Search

Background and purpose Modafinil is a potent eugeroic (wakefulness-promoting) drug that is prescribed to treat narcolepsy and has a low incidence of abuse. Although previous studies have shown that modafinil-induced arousal depends on the dopamine receptors and transporters, the specific part/s of the dopamine transmitter system underlying this mechanism remained unclear. Here, we investigated the role of mesencephalic dopamine neurons in modafinil-evoked arousal. Experimental approach A dopamine indicator (dLight1.1) was employed to detect dopamine changes in the nucleus accumbens (NAc) and dorsal striatum. We specifically lesioned mesencephalic dopamine neurons via diphtheria toxin (DTA) in the dopamine transporter (DAT)-Cre mice. Then, the sleep-wake states were recorded to evaluate the effect of modafinil on arousal. Finally, the extent of DTA-induced lesions was determined by immunohistochemistry. Key results Modafinil promptly increased dopamine levels in the NAc and dorsal striatum in a dose-dependent manner. Lesioning of dopamine neurons in the substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) had no significant effects on physiological sleep-wake cycles. Modafinil at 90 mg·kg-1 increased continuous wakefulness for 355 min in control mice. However, these effects were slightly decreased by 6.7% in the SNc-lesioned mice and were prominently diminished by 32.8% in VTA-lesioned mice. Furthermore, the modafinil-induced arousal was completely blocked in the SNc-VTA-lesioned mice, whereas lesions of the dorsal raphe nucleus had no effect. Conclusion and implications Taken together, our findings indicate that mesencephalic dopamine neurons are essential for modafinil-induced arousal.

Objectives: To summarize the experience of the first 500 robot-assisted laparoscopic radical prostatectomy (RALP) cases by one surgeon and analyze the influencing factors of functional and oncological outcomes. Methods: Between April 2012 and October 2017, 500 patients who underwent RALP were included and divided sequentially into five equal groups. Patients’ preoperative, perioperative and postoperative outcomes were analyzed and evaluated, and the Kruskal-Wallis test was used to analyze and compare the effect of surgeon experience by case. Results: There is a statistically significant reduction in operative time, intraoperative estimated blood loss and postoperative hospital stay time (all p

Background Sleep disorders are highly prevalent among stroke survivors and impede stroke recovery. It is well established that melatonin has neuroprotective effects in animal models of ischemic stroke. However, as a modulator of endogenous physiological circadian rhythms, the effects of melatonin on poststroke sleep disorders remain unclear. In the present study, we investigated how melatonin delivered intraperitoneally once daily in the subacute phase after stroke onset, influencing neuronal survival, motor recovery, and sleep–wake profiles in rats. Methods Transient ischemic stroke in male Sprague–Dawley rats was induced with 30 min occlusion of the middle cerebral artery. Melatonin or vehicle was delivered intraperitoneally once daily in the subacute phase, from 2 to 7 days after stroke. Electroencephalogram and electromyogram recordings were obtained simultaneously. Results Compared to the effects observed in the vehicle‐treated ischemic group, after 6 daily consecutive treatment of melatonin at 10 mg/kg starting at ischemic/reperfusion day 2, the infarct volume was significantly decreased (from 39.6 to 26.2%), and the degeneration of axons in the ipsilateral striatum and the contralateral corpus callosum were significantly alleviated. Sensorimotor performances were obviously improved as evidenced by significant increases in the latency to falling off the wire and in the use of the impaired forelimb. In addition to those predictable results of reducing brain tissue damage and mitigating behavioral deficits, repeated melatonin treatment during the subacute phase of stroke also alleviated sleep fragmentation through reducing sleep‐wake stage transitions and stage bouts, together with increasing stage durations. Furthermore, daily administration of melatonin at 9 a.m. significantly increased the nonrapid eye movement sleep delta power during both the light and dark periods and decreased the degree of reduction of the circadian index. Conclusions Melatonin promptly reversed ischemia‐induced sleep disturbances. The neuroprotective effects of melatonin on ischemic injury may be partially associated with its role in sleep modulation., Although sleep disturbances are highly prevalent among stroke survivors and impede post‐stroke recovery, they are still insufficiently considered in the prevention and management of stroke patients. Little attention has been paid to its physiological consequences of melatonin of regulating circadian rhythms on stroke subjects. Our results showed that in addition to the predictable effects on reducing brain damage and mitigating behavioral deficits, repeated melatonin treatment during the sub‐acute phase of stroke also ameliorated circadian rhythm disruption, alleviated sleep fragmentation, and increased sleep depth in ischemic rats. The findings revealed the ability of melatonin to quickly and promptly reverse ischemia‐induced sleep disturbances; a new perspective on how melatonin protect the brain against ischemia injury; and a suitable strategy for improving clinical outcomes in acute stroke victims.

Purpose: Palliative transurethral resection of the prostate (pTURP) in metastatic prostate cancer (mPCa) is reported to be rarely applied in clinics. We prospectively evaluated the ability of pTURP to achieve tumor control in patients with mPCa. Patients and Methods: A prospective study of patients with mPCa from 2011 to 2018 was conducted. The patients were divided into two groups: a pTURP + androgen deprivation therapy (ADT) group and an ADT group. Castration-resistant prostate cancer (CRPC)-free survival and cancer-specific survival (CSS) were analyzed as research endpoints between the groups using a Kaplan-Meier estimator. Results: A total of 188 patients with mPCa were enrolled in the study from our center, of which 110 patients were in the pTURP + ADT group, and 78 patients were in the ADT group. The basic clinical characteristics were comparable between the groups. There were no reoperations or severe complications in the pTURP + ADT group. The median follow-up was 29 months. The median CRPC-free survival was significantly increased when the 7-month prostate-specific antigen (PSA) was 5 (82.2% vs 63.2%, p < 0.01). In subgroup analysis, pTURP + ADT could significantly improve patients' CSS when PSA ≥65 ng/mL, Gleason Score (GS) ≥8, and bone metastasis ≤5. Conclusions: We used our center-based cancer database to analyze survival in patients with mPCa undergoing pTURP. In the study population, pTURP + ADT was indicated to benefit CSS and shown to be safe. Moreover, we suggest that mPCa patients with PSA ≥65 ng/mL, GS ≥8, and bone metastasis ≤5 may perform pTURP before ADT.

MicroRNAs (miRNAs) play important roles in kidney development and maintenance of kidney physiological functions. MiR-377 has been reported to regulate inflammation in cardiac and cerebral ischemia. However, it remains unclear whether it has a similar function in renal ischemia/reperfusion (I/R). Using I/R model mice, miR-377 expression was determined by qRT-PCR in the renal tissues. Renal function was assessed by detection of the concentrations of blood urea nitrogen (BUN) and serum creatinine (Cr). Oxidative stress was evaluated by ELISA analysis of oxidation-related enzymes and molecules. Inflammatory factor concentration and other protein levels were analyzed by the ELISA assay and Western blot, respectively. Our study found that renal I/R stimulated miR-377 expression, while the inhibition of miR-377 attenuated renal I/R injury, and blocked renal I/R-induced oxidative stress and inflammation. Meantime, NF-κB and MAPK signaling were activated by renal I/R, which could also be reversed by miR-377 inhibitor. Furthermore, vascular endothelial growth factor (VEGF) depletion by siRNA completely abrogated the impact of miR-377 on renal I/R-induced oxidative stress, inflammation and renal dysfunction. In conclusion, renal I/R induced miR-377 expression, which upregulated VEGF expression to attenuate renal I/R-induced oxidative stress and inflammation, and finally ameliorated renal dysfunction.

Bai Le Mian capsule (BLMC), which is composed of fifteen kinds of traditional Chinese Medicine, is a popular traditional Chinese medicine for the treatment of insomnia with anxiety. This study was to investigate the anxiolytic effect of BLMC in mice. BLMC (81, 162, and 325 mg/kg, i.g.) was given once or consecutively for 2 weeks, and anxiety behaviors were tested by the elevated plus maze, open field, and light/dark box, in normal mice and anxious model mice by meta-chlorophenyl-piperazine, a compound with known anxiogenic actions. In normal mice, single administration of BLMC at 325 mg/kg prolonged the time spent in central area by 2.1-fold in open-field test. Repeated administration once a day for 2 weeks, BLMC at 325 mg/kg increased the time spent in central area, open arms and light box by 2.8-, 2.0-, and 1.7-fold, respectively. Similarly, in anxious model mice, single treatment of BLMC at 325 mg/kg increased more time in the open arms by 2.1-fold. Consecutive administration for 2 weeks, BLMC at 325 mg/kg increased the time spent in open arms and light box by 2.3- and 2.1-fold. Immunohistochemical study showed that mCPP increased c-Fos expression in the central nucleus of the amygdala and bed nucleus of stria terminalis by 57% and 60%, and the mCPP-induced c-Fos expression could be reversed by single administration of BLMC. These results indicate that BLMC is an effective treatment for anxiety in mice.

Stroke is one of the most devastating complications after bone fracture. However, due to the rarity of the complication, the risk factor for post fracture stroke remains unknown. We retrospectively reviewed 2914 fractured adults referred to the first affiliated hospital of Xi'an Jiaotong University, a regional referral center of China, from January 2008 to May 2013. As a result, among the 2914 patients, 13 of them had newly onset stroke within a median of 4 days after bone fractures (ranging from 1 to 25 days). The overall prevalence of post fracture stroke was 0.446%. The post fracture stroke prevalence in patients older than 68 years old was 3.542%. Compared to patients with vertebral (0.124%) and femur (0.619%) fractures, patients with hip fractures had a higher prevalence of post fracture stroke (2.320%) (P 0.001). Univariate analysis showed that hyperlipidemia, history of prior fracture, more comorbidities, higher CHADS2 score and higher neutrophil counts at admission were more often observed among patients who had post fracture stroke (P 0.05). With the multiple logistic regression analysis, we identified that history of prior fracture was an independent risk factor for post fracture ischemic stroke (OR = 6.417, 95% CI = 1.581-26.051, P = 0.009). Our study illustrates that the history of prior fracture is associated with a 6.4-fold increase in the risk of post fracture ischemic stroke.

Priapism secondary to chronic myeloid leukemia (CML) is rarely observed in the clinic. Here, we present an 18-year-old patient with priapism for over 72 h due to hyperleukocytosis. Emergent interventions such as therapeutic aspiration and intracorporal injection of phenylephrine failed before a surgical corpora cavernosa-corpus spongiosum shunt was inserted to relieve symptoms. During hospitalization, bone marrow aspiration confirmed the diagnosis of CML. Keywords: Priapism, Chronic myeloid leukemia, Surgical cavernosa-corpus spongiosum shunt

Min Qu,1,* Bijun Lian,1,2,* Yan Wang,1,* Wenhui Zhang,1 Feng Zhu,1,3 Tao Wang,4 Xiaodong Yue,5 Zepeng Jia,1 Huan Chen,1 Husheng Li,1 Jing Li,1,6 Xu Gao1 1Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 2Department of Urology, The 903th PLA Hospital, Hangzhou, People’s Republic of China; 3Department of Urology, Tianyou Hospital, Tongji University, Shanghai, People’s Republic of China; 4Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 5Shanghai Institute for Advanced Communication and Data Science, Shanghai University, Shanghai, People’s Republic of China; 6Center for Translational Medicine, Second Military Medical University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing LiCenter for Translational Medicine, Second Military Medical University, No. 800 Xiangyin Road, Yangpu District, Shanghai, 200438, People’s Republic of ChinaTel +86 021-31161718Email ljing@smmu.edu.cnXu GaoDepartment of Urology, Changhai Hospital, No. 168 Changhai Road, Yangpu District, Shanghai, 200438, People’s Republic of ChinaTel +86 021-31161717Email gaoxu.changhai@foxmail.comPurpose: Through an observational study to present a new approach for obtaining high-quality samples for the targeted therapy of prostate cancer.Patients and Methods: Parallel biopsy, which was defined as collecting the tissue from the same site by two biopsies, was performed on patients with elevated PSA. Each tissue was stained by ink to identify the pathological characteristics, including Gleason score and tumor tissue ratio. Kendall tau-b test and intraclass correlation coefficient test were used to compare the consistency between each paired sample. Then, based on the pathology of the biopsies, high-quality tissues would be selected for sequencing, and PyClone model was used to track the clonal evolution.Results: In total, 252 pairs of biopsies were collected. The consistency of Gleason score between each paired biopsy is 0.777 (p< 0.01), and the consistency of tumor tissue ratio is 0.853 (p< 0.01). With the application of parallel biopsy, on average five nonsynonymous mutations could be identified in patients with castration-resistant prostate cancer. Six out of eight had at least one biology-relevant alteration in patients, guiding further treatment. Meanwhile, clonal evolution was constructed to investigate the progress of tumor.Conclusion: Parallel biopsy is a reliable approach to collect high-quality tissue and shows potential application in precision medicine.Keywords: prostate cancer, prostate biopsy, next-generation sequencing, clonal evolutionary tree, precision medicine

Objective We reviewed relevant research on rituximab (RTX) treatment for pediatric immune thrombocytopenia (ITP) to elucidate the efficacy and safety of RTX. Methods Prospective clinical trials of RTX for the treatment of pediatric ITP were collected by searching the PubMed, Cochrane Library, Web of Science, and OVID: EMBASE databases and ClinicalTrials.gov. We examined rates of overall response (OR), complete response (CR), partial response (PR), sustained response (SR), relapse (R), and adverse drug reaction (ADR). The Methodological Index for Nonrandomized Studies scale was used, and sensitivity analyses were performed. Results For five studies, including 100 patients, the pooled OR, CR, PR, SR, R, and ADR rates were 52% (95% CI: 0.36–0.77, I2 = 78%), 52% (95% CI: 0.41–0.67, I2 = 45%), 18% (95% CI: 0.10–0.33, I2 = 33%), 43% (95% CI: 0.29–0.63, I2 = 0%), 25% (95% CI: 0.06–0.96, I2 = 52%), and 30% (95% CI: 0.15–0.58, I2 = 64%), respectively. Conclusion There is evidence, albeit low quality, that RTX may be a better second-line therapy than splenectomy for children with ITP; however, its efficacy and safety need to be validated by further high-quality clinical trials, such as randomized controlled trials.

Background：Vascular factors and mitochondria dysfunction contributeto thepathogenesis of Alzheimer’s Disease (AD).DL-3-n-butylphthalide (NBP)has an effect in protecting mitochondria and improving microcirculation. We investigated the effect of NBP in patients with mild-moderate AD already receiving donepezil.Methods: It was a prospective cohort study. 92 mild-moderate AD patients were classified into the donepezil alone group (n=43) or the donepezil combined NBP group (n=49) for 48 weeks. The primary outcome was change of Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) from baseline after treatment 48 weeks. All patients were also evaluated with clinician’s interview-based impression of change plus caregiver input (CIBIC-plus), Alzheimer's disease cooperative study-activities of daily living (ADCS-ADL) and neuropsychiatric inventory (NPI) every 12 weeks. All patients were monitored for adverse events (AEs). The efficacy was analyzed using logistic regression analysis.Results:The univariate analysis showed that age wasolder in donepezil alone group(P=0.005), prevalence of hypertension was higher in donepezil alone group(P=0.026).The ADAS-cog score change from baseline in thedonepezil alone group was significant than that in the donepezil combined NBP group at 48 weeks(1.82±5.20 vs -0.38±4.46, P=0.048). The multivariate logistic regression analysis showed that between the 2 groups, there were significant differencesin changes on the ADAS-cog(OR=0.879,95% CI:[0.785,0.984],P=0.026),MMSE(OR=1.270,95% CI:[1.036,1.557],P=0.021), and ADCS-ADL(OR=1.067,95% CI:[1.002,1.136],P=0.042) but no significant differences for changes on the NPI(OR=0.955,95% CI:[0.901，1.013],P=0.125)and CIBIC-plus (OR=0.356,95% CI:[0.093,1.364],P=0.132). The occurrence of AEs was similar in the 2 groups.Conclusions:Over the 48-week treatment period, donepezil combined NBP group had slower cognitive decline and better activities of daily living in patients with mild to moderate AD. These indicated that the multi-target therapeutic effect of NBP may be a new choice for AD treatment.Trial registration:Clinical trial registration URL:https://clinicaltrials.gov/ct2/show/NCT02711683?term=NCT02711683&draw=2&rank=1ClinicalTrials.gov Identifier: NCT02711683. Date of registration: March 14,2016.

BACKGROUND:The effectiveness of predicting the incidence of supine hypotension syndrome (SHS) after spinal anesthesia was measured by ultrasonic measurement of the variation of brachial artery peak velocity in different positions of parturient. METHODS: Parturient scheduled for elective cesarean section. ASAI or Ⅱ, were divided into SHS group and no SHS group (SBP in the upper extremity decreased by>30 mmHg or decreased toRESULTS:Among the 84 patients, 41 cases (48.81%) developed SHS after spinal anesthesia. brachial artery peak velocity maximum (Vpmax), brachial artery peak velocity minimum (Vpmin) and brachial artery peak velocity variation (ΔVp) were different before and after the transformation position. The difference in SHS group is significantly greater than non SHS group (PCONCLUSION:The difference of brachial artery peak velocity measured by ultrasonic in different positions of parturient during the Valsalva maneuver can effectively predict the occurrence of SHS, in which ΔVpmin≥10.55cm/s has better predictive effect.Trial registration: China Clinical Trial Register ChiCTR1900022704, prospective registered on 23. April 2019.

Zao Ren An Shen capsule (ZRASC) which is composed of three kinds of traditional Chinese herbs is a popular Chinese medicine for the treatment of insomnia. This study investigated the hypnotic effect of ZRASC in an anxiety-like mouse model. We determined the role of ZRASC in anxiety and co-morbid insomnia using electroencephalogram and electromyogram recordings. Anxiety-like behaviors were tested by using the open-field, light/dark box, or elevated plus-maze in mice. Immunohistochemical techniques were employed to reveal the mechanism by which ZRASC regulated anxiety and insomnia. ZRASC at 680 mg/kg prolonged the time spent in the central area, open arms area, and light box by 1.9, 2.3, and 1.7-fold respectively, compared with the vehicle control group in immobilization stress (IMS) mice. ZRASC at 680 mg/kg given at 08:00 h increased the amount of non-rapid eye movement sleep by 1.4-fold in a 2-h period after dosing in IMS mice. However, it did not alter the sleep-wake behaviors in normal mice. Immunohistochemistry showed that IMS increased c-Fos expression in the neurons of the stria terminalis and tuberomammillary nucleus by 1.8 and 1.6-fold, respectively. In addition, ZRASC (680 mg/kg) reversed the IMS-induced c-Fos expression. Our results suggest that ZRASC is an effective therapeutic strategy for both anxiety disorder and sleep disturbances in an anxiety-like mouse model.

Background: The role of local treatment in oligometastatic prostate cancer (PCa) is gaining interest with the oligometastases hypothesis proposed and the improvement of various surgical methods and techniques. This study aimed to compare the short-term therapeutic outcomes of robotic-assisted laparoscopic radical prostatectomy (RALP) for oligometastatic prostate cancer (OPC) vs. localized PCa using propensity score matching. Methods: Totally 508 consecutive patients underwent RALP as a first-line treatment. The patients were divided into two groups according to oligometastatic state: the OPC group (n = 41) or the localized PCa group (n = 467). Oligometastatic disease was defined as the presence of two or fewer suspicious lesions. The association between the oligometastatic state and therapeutic outcomes of RALP was evaluated, including biochemical recurrence (BCR) and overall survival (OS). A Cox proportional hazards model was used to assess the possible risk factors for BCR. Results: Totally 41 pairs of patients were matched. The median operative time, the median blood loss, the overall positive surgical margin rate, the median post-operative hospital stays, and the post-operative urinary continence recovery rate between the two groups showed no statistical significance. The 4-year BCR survival rates of the OPC group and localized PCa group were 56.7% and 60.8%, respectively, without a significant difference (P= 0.804). The 5-year OS rates were 96.3% and 100%, respectively (P = 0.326). Additionally, the results of Cox regression showed that oligometastatic state was not an independent risk factor for BCR (P = 0.682). Conclusions: Our findings supported the safety and effectiveness of RALP in OPC. Additionally, oligometastatic state and sites did not have an adverse effect on BCR independently. Key words: Oligometastatic; Prostate cancer; Robotics; Propensity score matching

OBJECTIVE The aim of this study was to assess the efficacy and safety following endoscopic management of Zenker's diverticulum (ZD) using a needle-knife technique. METHODS A systematic search of PubMed, Embase and Cochrane library databases was performed. All original studies reporting efficacy and safety of needle-knife technique for treatment of ZD were included. Pooled event rates across studies were expressed with summative statistics. Main outcomes, such as rates of immediate symptomatic response (ISR), adverse events and recurrence, were extracted, pooled and analyzed. Heterogeneity among studies was assessed using the R statistic. The random effects model was used and results were expressed with forest plots and summative statistics. RESULTS Thirteen studies included 589 patients were enrolled. Pooled event rates for ISR, overall complication, bleeding and perforation were 88% (95% confidence interval [CI] 79-94%), 13% (95% CI 8-22%), 5% (95% CI 3-10%) and 7% (95% CI 4-12%), respectively. The pooled data demonstrated an overall recurrence rate of 14% (95% CI 9-21%). Diverticulum size of at least 4 cm and less than 4 cm demonstrated pooled adverse event rates of 17% (95% CI 10-27%) and 7% (95% CI 2-18%), respectively. When using diverticuloscope as an accessory, pooled ISR and adverse events rates were 84% (95% CI 58-95%) and 10% (95% CI 3-26%), respectively. CONCLUSION Flexible endoscopic procedures using needle-knife offers a relatively safe and effective treatment of symptomatic ZD, especially for ZD of

Background This study aimed to identify the clinical and pathological characteristics and the possible prognostic factors for Chinese patients with early-stage ovarian endometrioid carcinoma. Methods The present study reviewed the medical records of patients who received initial treatment and a postoperative pathological diagnosis of ovarian endometrioid carcinoma at our center. In all, 78 patients had stage I ovarian endometrioid carcinoma. Results In this series, the 5-year overall survival rate and 5-year disease-free survival (DFS) rates of patients with stage I ovarian endometrioid carcinoma was 98.7% and 87.2%, respectively. Univariate analysis showed the factors that influence the DFS rates include menopausal status, FIGO stage, histological grade, lymphadenectomy, cytology of ascites. Multivariate analysis showed that grade 3 and lymphadenectomy were the independent prognostic factors of DFS for Stage I ovarian endometrioid carcinoma (P = 0.0259, 0.0276 respectively). However, the coexisting endometriosis, concomitant endometrial disorders, dissection of para-aortic lymph node and more courses of thermotherapy had no influence on DFS. Besides, it was found that 19.3% of patients in this series had synchronous early stage and well-to-moderate differentiated endometrial carcinoma. Conclusions Grade 3 and lymphadenectomy were indicated as the independent factors of DFS for stage I patients with ovarian endometrioid carcinoma. The endometrial changes should be considered seriously when fertility-sparing surgery was planned.

// Hai-Rui Wang 1, 2, * , Yu-Cong Li 3, * , Hui-Qin Guo 4 , Lu-Lu Yu 1 , Zeni Wu 1 , Jian Yin 1 , Guang-Dong Liao 5 , Yi-Min Qu 2 , Yu Jiang 2 , Dong Wang 3 and Wen Chen 1 1 Department of Cancer Epidemiology, National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China 2 School of Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China 3 Department of Gynecological Oncology, Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing, PR China 4 Department of Pathology, National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China 5 Department of Gynecology and Obstetrics, The West China Second University Hospital, Sichuan University, Chengdu, PR China * These authors have contributed equally to this work Correspondence to: Wen Chen, email: chenwen@cicams.ac.cn Dong Wang, email: cqwindow120@163.com Keywords: HPV, p16/Ki-67 dual staining, p16/mcm2, cervical cancer screening, cytology Received: October 15, 2016 Accepted: July 11, 2017 Published: August 03, 2017 ABSTRACT Most human papillomavirus (HPV) infections are transient and additional triage approaches should be built after HPV-based primary cervical cancer screening. We evaluated the accuracy of p16/Ki-67 and p16/mcm2 dual staining as biomarkers for triaging HPV positive women in China. 4070 participants aged 35 to 64 years attending ongoing cervical cancer screening were enrolled in 2015-2016. Cervical exfoliated cells were collected for HPV DNA analysis and the residual positive specimens were tested for liquid-based cytology and biomarkers. Women infected with HPV 16/18 type or other 12 high-risk HPV types with abnormal cytology results received colposcopy. We found the positive rates of both biomarkers increased significantly with histology severity. p16/Ki-67 positivity in HPV16/18 group, other 12 high-risk HPV group and HPV negative group was 50.0%, 33.7% and 8.9%, respectively. The corresponding p16/mcm2 positivity was 70.0%, 56.3% and 6.7%, respectively. The sensitivity and specificity of p16/Ki-67 for CIN2+ in all HPV-positive women were 91.7% and 63.5%, with a referral rate of 36.2%, while p16/mcm2 were 87.5% and 42.1%, with a referral rate of 58.4%, respectively. The sensitivity of p16/Ki-67 increased to 95.8% for CIN2+ and 100% for CIN3+ when combined with high-grade cytology, without decrease in specificity. Our studies suggest that p16/Ki-67 is an efficient triaging biomarker for HPV-positive women and could reduce colposcopy workload. p16/mcm2 is more sensitive compared with cytology for identifying cervical lesions.

β-Amyloid (Aβ) deposition has a central role in the pathogenesis of Alzheimer disease (AD). Previous studies have indicated that as a risk factor for AD, diabetes mellitus (DM) could induce Aβ deposition in the brain, but the mechanism is not fully elucidated. Autophagy-lysosome is a cellular pathway involved in protein and organelle degradation. In the present study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether autophagy-lysosome is related to Aβ1-42 clearance in DM. We found that DM rats had a longer escape latency and less frequent entry into the target zone than that of the control group (p

Prostaglandin D2 (PGD2) is one of the most potent endogenous sleep promoting substances. PGD2 activates the PGD2 receptor (DPR) and increases the extracellular level of adenosine in wild-type (WT) mice but not DPR knockout (KO) mice, suggesting that PGD2-induced sleep is DPR-dependent, and adenosine may be the signaling molecule that mediates the somnogenic effect of PGD2. The aim of this study was to determine the involvement of the adenosine A2A receptor (A2AR) in PGD2-induced sleep. We infused PGD2 into the lateral ventricle of WT and A2AR KO mice between 20:00 and 2:00 for 6 h, and electroencephalograms and electromyograms were simultaneously recorded. In WT mice, PGD2 infusion dose-dependently increased non-rapid eye movement (non-REM, NREM) sleep, which was 139.1%, 145.0% and 202.7% as large as that of vehicle-treated mice at doses of 10, 20 and 50 pmol/min, respectively. PGD2 infusion at doses of 20 and 50 pmol/min also increased REM sleep during the 6-h PGD2 infusion and 4-h post-dosing periods in WT mice to 148.9% and 166.7%, respectively. In A2AR KO mice, however, PGD2 infusion at 10 pmol/min did not change the sleep profile, whereas higher doses at 20 and 50 pmol/min increased the NREM sleep during the 6-h PGD2 infusion to 117.5% and 155.6%, respectively, but did not change the sleep in the post-dosing period. Moreover, PGD2 infusion at 50 pmol/min significantly increased the episode number in both genotypes but only enhanced the episode duration in WT mice. The results demonstrate that PGD2-induced sleep in mice is mediated by both adenosine A2AR-dependent and -independent systems.

Interleukin-1β (IL-1β) and prostaglandin (PG) D2 are endogenous sleep-promoting substances. Since it was reported that a highly selective cyclooxygenase-2 (COX-2) inhibitor, NS398, completely inhibited IL-1β-induced sleep in rats, IL-1β-induced sleep had been believed to be mediated by prostanoids, most probably PGD2. However, in the present study, pretreatment of rats with NS398 (3mg/kg) did not suppress the 64.2% increased non-rapid eye movement (non-REM, NREM) sleep during infusion of IL-1β (10ng) for 6h in the nocturnal (active) period between 23:00 and 5:00 into the subarachnoid space of the PGD2-sensitive sleep-promoting zone of the basal forebrain. Meanwhile, IL-1β at doses of 1.7 and 5μg/kg also significantly increased NREM sleep for 6h after intraperitoneal injection at 20:00 (light-off time) by 76.8% and 121.1%, respectively, in wild-type (WT) mice, by 67.7% and 147.3%, respectively, in WT mice pretreated with NS398 (5mg/kg) and by 108.9% and 121.6%, respectively, in PGD2 receptor (DP1R) knockout mice. These results indicate that IL-1β-induced NREM sleep is independent of the PGD2/DP1R system and other COX-2-derived prostaglandins in rats and mice.

Objective: To evaluate the safety profile and short-term functional outcome of sustainable functional urethral reconstruction (SFUR) in robotic-assisted radical prostatectomy (RARP). Methods: One hundred and sixty-two consecutive prostate cancer patients who underwent RARP were retrospectively analyzed, in which 53 had undergone SFUR while the other 109 had undergone conventional RARP procedures. Immediate, 2-week, 1-month and 3-month continence recovery and other perioperative data were compared to evaluate short-term surgical and functional outcome. Results: The median age was 68 and 67 years in the experimental group and control group, respectively (p=0.206), with a median prostate-specific antigen (PSA) of 13.6 ng/mL (interquartile range [IQR], 8.46–27.32 ng/mL) in the experimental group and 13.84 ng/mL (IQR, 9.12–26.80 ng/mL) in control group (p=0.846). Immediate, 2-week, 1-month and 3-month continence recovery rates between the groups were 34.0% vs. 3.7%, 50.9% vs. 14.7%, 62.3% vs. 27.5%, and 79.2% vs. 63.3% (all p

Diabetic rats display cognition impairments accompanied by activation of NF-κB signalling and increased Aβ expression. Ghrelin has been suggested to improve cognition in diabetic rats. In this study, we investigated the role of ghrelin on cognition and NF-κB mediated Aβ production in diabetic rats. A diabetic rat model was established with streptozotocin (STZ) injection, and diabetic rats were intracerebroventricularly administered with ghrelin or (D-lys3)-GHRP-6 (DG). Our results showed that diabetic rats had cognition impairment in the Morris water maze test, accompanied by the higher expression of Aβ in the hippocampus. Western blot analysis showed that diabetic rats exhibited significantly decreased levels of GHSR-1a and protein phosphatase 1 (PP1) in the hippocampus and increased activation of the IKK/NF-κB/BACE1 pathway. Chronic ghrelin administration upregulated hippocampal PP1 expression, suppressed IKK/NF-κB/BACE1 mediated Aβ production, and improved cognition in STZ-induced diabetic rats. These effects were reversed by DG. Then, primary rat hippocampal neurons were isolated and treated with high glucose, followed by Ghrelin and DG, PP1 or IKK. Similar to the in vivo results, high glucose suppressed the expression levels of GHSR-1a and PP1, activated the IKK/NF-κB/BACE1 pathway, increased Aβ production. Ghrelin suppressed IKK/NF-κB/BACE1 induced Aβ production. This improvement was reversed by DG and a PP1 antagonist and was enhanced by the IKK antagonist. Our findings indicated that chronic ghrelin administration can suppress IKK/NF-κB/BACE1 mediated Aβ production in primary neurons with high glucose treatment and improve the cognition via PP1 upregulation in diabetic rats.

The cardiac contractile force is an important predictor of healthy and cardiovascular diseases. The changes of cardiomyocyte contractile force in response to American ginseng root water extract (AGRWE) detected by atomic force microscope have not been investigated yet. This study examined the effects of AGRWE on single beating cardiomyocytes extracted from a newborn rat. The same cardiomyocytes were incubated with AGRWE at a concentration of 50 μg/ml for about 30 min, and the cardiomyocytes' contractile force increased from 1.74 ± 1.01 to 3.49 ± 1.53 nN. The mean value of the contractile strain calculated was 3.32 ± 1.55% for the cardiomyocyte before the treatment with AGRWE, while for the cardiomyocyte treated with AGRWE it increased to 4.60 ± 1.35%. The results also showed that the beating rate of the same single beating cardiomyocytes was decreased from 34 ± 11 beats/min (control, n = 10) to 20 ± 9 beats/min. In conclusion, the experimental results have shown clearly that the contractile forces and strain of single beating cardiomyocytes treated with AGRWE are significantly higher than the control group, while the heart rate was decreased. It suggests that ginseng agents are promising candidates in improving cardiac functions for treating heart failure.

Rapid eye movement (REM) sleep behavior disorder in humans is often accompanied by a reduced ability to smell and detect odors, and olfactory bulbectomized rats exhibit increased REM sleep, suggesting that the olfactory bulb (OB) is involved in REM-sleep regulation. However, the molecular mechanism of REM-sleep regulation by the OB is unknown. Adenosine promotes sleep and its A2A receptors (A2AR) are expressed in the OB. We hypothesized that A2AR in the OB regulate REM sleep. Bilateral microinjections of the A2AR antagonist SCH58261 into the rat OB increased REM sleep, whereas microinjections of the A2AR agonist CGS21680 decreased REM sleep. Similar to the A2AR antagonist, selective A2AR knockdown by adeno-associated virus carrying short-hairpin RNA for A2AR in the rat OB increased REM sleep. Using chemogenetics on the basis of designer receptors exclusively activated by designer drugs, we demonstrated that the inhibition of A2AR neurons increased REM sleep, whereas the activation of these neurons decreased REM sleep. Moreover, using a conditional anterograde axonal tract-tracing approach, we found that OB A2AR neurons innervate the piriform cortex and olfactory tubercle. These novel findings indicate that adenosine suppresses REM sleep via A2AR in the OB of rodents.

Objective To investigate the learning curve of robotic-assisted laparoscopic radical prostatectomy (RALP) and analyze whether a surgeon's prior surgical experience has effects on the surgery. Patients and Methods From April 2012 to August 2015, 3 surgeons performed RALP on 355 consecutive patients with prostate cancer. Among these cases, 184 were by surgeon A with prior open experiences, 92 by surgeon B with both open and laparoscopic experiences, and 79 by surgeon C with laparoscopic experiences only. Perioperative, oncological, and functional outcomes were evaluated and compared between surgeons. Learning curve patterns were evaluated to determine the number of cases to reach plateau. Results Marked difference was observed in operative time among the 3 groups (all P .05). Length of hospital stay was also statistically significant (all P .001), except for that between Group B and Group C ( P = .739). Continence at 1-year and 6-month postoperatively was better in Groups B and C compared with Group A ( P .001). Intraoperative blood loss, pathologic stage, positive surgical margin, biochemical recurrence-free rate, and other pathological findings showed no statistical significance between the groups. The number of cases required to reach plateau may vary for surgeons with different surgical experiences. Conclusion Different early surgical background may affect the perioperative parameters of novice RALP surgeons. Previous laparoscopic experiences may provide additional advantage in learning curve parameters compared with surgeons with open experiences only. A better overall continence for laparoscopic surgeons requires further validation.

Histamine, an important modulator of the arousal states of the central nervous system, has been reported to contribute an excitatory drive at the hypoglossal motor nucleus to the genioglossus (GG) muscle, which is involved in the pathogenesis of obstructive sleep apnea. However, the effect of histamine on hypoglossal motoneurons (HMNs) and the underlying signaling mechanisms have remained elusive. Here, whole-cell patch-clamp recordings were conducted using neonatal rat brain sections, which showed that histamine excited HMNs with an inward current under voltage-clamp and a depolarization membrane potential under current-clamp via histamine H1 receptors (H1Rs). The phospholipase C inhibitor U-73122 blocked H1Rs-mediated excitatory effects, but protein kinase A inhibitor and protein kinase C inhibitor did not, indicating that the signal transduction cascades underlying the excitatory action of histamine on HMNs were H1R/Gq/11 /phospholipase C/inositol-1,4,5-trisphosphate (IP3). The effects of histamine were also dependent on extracellular Na(+) and intracellular Ca(2+), which took place via activation of Na(+)-Ca(2+) exchangers. These results identify the signaling molecules associated with the regulatory effect of histamine on HMNs. The findings of this study may provide new insights into therapeutic approaches in obstructive sleep apnea. We proposed the post-synaptic mechanisms underlying the modulation effect of histamine on hypoglossal motoneuron. Histamine activates the H1Rs via PLC and IP3, increases Ca(2+) releases from intracellular stores, promotes Na(+) influx and Ca(2+) efflux via the NCXs, and then produces an inward current and depolarizes the neurons. Histamine modulates the excitability of HMNs with other neuromodulators, such as noradrenaline, serotonin and orexin. We think that these findings should provide an important new direction for drug development for the treatment of obstructive sleep apnea.

Early referral to palliative care (PC) services has been shown to improve quality of life in advanced cancer. However, limitations in trained PC workforce raise issues with the sustainability of delivering PC with early PC referral. Classifying PC into generalist and specialist components could be one approach to sustainable PC delivery models but a quantitative guide for this classification is presently lacking in the literature.To undertake a retrospective examination of clinical data obtained from a PC benchmarking project to develop a quantitative framework guiding classification of PC services into specialist and generalist components.A descriptive retrospective study of data from 2726 hospitalized inpatients under the care of a tertiary consultative PC service over a 2-year period was conducted. Daily categorical symptom, overall psychological and social distress scores at the start and end of 3392 palliative care episodes as well as the number of visits made by the PC team to patients were extracted for analysis.More than 50% of patients had symptom, overall psychological or social distress scores of nil or mild severity at episode start and end. Approximately 20% of all 2726 patients accounted for approximately half of all visits made by the team regardless of the reasons for review. This patient percentage minority had more PC episodes starting with moderate or severe pain. These findings suggest a Pareto-like distribution in the occurrence of moderate/severe PC problems and the intensity of PC input.Large-scale clinical data supports the use of a Pareto-based quantitative framework for a workforce comprising of mainly generalist PC staff supported by smaller numbers of PC specialists.

The olfactory tubercle (OT), an important nucleus in processing sensory information, has been reported to change cortical activity under odor. However, little is known about the physiological role and mechanism of the OT in sleep-wake regulation. The OT expresses abundant adenosine A2A receptors (A2ARs), which are important in sleep regulation. Therefore, we hypothesized that the OT regulates sleep via A2ARs. This study examined sleep-wake profiles through electroencephalography and electromyography recordings with pharmacological and chemogenetic manipulations in freely moving rodents. Compared with their controls, activation of OT A2ARs pharmacologically and OT A2AR neurons via chemogenetics increased non-rapid eye movement sleep for 3 and 5 h, respectively, while blockade of A2ARs decreased non-rapid eye movement sleep. Tracing and electrophysiological studies showed OT A2AR neurons projected to the ventral pallidum and lateral hypothalamus, forming inhibitory innervations. Together, these findings indicate that A2ARs in the OT play an important role in sleep regulation., info:eu-repo/semantics/published

Paeoniflorin (PF, C23H28O11), one of the principal active ingredients of Paeonia Radix, exerts depressant effects on the central nervous system. We determined whether PF could modulate sleep behaviors and the mechanisms involved. Electroencephalogram and electromyogram recordings in mice showed that intraperitoneal PF administered at a dose of 25 or 50 mg/kg significantly shortened the sleep latency and increased the amount of non-rapid eye movement (NREM). Immunohistochemical study revealed that PF decreased c-fos expression in the histaminergic tuberomammillary nucleus (TMN). The sleep-promoting effects and changes in c-fos induced by PF were reversed by 8-cyclopentyl-1,3-dimethylxanthine (CPT), an adenosine A1 receptor antagonist, and PF-induced sleep was not observed in adenosine A1 receptor knockout mice. Whole-cell patch clamping in mouse brain slices showed that PF significantly decreased the firing frequency of histaminergic neurons in TMN, which could be completely blocked by CPT. These results indicate that PF increased NREM sleep by inhibiting the histaminergic system via A1 receptors.

Background Clinico-pathological characteristics and possible prognostic factors among women with epithelial ovarian carcinoma (EOC) with or without concurrent endometriosis were explored. Method We retrospectively identified 304 patients with EOC treated primarily at Peking Union Medical College Hospital with median follow-up time of 60 months. Results Of 304 patients with EOC, concurrent endometriosis was identified in 69 (22.7%). The patients with concurrent endometriosis were younger and more probably post-menopausal at onset, were less likely to have abdominal distension, with significantly lower level of pre-surgery serum Ca125 and less possibility of having the history of tubal ligation. The women with concurrent endometriosis group were more likely to have early stage tumors (88.41% versus 52.77%), receive optimal cytoreductive surgery (92.75% versus 71.06%), and less likely to have lymph node metastasis or to develop platinum resistance disease (7.25% versus 14.89%, and 7.35% versus 20%), when compared with women without coexisting endometriosis. The univariate analysis showed that concurrent endometriosis was a prognostic factor for overall survival (OS) and disease-free survival (DFS), but this association just remained in the DFS by multivariate analysis. Besides, multivariate analysis also showed that FIGO stage, residual disease, chemotherapy cycles, chemotherapy resistance and concomitant hypertension were the independent impact factors of OS for EOC patients; whereas FIGO stage, lymphadenectomy, residual disease, coexisting endometriosis and chemoresistance were independent impact factors of DFS for those patients. Conclusions EOC patients with concurrent endometriosis showed distinct characteristics and had longer overall survival and disease-free survival when compared with those without endometriosis. Endometriosis was the independent prognostic factor for DFS for patients in this series.

Ethanol has extensive effects on sleep and daytime alertness, causing premature disability and death. Adenosine, as a potent sleep-promoting substance, is involved in many cellular and behavioral responses to ethanol. However, the mechanisms of hypnotic effects of ethanol remain unclear. In this study, we investigated the role of adenosine in ethanol-induced sleep using C57BL/6Slac mice, adenosine A2A receptor (A2AR) knockout mice, and their wild-type littermates. The results showed that intraperitoneal injection of ethanol (3.0 g/kg) at 21:00 decreased the latency to non-rapid eye movement (NREM) sleep and increased the duration of NREM sleep for 5 h. Ethanol dose-dependently increased NREM sleep, which was consistent with decreases in wakefulness in C57BL/6Slac mice compared with their own control. Caffeine (5, 10, or 15 mg/kg), a nonspecific adenosine receptor antagonist, dose-dependently and at high doses completely blocked ethanol-induced NREM sleep when administered 30 min prior to (but not after) ethanol injection. Moreover, ethanol-induced NREM sleep was completely abolished in A2AR knockout mice compared with wild-type mice. These findings strongly indicate that A2AR is a key receptor for the hypnotic effects of ethanol, and pretreatment of caffeine might be a strategy to counter the hypnotic effects of ethanol.

OBJECTIVE Increased pulse pressure (PP) has been implicated in the development and progression of Alzheimer's disease in middle-aged and elderly adults. Considering the close relationship between peripheral amyloid-β clearance and brain amyloid-β deposition, we investigated the potential association between PP and plasma amyloid-β transport function. METHODS In this cross-sectional study, a total of 1118 participants underwent a health assessment and quantification of plasma amyloid-β and amyloid-β transporter expression. Relationships between plasma levels of amyloid-β1-40, amyloid-β1-42, soluble low-density lipoprotein receptor-related protein-1 (sLRP1), soluble receptor for advanced glycation end products (sRAGE), and PP were determined using multiple linear regressions. RESULTS PP was a significant determinant of amyloid-β1-40 level (β = 0.059, P = 0.036) and log-transformed sRAGE (β = -0.002, P = 0.029) independent of age, sex, body mass index, pulse rate, mean arterial pressure, blood glucose, blood lipids, lifestyle, and medical history. Additionally, log-transformed soluble low-density lipoprotein receptor-related protein-1 and log-transformed sRAGE were positively associated with plasma amyloid-β1-40 level (β = 3.610, P

Sit-stand workstations are available for office work purposes but there is a dearth of quantitative evidence to state benefits for lower limb outcomes while using them. And there are no guidelines on what constitutes appropriate sit/stand time duration. The primary aim of this study has been to compare muscle activity and perceived discomfort in the lower extremity during various combinations of sit/stand time duration associated with a sit-stand workstation separately and to evaluate the effects of the sit-stand workstation on the lower extremity during the text entry task.During the 5 days, all participants completed a 2-h text entry task each day for various sit/stand time duration combinations as follows: 5/25 min, 10/20 min, 15/15 min, 20/10 min, 25/5 min. Lower extremity muscular exposure of 12 male and 13 female participants was collected at 8 sites by surface electromyography and body discomfort was calculated by a questionnaire under those 5 conditions.Results have demonstrated that lower extremity muscle activity has been significantly varied among the 5 sit/stand time duration groups. Perceived level of discomfort (PLD) has not differed significantly for 9 out of 10 body parts.The muscle activity of the thigh region was influenced by sit/stand time duration significantly. Ergonomic exposures of lower extremity when using a sit-stand workstation were increased, particularly during the long time standing posture. Results indicate that body mass index (BMI) and gender were not significant factors in this study. Combination of sit/stand time duration 25/5 min appears to show positive effects on relief of muscle exposure of back of thigh in the shifts of sitting and standing work position. Med Pr 2017;68(3):315-327.Sit-stand workstations are available for office work purposes but there is a dearth of quantitative evidence to state benefits for lower limb outcomes while using them. And there are no guidelines on what constitutes appropriate sit/stand time duration. The primary aim of this study has been to compare muscle activity and perceived discomfort in the lower extremity during various combinations of sit/stand time duration associated with a sit-stand workstation separately and to evaluate the effects of the sit-stand workstation on the lower extremity during the text entry task.During the 5 days, all participants completed a 2-h text entry task each day for various sit/stand time duration combinations as follows: 5/25 min, 10/20 min, 15/15 min, 20/10 min, 25/5 min. Lower extremity muscular exposure of 12 male and 13 female participants was collected at 8 sites by surface electromyography and body discomfort was calculated by a questionnaire under those 5 conditions.Results have demonstrated that lower extremity muscle activity has been significantly varied among the 5 sit/stand time duration groups. Perceived level of discomfort (PLD) has not differed significantly for 9 out of 10 body parts.The muscle activity of the thigh region was influenced by sit/stand time duration significantly. Ergonomic exposures of lower extremity when using a sit-stand workstation were increased, particularly during the long time standing posture. Results indicate that body mass index (BMI) and gender were not significant factors in this study. Combination of sit/stand time duration 25/5 min appears to show positive effects on relief of muscle exposure of back of thigh in the shifts of sitting and standing work position. Med Pr 2017;68(3):315–327.

GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA in the CNS and regulates GABAergic transmission. Compounds that inhibit GAT1 are targets often used for the treatment of epilepsy; however sedation has been reported as a side effect of these agents, indicating potential sedative and/or hypnotic uses for these compounds. In the current study, we observed the sleep behaviors of mice treated with NO-711, a selective GAT1 inhibitor, in order to elucidate the role of GAT1 in sleep-wake regulation during the active phase. The data revealed that NO-711 at a high dose of 10 mg/kg caused a marked enhancement of EEG activity in the frequency ranges of 3-25 Hz during wakefulness as well as rapid eye movement (REM) sleep. During the non-REM (NREM) sleep, NO-711 (10 mg/kg) elevated EEG activity in the frequency ranges of 1.5-6.75 Hz. Similar changes were found in mice treated with a low dose of 3 mg/kg. NO-711 administered i.p. at a dose of 1, 3 or 10 mg/kg significantly shortened the sleep latency of NREM sleep, increased the amount of NREM sleep and the number of NREM sleep episodes. NO-711 did not affect the sleep latency and the amount of REM sleep. NO-711 dose-dependently increased c-Fos expression in sleep-promoting nucleus of the ventrolateral preoptic area and median preoptic area. However, c-Fos expression was decreased in the wake-promoting nuclei, tuberomammillary nucleus and lateral hypothalamus. These results indicate that NO-711 can increase NREM sleep in mice.

Purpose: To explore the correlation of vascular risk factors for Alzheimer’s disease (AD) in Chinese population. Methods: A total of 123 outpatients with probable AD followed up for 3 years were investigated. Severity of cognitive impairment and functional ability was assessed using Mini-Mental State Examination (MMSE) and modified activities of daily living (ADLs), respectively. The incidence of vascular risk factors was studied in patients with AD. Results: Univariate analysis showed significance difference in MMSE and ADL scores between patients with and without vascular risk factors ( P < .05). Multiple regression analysis showed age, education, hyperhomocysteinemia, and hypertension were significant variables associated with annual MMSE, while there were no significant correlations between annual MMSE and sex, initial MMSE, diabetes, and so on. Conclusions: Vascular risk factors are common comorbidities in patients with AD in China, with younger, better educated ones showing faster cognitive decline. Hypertension and hyperhomocysteinemia may also aggravate the progression, and it is important to prevent and treat patients with AD.

Background and objective To investigate the association between handedness and the side of symptom dominance in Parkinson's disease (PD). Patients and methods One hundred and forty-six PD patients with symmetric symptoms (92 males and 54 females), aged 64.3 ± 9.1 years old, from a series of 247 PD patients were assessed for handedness and clinical features. The severity of PD was scored by unified Parkinson's disease rating scale (UPDRS) and Hoehn-Yahr staging on the �ON� state. Results Of 134 right-handed patients (91.8%), 83 (61.7%) had an initial onset on the right side (P = 0.008), while of 12 left-handed patients (8.2%), 9 (75.0%) had an initial onset on the left side (P = 0.013). Out of right-handed patients, 103 (76.9%) had the right-side dominance of PD symptoms (P < 0.001). Among the left-handed subjects, 7 patients (58.3%) had left-sided and 5 patients (41.7%) had right-sided symptom dominance (P = 0.564). In general, dominant side of symptoms was in accordance with handedness (P = 0.008). In right-handed patients, rest tremor was the most common initial symptom (P < 0.001), while rest tremor and rigidity-bradykinesia were initial symptoms in left-handed patients (P = 0.366). Conclusions PD symptoms emerge more often on the dominant hand-side, and the dominant side of symptoms is in accordance with handedness.

Diabetes mellitus (DM) has been regarded as an important risk factor for Alzheimer’s disease (AD), and diabetic patients and animals have shown cognitive dysfunction. More research has shown that the amyloid-β (Aβ), which is a hallmark of AD, was found deposited in the hippocampus of diabetic rats. This Aβ accumulation is regulated by the receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein (LRP-1). However, the expression of RAGE and LRP-1 in diabetic rats is not very clear. In the present study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether the expression of RAGE and LRP-1 is related to Aβ1–42 deposition at the hippocampus, prefrontal lobe, and amygdala in DM. We found that diabetic rats had longer escape latency and less frequency of entrance into the target zone than that of the control group (P

Context The Kidney Disease Quality of Life (KDQOL™) instrument is widely used to assess care of end-stage renal disease (ESRD) patients. Objectives This study aimed to demonstrate the measurement properties of the Chinese (simplified characters) version of the KDQOL-Short Form™ (KDQOL-SF™) in ethnic Chinese ESRD patients in Singapore. Methods Seventy-eight new ESRD patients, initially conservatively managed, were interviewed and followed-up; 31 later commenced dialysis. Quality of life (with the KDQOL-SF), Karnofsky Performance Status, and estimated glomerular filtration rate (eGFR) were assessed at 0, 3, 6, 9, 12, 18, and 24 months. Nonparametric statistics were used to assess correlation and changes. Results The patterns of descriptive summary and floor and ceiling effects were similar to those reported in the original English version. Most of the kidney disease-targeted scales and the generic scales of the KDQOL-SF demonstrated 1) criterion validity in terms of correlation with objectively measured and/or subjectively rated variables, 2) convergent/divergent validity in terms of correlation patterns between kidney disease-targeted and generic scales, and 3) responsiveness to change in terms of difference before and after dialysis, except for Work Status. Internal consistency reliability was satisfactory, but that for the Work Status scale was too low (alpha=0.32) and for two other kidney disease-targeted scales, Sexual Function and Dialysis Staff Encouragement, was too high (1.0). Conclusion Most of the scales in the Chinese version of the KDQOL-SF were valid and achieved internal consistency reliability, except for the Work Status scale. Also, the internal consistency reliability of two disease-targeted scales was too high, suggesting room for reduction of some items to reduce burden on respondents.

β-Amyloid (Aβ) accumulation in the brain is the major pathophysiology of Alzheimer disease (AD). Hypertension is a risk factor for AD by promoting Aβ deposition. Traditional Chinese medicinal compound tongxinluo (TXL) can improve blood circulation and endothelium-dependent vasodilation. This study investigates the effects of TXL on cognition and Aβ using spontaneously hypertensive rats (SHRs). TXL was intragastrically administered to SHRs at low-dose, mid-dose and high-dose for 15, 30 or 60days. Cognition was evaluated with a Morris Water Maze (MWM). Aβ in the brain was detected by western blot, ELISA and Thioflavin-S staining. Western blot and RT-PCR were employed to exam the expression of receptor for advanced glycation end products (RAGE), low-density lipoprotein receptor-related protein-1 (LRP-1) and amyloid precursor protein (APP). After TXL treatment for 60days, compared with the vehicle, the number of crossed platform and the time spent in the target quadrant increased in parallel with the increasing length of treatment in MWM. Moreover, the Aβ in the hippocampus significantly decreased compared to the vehicle group, both in western blot and ELISA. Additionally, TXL reduced RAGE expression in a dose- and time-depended manner, but LRP-1 expression had no difference between TXL groups and vehicle groups. Furthermore, the β-secretase expression was significantly decreased compared to the vehicle group, but APP expression had no difference. In conclusion, TXL improved cognition and decreased Aβ in SHRs in a dose- and time-dependent manner, the underlying mechanism may involved in inhibiting RAGE and β-secretase expression.

Thymectomy is routinely carried out in patients with myasthenia gravis (MG) and thymomas. However, there is still a dispute as to whether MG patients with thymic hyperplasia should undergo thymectomy. We aimed to investigate the pathological findings in the thymus in patients with co-existing MG and thymic hyperplasia or thymomas treated with thymectomy, as well as effects of immunosuppression. Thirty-three patients with MG were selected and grouped accordingly: patients with no thymic abnormalities, patients with thymic hyperplasia, and patients with thymomas. All patients were treated with methylprednisolone alongside immunosuppression. A separate cohort of 24 MG patients with thymic hyperplasia or thymomas and treated with thymectomy were selected. As controls, 5 patients with thymomas or thymic carcinoma without MG were selected. Expression of CD5, extracellular regulated protein kinases1/2 mitogen activated protein kinase (ERK1/2MAPKs) and CD95 ligand (FasL) in the thymus was examined. Methylprednisolone and immunosuppressive therapy are highly effective in MG patients with normal thymus tissue and MG patients with thymic hyperplasia compared to MG patients with thymomas alone. CD5 expression was highest in MG patients with thymic hyperplasia, correlating with expression of ERK1/2MAPKs. FasL expression was similar across all groups. Thymomas may be distinguished from thymic hyperplasia by expression of CD5 and ERK1/2MAPKs. Thymectomy is the preferred treatment for MG patients with thymomas but may not be necessary in MG patients with thymic hyperplasia who are treated with immunosuppressive therapy.

Ethanol, one of the most frequently used and abused substances in our society, has a profound impact on sedation. However, the neuronal mechanisms underlying its sedative effect remain unclear. In this study, we investigated the effects of ethanol on histaminergic neurons in the tuberomammillary nucleus (TMN), a brain region thought to be critical for wakefulness. Coronal brain slices (250 μm thick) containing the TMN were prepared from GAD67-GFP knock-in mice. GAD67-GFP was used to identify histaminergic neurons in the TMN. The spontaneous firing and membrane potential of histaminergic neurons, and GABAergic transmission onto these neurons were recorded using whole-cell patch-clamp recordings. Drugs were applied through superfusion. Histaminergic and GAD67-expressing neurons in the TMN of GAD67-GFP mice were highly co-localized. TMN GFP-positive neurons exhibited a regular spontaneous discharge at a rate of 2–4 Hz without burst firing. Brief superfusion of ethanol (64, 190, and 560 mmol/L) dose-dependently and reversibly suppressed the spontaneous firing of the neurons in the TMN; when synaptic transmission was blocked by tetrodotoxin (1 μmol/L), ethanol caused hyperpolarization of the membrane potential. Furthermore, superfusion of ethanol markedly increased the frequency and amplitude of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs), which were abolished in the presence of the GABAA receptor antagonist bicuculline (20 μmol/L). Finally, ethanol-mediated enhancement of sIPSCs and mIPSCs was significantly attenuated when the slices were pretreated with the GABAB agonist baclofen (30 μmol/L). Ethanol inhibits the excitability of histaminergic neurons in mouse TMN slices, possibly via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites.

Bone fracture occurs in stroke patients at different times during the recovery phase, prolonging recovery time and increasing medical costs. In this review, we discuss the potential risk factors for post-stroke bone fracture and preventive methods. Most post-stroke bone fractures occur in the lower extremities, indicating fragile bones are a risk factor. Motor changes, including posture, mobility, and balance post-stroke contribute to bone loss and thus increase risk of bone fracture. Bone mineral density is a useful indicator for bone resorption, useful to identify patients at risk of post-stroke bone fracture. Calcium supplementation was previously regarded as a useful treatment during physical rehabilitation. However, recent data suggests calcium supplementation has a negative impact on atherosclerotic conditions. Vitamin D intake may prevent osteoporosis and fractures in patients with stroke. Although drugs such as teriparatide show some benefits in preventing osteoporosis, additional clinical trials are needed to determine the most effective conditions for post-stroke applications.

When food is available during a restricted and predictable time of the day, mammals exhibit food-anticipatory activity (FAA), an increase in locomotor activity preceding the presentation of food. Although many studies have attempted to locate the food-entrainable circadian oscillator in the central nervous system, the pathways that mediate food entrainment are a matter of controversy. The present study was designed to determine the role of dopaminergic and histaminergic systems on FAA. Mice were given access to food for 2 h (ZT12-ZT14), and FAA was defined as the locomotor activity that occurred 2 h before the availability of food. Dopamine D1 receptor (R), D2R, and histamine H1R-specific antagonists were used to clarify the role of dopamine and histamine receptors in FAA induced by food restriction (FR). FAA was monitored by infrared locomotor activity sensors. Mice were sacrificed at ZT12 on the 14th day of FR, and monoamine concentrations were determined by high-performance liquid chromatography coupled to electrochemical detection (HPLC-ECD). The results showed that pretreatment with the D1R antagonist SCH23390 at 1, 3, or 10 µg/kg significantly reduced FAA by 19% ( p < 0.05), 26% ( p < 0.05), or 19% ( p < 0.01), respectively, and the D2R antagonist raclopride at 22, 67, or 200 µg/kg significantly reduced FAA by 16% ( p < 0.05), 36% ( p < 0.01), or 41% ( p < 0.01), respectively, as compared with vehicle control. Moreover, coadministration of SCH23390 (10 µg/kg) and raclopride (200 µg/kg) synergistically inhibited FAA by 57% ( p < 0.01) as compared with vehicle control. Consistently, the levels of dopamine and its metabolites in the striatum and midbrain were significantly increased during FAA, even with the pretreatment of D1R and D2R antagonists. However, pretreatment with pyrilamine at 2.5, 5, or 10 mg/kg did not significantly reduce FAA, although it reduced the locomotor activity during the dark period in ad libitum mice. These results strongly indicate that the dopaminergic system plays an essential role in the FAA in mice.

The suprachiasmatic nucleus (SCN) is a master circadian pacemaker. It regulates the 24 h timing of many physiological processes, including sleeping and waking. After bilateral SCN lesions, the circadian rhythm of the sleep wake cycle was completely eliminated, but the characteristics of the sleep wake profile were not well clarified. In the present study, bilateral suprachiasmatic nucleus lesions (SCNX) were created in rats to determine the effects of SCNX on the sleep-wake profile in terms of number of episodes, mean duration of each stage and number of transitions between stages. Although bilateral SCN lesions completely eliminated the circadian rhythm in the sleepwake cycle, there was no significant change in the total amount of daily sleep or wakefulness before and after lesions. However, the SCN-lesioned rats exhibited anincreased episode number of wake and non-rapid eye movement (NREM) sleep during dark period and a decreased one during light period. The mean duration of wakefulness decreased significantly during the dark period and increased during the light period. The number of transitions between NREM sleep and wakefulness increased during the dark period and decreased during the light period. The NREM sleep power density and total number of episodes, number of transitions, and mean duration were not significantly different from those of sham controls when viewed over 24 h. These results indicate that lesions of suprachiasmatic nucleus did not alter the total amount of daily sleep but did modify the structure of sleepwake profiles in rats.

It has long been thought that the treatment of core anxiety symptoms will produce a satisfactory resolution of insomnia. Genistein, the principal isoflavone constituent of soybean, has been reported to exert anxiolytic-like effects in rats. Whether genistein modulates sleep behavior, however, remains to be elucidated. In the present study, we examined the effect of genistein on sleep wake profiles in freely moving mice by EEG and EMG recording as well as immunohistochemical staining for c-Fos. Our results showed that genistein administered i.p. at doses of 80 and 160 mg/kg significantly increased the amount of non-rapid eye movement (non-REMNREM) sleep and as well as the number of NREM sleep episodes, with a concomitant reduction of wakefulness. It increased the state transitions from wakefulness to NREM sleep and subsequently from NREM to wakefulness. However, genistein neither had an effect on the amount of REM sleep nor on EEG power density of NREM or REM sleep. Immunostaining revealed a reduction of c-Fos expression in neurons of the locus coeruleus and the tuberomammillary nucleus after administration of genistein, as compared with the vehicle control. These results indicate that treatment with genistein leads to an inhibition of arousal-promoting neurons and thus promotes NREM sleep, suggesting its potential application for the treatment of insomnia.

Study objectives To investigate possible differences in the effect of repeated sleep restriction (RSR) during adolescence and adulthood on sleep homeostasis and spatial learning and memory ability. Design The authors examined electroencephalograms of rats as they were subjected to 4-h daily sleep deprivation that continued for 7 consecutive days and assessed the spatial learning and memory by Morris water maze test (WMT). Participants Adolescent and adult rats. Measurements and results Adolescent rats exhibited a similar amount of rapid eye movement (REM) and nonrapid eye movement (NREM) sleep with higher slow wave activity (SWA, 0.5-4 Hz) and fewer episodes and conversions with prolonged durations, indicating they have better sleep quality than adult rats. After RSR, adult rats showed strong rebound of REM sleep by 31% on sleep deprivation day 1; this value was 37% on sleep deprivation day 7 in adolescents compared with 20-h baseline level. On sleep deprivation day 7, SWA in adult and adolescent rats increased by 47% and 33%, and such elevation lasted for 5 h and 7 h, respectively. Furthermore, the authors investigated the effects of 4-h daily sleep deprivation immediately after the water maze training sessions on spatial cognitive performance. Adolescent rats sleep-restricted for 7 days traveled a longer distance to find the hidden platform during the acquisition training and had fewer numbers of platform crossings in the probe trial than those in the control group, something that did not occur in the sleep-deprived adult rats. Conclusions Repeated sleep restriction (RSR) altered sleep profiles and mildly impaired spatial learning and memory capability in adolescent rats.

SUMMARY Aims: Safranal (2,6,6-trimethyl-1,3-cyclohexadiene-1-carboxaldehyde, C10H14O) is an active ingredient in the saffron, which is used in traditional medicine. It has been reported to have sedative and anti-epileptic effects, but its hypnotic effects remain uncertain. The aim of this study was to evaluate effects of safranal on sleep-wake cycle. Methods: We established hypnotic-model mice treated with a low dose of pentobarbital 20 mg/kg, and administered different doses of safranal, vehicle, or diazepam. The change of sleep-wake cycle was assessed by sleep recording and c-Fos expression in the brain was analyzed by immunohistochemistry. Results: Safranal increased the duration of non-rapid eye movement (NREM) sleep, shortened NREM sleep latency, and enhanced the delta power activity of NREM sleep. Immunohistochemical evaluation revealed that safranal increased c-Fos expression in the ventrolateral preoptic nucleus (VLPO), one of the putative sleep centers, and decreased it in the arousal histaminergic tuberomammillary nuclei (TMN). Conclusion: These findings indicate that safranal enhances NREM sleep in pentobarbital-treated mice. The hypnotic effects of safranal may be related to the activation of the sleep-promoting neurons in the VLPO and the simultaneous inhibition of the wakefulness-promoting neurons in the TMN, suggesting that safranal may be a hypnotic substance.

In humans, depression is associated with altered rapid eye movement (REM) sleep. However, the exact nature of the relationship between depressive behaviors and sleep abnormalities is debated. In this study, bilateral olfactory bulbectomy (OBX) was carried out to create a model of depression in rats. The sleep-wake profiles were assayed using a cutting-edge sleep bioassay system, and depressive behaviors were evaluated by open field and forced swimming tests. The monoamine content and monoamine metabolite levels in the brain were determined by a HPLC-electrochemical detection system. OBX rats exhibited a significant increase in REM sleep, especially between 15:00 and 18:00 hours during the light period. Acute treatment with fluoxetine (10 mg/kg, i.p.) immediately abolished the OBX-induced increase in REM sleep, but hyperactivity in the open field test and the time spent immobile in the forced swimming test remained unchanged. Neurochemistry studies revealed that acute administration of fluoxetine increased serotonin (5-HT) levels in the hippocampus, thalamus, and midbrain and decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA). The ratio of 5-HIAA to 5-HT decreased in almost all regions of the brain. These results indicate that acute administration of fluoxetine can reduce the increase in REM sleep but does not change the depressive behaviors in OBX rats, suggesting that there was no causality between REM sleep abnormalities and depressive behaviors in OBX rats.