKL axis in PBC remains unclear. METHODS: Forty patients with PBC were enrolled according to the inclusion criteria. The biochemical parameters (alkaline phosphatase, ALP; gamma-glutamyltransferase, GGT; alanine aminotransferase, ALT; aspartate transaminase, AST; total bilirubin, TB) were collected at baseline and followed-up after 6 months of treatment with ursodeoxycholic acid (UDCA, 15 mg/kg d). Stages of PBC were diagnosed based on liver biopsy histopathology according to Nakanuma's criteria. RANK expression in hepatic tissues was detected by immunohistochemistry. The cellular immunofluorescence method was used to locate the distribution of RANK in the human intrahepatic biliary epithelial cells (HIBECs) cultured in vitro. HIBECs were treated with RANKL at a concentration of 100 ng/ml or transfected with RANK-overexpressing lentivirus (LV-RANK). CCK-8 assay and cell cycle assay were used to detect the cell proliferation. Real-time PCR was used to detect the expression of IL-6, E-cadherin, VCAM, ICAM-1, TNF-α, and CD80. RESULTS: RANK expression in liver biopsies from early PBC patients (stage I + stage II) was significantly lower than that from advanced PBC patients (stage III + stage IV) (1.7 ± 0.63 vs. 2.3 ± 0.45 scores, P < 0.05). High-RANK patients seemed to have better response to UDCA than low-RANK patients (88.9% vs. 40.9%, P < 0.05). The baseline biochemical parameters between the two groups were comparable. The decline percentages of ALP and GGT after UDCA treatment were more obvious in high-RANK patients than those in low-RANK patients (53.90% ± 9.82% vs. 23.93% ± 6.24%, P < 0.05; 74.11% ± 7.18% vs. 48.00% ± 8.17%, P < 0.05, respectively). HIBECs proliferation was significantly inhibited after treatment of RANKL or transfection with LV-RANK. Increased expression of IL-6 and E-cadherin was observed in HIBECs treated with RANKL or LV-RANK. CONCLUSION: The overall hepatic RANK expression was associated with disease severity and biochemical response in PBC patients. Activation of RANK/RANKL signaling pathway inhibited cholangiocytes proliferation in vitro. Our study suggested that RANK/RANKL pathway might be a potential target of immunotherapy of PBC based on its involvement in the occurrence and development of the disease.

The Effect Of Fluvoxamine On Sleep Architecture Of Depressed Patients With Insomnia: An 8-Week, Open-Label, Baseline-Controlled Study.

BACKGROUND AND AIMS: Fluvoxamine can markedly increase the serum melatonin level, which regulates human circadian rhythm. However, only limited research has evaluated the effects of fluvoxamine on sleep architecture. Thus, the current study aims to investigate the effect of fluvoxamine on PSG characteristics and the impact of persistent insomnia on the prognosis of depression in the depressed individual with insomnia over the course of 8 weeks. METHODS: Thirty-one clinically depressed patients with insomnia were enrolled in this 8-week, open-label, baseline-controlled study, and 23 patients completed the study. All participants were assigned to receive fluvoxamine for 8 weeks. They were assessed by the PSG, Hamilton Rating Scale for Depression (17 items) (HRSD-17), Clinical Global Index, Pittsburgh Sleep Quality Index, and Epworth Sleepiness Scale at baseline and the following visits, which were at day 14, day 28, and day 56. A patient with an ≥4 HRSD-17 sleep disturbance factor score at both baseline and endpoint (day 56) was defined as a patient with persistent insomnia. RESULTS: Compared with baseline, the percentage of stage 3 sleep had significantly (F=11.630, P=0.001) increased in all 3 visits. Moreover, the percentage of rapid eye movement sleep was reduced during the study, with only a significant difference (F=3.991, P=0.027) between baseline and day 14. Finally, 47.8% (11/23) of the participants were in remission, and 60.9% (14/23) of them did not report insomnia. The clinical remission ratio of the persistent insomnia group (11.1% [1/9]) (χ2 =8.811, P=0.004) was significantly lower than that of the non-insomnia group (71.4% [10/14]) at the endpoint. Additionally, during the first clinical evaluation (day 14), patients without insomnia had significantly higher final remission ratios than patients with insomnia (80% [8/10] versus 30.8% [4/13]; χ2 =5.79; P=0.016). CONCLUSION: Fluvoxamine improved PSG parameters and ameliorated complaints of insomnia simultaneously during this 8-week study. Moreover, depressed individuals who reported persistent insomnia were at higher risk of remaining depressed by the end of the trial, which might be forecasted by the sleep status on day 14. TRIAL REGISTRATION: The Effect of Fluvoxamine on Polysomnogram in Depressed Patients with Insomnia; https://clinicaltrials.gov/ct2/show/NCT02442713. Registry identifier: NCT02442713. Registry date: May 13, 2015.

Telbivudine Treatment during Late Pregnancy Prevents Mother-to-Child Transmission of Hepatitis B Virus: A Retrospective Study.

Purpose: To investigate the efficacy of telbivudine (LdT) in blocking mother-to-child transmission (MTCT) of hepatitis B virus (HBV) during late pregnancy. Methods: A total of 651 pregnant women aged 18-40 in Nantong Third People's Hospital and Hospital affiliated to Nantong University with positive hepatitis B surface antigen (HBsAg) and HBV DNA were enrolled between January 2011 and December 2015. Patients with HBV DNA≥106 copies/mL (n=251) received LdT during late pregnancy according to the patients' will, while 136 high viral patients with HBV DNA≥106 copies/mL who did not take LdT therapy and 268 low viral patients with HBV DNA<106 copies/mL served as the controls. Results: At 7 months and 1 year postpartum, the basal HBV DNA serum level of treated patients declined significantly (P<0.001), while no obvious decline was observed in the untreated high viraemic controls (P<0.05) and untreated low viraemic controls (P<0.05). Only 1 infant (0.4%) in LdT group was HBsAg positive at 7 months, while 14 (5.2%) were in the untreated low viraemic controls (P<0.001) and 15 (11.0%) were in untreated high viraemic controls (P<0.001). Conclusion: For pregnant women with HBV DNA≥106 copies/mL, the use of LdT during late pregnancy could effectively reduce the MTCT rate of HBV.

Effective Gene Silencing Mediated by Polypeptide Nanoparticles LAH4-L1-siMDR1 in Multi-Drug Resistant Human Breast Cancer.

MDR (multi-drug resistance) is a major obstacle to the successful treatment of cancers. The combination therapeutic based on RNAi has been investigated as a potential strategy for reversing the MDR. However, the effective delivery of siRNA in vivo remains the challenge for the reality of these candidate RNAi drugs. Cationic peptides for gene delivery have attracted considerable attention due to their biocompatibility and high safety. Herein, self-assembled polypeptide nanoparticles LAH4-L1-siRNA (PNLS) were prepared and loaded with a siRNA (siMDR1) for overcoming MDR in human breast cancer MCF-7/ADR cells in vitro and in vivo. Owing to its cationic charges and α-helical conformation, the histidinerich peptide enhanced cellular uptake of siRNA and represented high gene silencing efficiency. The cellular uptake pathways and internalization process of PNLS into cells were further investigated. In vivo biodistribution indicated that the PNLS exhibited higher tumor-targeted delivery. More importantly, PNLS combined with PTX (Paclitaxel) showed antitumor effects and high MDR1 gene silencing efficiency in the tumor-bearing nude mice. Overall, the PNLS achieved the genetargeted knockdown in vivo and hold immense promise for a new therapeutic drug for breast cancer treatment.

Antitumor activity of the bioreductive prodrug 3-(2-nitrophenyl) propionic acid-paclitaxel nanoparticles (NPPA-PTX NPs) on MDA-MB-231 cells: in vitro and in vivo.

BACKGROUND: 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX) is a paclitaxel (PTX) bioreductive prodrug synthesized by our lab. We hypothesize that NPPA-PTX can self-assemble to form nanoparticles (NPs). MATERIALS AND METHODS: In the present research, the theoretical partition coefficient (XlogP) and Hansen solubility parameters of NPPA-PTX were calculated. NPPA-PTX nanoparticles prepared by NPPA-PTX and DSPE-PEG (NPPA-PTX:DSPE-PEG =1:0.1, w/w) (NPPA-PTX@PEG NPs) were prepared and characterized. The cellular uptake, in vitro antitumor activity, in vivo targeting effect, tumor distribution, in vivo antitumor activity, and safety of NPPA-PTX@PEG NPs were investigated. RESULTS: Our results indicate that NPPA-PTX can self-assemble to form NPPA-PTX@PEG NPs. Both the cellular uptake and safety of NPPA-PTX@PEG NPs were higher than those of Taxol. NPPA-PTX@PEG NPs could target tumor tissues by a passive targeting effect. In tumor tissues, NPPA-PTX@PEG NPs could completely transform into active PTX. The in vivo antitumor activity of NPPA-PTX@PEG NPs was confirmed in MDA-MB-231 tumor-bearing nude mice. CONCLUSION: The bioreductive prodrug NPPA-PTX could self-assemble to form NPs. The safety and antitumor activity of NPPA-PTX@PEG were confirmed in our in vitro and in vivo experiments. The NPPA-PTX@PEG NPs developed in this study could offer a new way of preparing bioreductive prodrug, self-assembled NPs suitable for antitumor therapy.

Ultrasound-Guided Percutaneous Microwave Ablation for Subserosal Uterine Myomas.

STUDY OBJECTIVE: To prospectively evaluate the clinical effectiveness and safety of ultrasound-guided percutaneous microwave ablation for symptomatic subserosal uterine myomas. DESIGN: Prospective observational study (Canadian Task Force classification II-1). SETTING: A teaching hospital (Department of Interventional Ultrasound, General Hospital of Chinese PLA, Beijing, China). PATIENTS: Sixty-nine patients with symptomatic subserosal uterine myomas treated with ultrasound-guided percutaneous microwave ablation. INTERVENTIONS: All 69 patients underwent ultrasound-guided percutaneous microwave ablation. The number of patients lost to follow-up at was 21 at 3 months, 34 at 6 months, and 35 at 12 months. MEASUREMENTS AND MAIN RESULTS: The efficacy of treatment was evaluated based the mean myoma volume shrinkage rate and changes in Uterine Fibroid Symptom and Quality of Life Questionnaire scores at 3, 6, and 12 months after therapy. Treatment safety was evaluated based on the Society of Interventional Radiology practice guidelines. The mean patient age was 40.3 ± 4.9 years (range, 26-49 years). The mean myoma volume was 221.74 ± 153.18 cm3 before ablation, decreasing to 87.24 ± 45.93 cm3 at 3 months after ablation (p < .001), 46.68 ± 24.7 cm3 at 6 months after ablation (p < .001), and 38.05 ± 24.93 cm3 at 12 months after ablation (p <.001), respectively. Between pretreatment and 3-month follow-up, the mean symptom severity score decreased from 34.53 ± 3.83 to 12.74 ± 3.07 (p < .001), and the mean health-related quality of life score increased from 45.25 ± 10.97 to 78.48 ± 11.39 (p < .001). Both scores remained stable at the 6- and 12-month follow-up time points. No permanent injury or fatal complications were seen in this series. CONCLUSION: Ultrasound-guided percutaneous microwave ablation of subserosal uterine myomas is a promising treatment method. Further studies with larger sample sizes and a control group are needed.

The associations of long-time mobile phone use with sleep disturbances and mental distress in technical college students: a prospective cohort study.

Study Objectives: To determine the longitudinal associations of long-time mobile phone use (LTMPU) with sleep disturbances and mental distress in a prospective cohort of technical college students. Methods: A total of 4333 (response rate: 91.5%) and 3396 (response rate: 78.4%) participants were recruited at baseline and 8-month follow-up, respectively. Data were collected by a set of questionnaires including socio-demographics, lifestyle practice, duration of mobile phone use per day, sleep patterns on weekdays and weekends, as well as Insomnia Severity Index, Epworth Sleepiness Scale, reduced Morningness-Eveningness Questionnaire, Beck Depression Inventory, and Zung Self-Rating Anxiety Scale. LTMPU was defined as using mobile phone ≥4 hours/day. Results: At baseline, 23.5% (n = 1020) of the participants reported using mobile phone ≥ 4 hours/day. LTMPU at baseline was positively associated with the new incidences (range, adjusted odds ratio 1.31-1.53) of a series of the sleep disturbances and mental distress at follow-up. The discontinuation of LTMPU was associated with an amelioration of the risks of most of these problems. Cross-lagged analyses revealed bidirectional associations of the duration of mobile phone use with poor sleep and mental health outcomes. Conclusions: LTMPU predicts the new incidences of most sleep disturbances and mental distress, while discontinuation of LTMPU is associated with amelioration of these problems. Moreover, there are bidirectional associations between the duration of mobile phone use and various sleep and mental outcomes. These findings highlight the critical role of prevention and early recognition of excessive mobile phone use and their accompanied mental and sleep problems.

Anti-tumour activity of low molecular weight heparin doxorubicin nanoparticles for histone H1 high-expressive prostate cancer PC-3M cells.

Nucleus-targeting drug delivery systems (NTDDs) deliver chemotherapeutic agents to nuclei in order to improve the efficacy of anti-tumour therapy. Histone H1 (H1) plays a key role in establishing and maintaining higher order chromatin structures and could bind to cell membranes. In the present study, we selected H1 as a target to prepare a novel H1-mediated NTDD. Low molecular weight heparin (LMHP) and doxorubicin (DOX) were combined to form LMHP-DOX. Then, a novel NTDD consisting of LMHP-DOX nanoparticles (LMHP-DOX NPs) was prepared by self-assembly. The characteristics of LMHP-DOX and LMHP-DOX NPs were investigated. Histone H1 high-expressive prostate cancer PC-3M cell line was selected as the cell model. Cellular uptake, and the in vitro and in vivo anti-tumour activity of LMHP-DOX NPs were evaluated on H1 high-expressive human prostate cancer PC-3M cells. Our results indicated that intact LMHP-DOX NPs mediated by H1 could be absorbed by H1 high-expressive PC-3M cells, escape from the lysosomes to the cytoplasm, and localize in the perinuclear region via H1-mediated, whereby DOX could directly enter the cell nucleus and quickly increase the concentration of DOX in the nuclei of H1 high-expressive PC-3M cells to enhance the apoptotic activity of cancer cells. The anti-coagulant activity of LMHP-DOX NPs was almost completely diminished in rat blood compared with that of LMHP, indicating the safety of LMHP-DOX NPs. Compared to traditional NTDD strategies, LMHP-DOX NPs avoid the complicated modification of nucleus-targeting ligands and provide a compelling solution for the substantially enhanced nuclear uptake of chemotherapeutic agents for the development of more intelligent NTDDs.

The Role of Microbiome in Insomnia, Circadian Disturbance and Depression.

Good sleep and mood are important for health and for keeping active. Numerous studies have suggested that the incidence of insomnia and depressive disorder are linked to biological rhythms, immune function, and nutrient metabolism, but the exact mechanism is not yet clear. There is considerable evidence showing that the gut microbiome not only affects the digestive, metabolic, and immune functions of the host but also regulates host sleep and mental states through the microbiome-gut-brain axis. Preliminary evidence indicates that microorganisms and circadian genes can interact with each other. The characteristics of the gastrointestinal microbiome and metabolism are related to the host's sleep and circadian rhythm. Moreover, emotion and physiological stress can also affect the composition of the gut microorganisms. The gut microbiome and inflammation may be linked to sleep loss, circadian misalignment, affective disorders, and metabolic disease. In this review article, we discuss various functions of the gut microbiome and how its activities interact with the circadian rhythms and emotions of the host. Exploring the effects of the gut microbiome on insomnia and depression will help further our understanding of the pathogenesis of mental disorders. It is therefore important to regulate and maintain a normal gastrointestinal micro-ecological environment in patients when treating mental disorders.

Intravenous Transplantation of Mesenchymal Stem Cells Reduces the Number of Infiltrated Ly6C+ Cells but Enhances the Proportions Positive for BDNF, TNF-1α, and IL-1ß in the Infarct Cortices of dMCAO Rats.

The resident microglial and infiltrating cells from peripheral circulation are involved in the pathological processes of ischemia stroke and may be regulated by mesenchymal stem/stromal cell (MSC) transplantation. The present study is aimed at differentiating the neurotrophic and inflammatory roles played by microglial vs. infiltrating circulation-derived cells in the acute phase in rat ischemic brains and explore the influences of intravenously infused allogeneic MSCs. The ischemic brain injury was induced by distal middle cerebral artery occlusion (dMCAO) in SD rats, with or without MSC infusion in the same day following dMCAO. Circulation-derived infiltrating cells in the brain were identified by Ly6C, a majority of which were monocytes/macrophages. Without MSC transplantation, among the infiltrated Ly6C+ cells, some were positive for BDNF, IL-1ß, or TNF-α. Following MSC infusion, the overall number of Ly6C+ infiltrated cells was reduced by 50%. In contrast, the proportions of infiltrated Ly6C+ cells coexpressing BDNF, IL-1ß, or TNF-α were significantly enhanced. Interestingly, Ly6C+ cells in the infarct area could produce either neurotrophic factor BDNF or inflammatory cytokines (IL-1ß or TNF-α), but not both. This suggests that the Ly6C+ cells may constitute heterogeneous populations which react differentially to the microenvironments in the infarct area. The changes in cellular composition in the infarct area may have contributed to the beneficial effect of MSC transplantation.

Downregulation of iNOS, IL-1ß, and P2X7 Expression in Mast Cells via Activation of PAR4 Contributes to the Inhibition of Visceral Hyperalgesia in Rats.

Protease-activated receptor 4 (PAR4) is implicated in the inhibition of visceral hyperalgesia. In the present study, the effects of PAR4 activation on visceral hypersensitivity and expression of inflammatory mediators, including interleukin-1ß (IL-1ß), P2RX7 purinergic receptor (P2X7), inducible nitric oxide synthase (iNOS), and tryptase, in mast cells (MCs) were investigated via in vivo and in vitro studies. The numbers of tryptase-positive MCs with extensive PAR4, P2X7, and iNOS expression were increased in the colons of visceral hyperalgesia rats compared with controls. Intracolonic administration of PAR4-activating peptide (PAR4-AP) significantly attenuated the visceral hypersensitivity to colorectal distention and reduced the iNOS, IL-1ß, P2X7, and tryptase protein and mRNA levels in the colonic mucosa. Treatment of rat bone marrow MCs (BMMCs) with PAR4-AP also reduced the iNOS, IL-1ß, P2X7, and tryptase protein and mRNA levels. ERK1/2 and p38 activators (t-butylhydroquinone, tBHQ, and U-46619) reversed the suppressive effect of PAR4 activation on IL-1ß and iNOS expression, whereas ERK1/2 and p38 inhibitors (PD98059 and SB203580) reversed the suppressive effect of PAR4 activation on P2X7 and tryptase expression. Our results indicate that the downregulation of inflammatory mediators, including iNOS, IL-1ß, P2X7, and tryptase, in MCs that are mediated by PAR4 activation could inhibit visceral hyperalgesia via the mitogen-activated protein kinase (MAPK) signal pathway.

Reversal of Ovarian Cancer Multidrug Resistance by a Combination of LAH4-L1-siMDR1 Nanocomplexes with Chemotherapeutics.

The mortality of ovarian cancer stably ranks first in gynecological malignancies due to the lack of specific symptoms and diagnostic methods at an early stage. For most patients, the cancer cells had metastasized before they were diagnosed. As a result, 90% of them died of multidrug resistance (MDR) to chemotherapeutics. In our study, RNAi technology was introduced and applied to overcome this big problem. LAH4-L1, an amphipathic cationic polypeptide, was reported to have high transfection efficiency and was first selected by us to deliver siMDR1 for overcoming ovarian cancer cells MDR. In this research, LAH4-L1-siRNA nanocomplexes (LSCs) delivery system was designed via electrostatic interactions. The nanocomplexes could realize 87.3% MDR1 gene silence and 85% P-gp down-regulation on SKOV-3 cells. What's more, with the combination of chemotherapeutics, SKOV-3 cells growth inhibition can reach to 82.9%. We have also found that there was about 50% reduction on cells migration when MDR1 gene was down-regulated. Besides what have been mentioned above, physicochemical characteristics, cytotoxicity, pH responsivity, cells cycle, cellular uptake, and endosomal escape abilities were also studied in this research. In conclusion, lower cytotoxicity, higher down-regulation of targeted gene, and great cell inhibition, when combined with chemotherapeutics, all show the great potential of LSCs for the reversal of multidrug resistance on SKOV-3 cells in the future.