Interaction of six protoberberine alkaloids with human organic cation transporters 1, 2 and 3

1.?Organic cation transporters (OCTs) play an important role in drug safety and efficacy. Protoberberine alkaloids are ubiquitous organic cations or weak bases with remarkable biological actives. This study was to elucidate the potential interaction of alkaloids (coptisine, jatrorrhizine, epiberberine, berberrubine, palmatine and corydaline) with OCTs using Madin–Darby canine kidney (MDCK) cells stably expressing human OCT1, OCT2 and OCT3.

2.?All the tested alkaloids significantly inhibited the uptake of MPP⁺, a model OCT substrate, in MDCK-hOCTs cells with the IC₅₀ of 0.931–9.65?μM. Additionally, coptisine, jatrorrhizine and epiberberine were substrates of all the hOCTs with the K_m of 0.273–5.80?μM, whereas berberrubine was a substrate for hOCT1 and hOCT2, but not for hOCT3, the K_m values were 1.27 and 1.66?μM, respectively. The transport capacity of coptisine in MDCK cells expressing the variants of hOCT1-P341L or hOCT2-A270S was significantly higher than that in wild-type (WT) cells with the Cl_int (V_max/K_m) of 379?±?7.4 and 433?±?5.7?μl/mg protein/min, respectively.

3.?The above data indicate that the tested alkaloids are potent inhibitors, and coptisine, jatrorrhizine, epiberberine and berberrubine are substrates of hOCT1, hOCT2 and/or hOCT3 with high affinity. In addition, the variants (OCT1-P341L and OCT2-A270S) possess higher transport capacity to coptisine than WT hOCTs.     

ARL4C stabilized by AKT/mTOR pathway promotes the invasion of PTEN-deficient primary human glioblastoma

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency in primary human glioblastoma (GBM) is associated with increased invasiveness and poor prognosis with unknown mechanisms. Therefore, how loss of PTEN promotes GBM progression remains to be elucidated. Herein, we identified that ADP-ribosylation factor like-4C (ARL4C) was highly expressed in PTEN-deficient human GBM cells and tissues. Mechanistically, loss of PTEN stabilized ARL4C protein due to AKT/mTOR pathway-mediated inhibition of ARL4C ubiquitination. Functionally, ARL4C enhanced the progression of GBM cells in vitro and in vivo. Moreover, microarray profiling and GST pull-down assay identified that ARL4C accelerated tumor progression via RAC1-mediated filopodium formation. Importantly, targeting PTEN potently inhibited GBM tumor progression in vitro and in vivo, whereas overexpression of ARL4C reversed the tumor progression impaired by PTEN overexpression. Clinically, analyses with patients' specimens validated a negative correlation between PTEN and ARL4C expression. Elevated ARL4C expression but PTEN deficiency in tumor was associated with poorer disease-free survival and overall survival of GBM patients. Taken together, ARL4C is critical for PTEN-deficient GBM progression and acts as a novel prognostic biomarker and a potential therapeutic candidate. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Seasonal and weather variation of sleep and physical activity in 12–14-year-old children

Background: Understanding variation in physical activity (PA) and sleep is necessary to develop novel intervention strategies targeting adolescents’ health behaviors. We examined the extent to which PA and sleep vary by aspects of the physical environment. Participants: We performed a cross-sectional analysis of 669 adolescents in the Project Viva cohort. Methods: We estimated total PA, sleep duration, sleep efficiency, and sleep midpoint timing from wrist accelerometers. We used multivariable linear regression models and generalized estimated equations to assess associations of PA and sleep with season and daily weather conditions obtained from the National Oceanic and Atmospheric Administration archive. Results: Mean age was 12.9 (SD 0.6) years; 51% were female and 68% were white. Mean sleep duration was 466 (SD 42) min per night and total PA was 1,652 (SD 431) counts per min per day. Sleep midpoint time was 41 (95% CI: 27 to 54) min later in summer, 28 (95% CI: ?41 to ?14) min earlier in spring, and 29 (95% CI: ?43 to ?15) min earlier in autumn compared to winter. Higher temperature and longer day length both were associated with small reductions of nightly sleep duration. Adolescents were less physically active during winter and on rainy and short sunlight days. There was an inverse U-shaped relationship between PA and mean temperature. Conclusions: Season was associated with large changes in sleep timing, and smaller changes in other sleep and PA measurements. Given the importance of sleep and circadian alignment, future health behavioral interventions may benefit by targeting “season-specific” interventions.     

Maxillary removable prostheses retained by telescopic crowns on two implants or two canines

Precision telescopic attachments allow for rigid connection between removable prostheses and abutments. However, it is still unknown whether implants can bear similar long-term loading forces as teeth when telescopic crowns are used as retention devices. It was the aim of this prospective clinical study to observe maxillary removable partial dentures that were retained by telescopic crowns on two endosseous implants in the canine regions. In a control group, identical dentures were fabricated that were retained by telescopic crowns on the maxillary canines. The implant group consisted of 14 patients, and the control group included 8 patients. Mean observation time of the prostheses was 25.6 months. Radiographic bone levels and periodontal parameters did not reveal specific differences between the two groups. However, five implants failed, and there were no failures in the control group. Survival rates were 48.9% for the implant group and 100% for the control group, with a significant difference between the two groups. Within the limits of this study, it is concluded that the telescopic connection might be too rigid (thus delivering overloading) for two single implants in the canine region of the maxilla supporting a removable denture.     

Surgical treatment of active infective aortic valve endocarditis with associated periannular abscess--11 year results.

AIMS: The aim of the study was to evaluate the long-term results of allograft and prosthetic valve replacement in the treatment of infective aortic valve endocarditis with periannular abscess. METHODS: Between March 1988 and March 1996, 65 patients underwent surgery for active aortic valve endocarditis and paravalvular abscess. The indications for surgery were congestive heart failure, systemic emboli and atrioventricular block III. The pre-operative evaluation was performed with transoesophageal echocardiography. Aortic valve replacement was performed with allografts in 47 cases, with mechanical valves in 15, and bioprosthetic valves in three cases. All patients with total ventricular-aortic dehiscence and prosthetic valve endocarditis were treated with allografts. RESULTS: The 30-day mortality rate was 23.5% in the prosthetic group, when compared with 8.5% in the patients treated with allografts. The rate of recurrent valve infections during the 11-year follow-up period was 27.1% in the prosthetic group and 3.2% in the allograft group. The actuarial 11-year survival rate was 82.1% in the allograft group and 64.7% in the prosthetic group. CONCLUSION: Aortic allografts are an effective treatment for infective aortic valve endocarditis with associated periannular abscess. The operative mortality and recurrent infection rates are lower than in the prosthetic group, resulting in a significantly higher survival rate. Diagnosis and surgical management of these cases should be based on pre-operative transoesophageal echocardiography.     

浙江省肾综合征出血热疫苗效果免疫(感染)增强和免疫策略研究

目的 :观察肾综合征出血热 (HFRS)乳鼠脑纯化Ⅰ型灭活疫苗在浙江省HFRS高发疫区大面积人群接种后的安全性 ,考核血清学及近期、中期流行病学效果。方法 :采用间接免疫荧光法 (IFAT)检测特异性IgG抗体 ,用微量细胞病变中和试验 (MCPENT)检测中和抗体滴度。结果 :共接种 10 4 6 0人 ,全程接种者占 97.30 % ,对照 16 159人。全程接种后两周进行血清学观察 ,荧光抗体阳转率为 10 0 .0 0 % (6 7/ 6 7) ,中和抗体阳转率为 4 4 .4 4 % ,几何平均滴度分别为 72 .12和 4 .6 2。1年后加强免前、免后两周和免后 1年 ,荧光抗体阳性率分别为 2 8.57%、83.33%、75.0 0 % ;中和抗体阳性率分别为 14.80 %、55.56 %、35.0 0 %。疫苗近期 (基础免疫后 1年 )和中期 (基础免疫后 2年 )流行病学防病效果良好 ,人群保护率达 10 0 %。目前未发现接种人群中有免疫 (感染 )增强问题。结论 :HFRS疫苗近期和中期流行病学防病效果明显 ,取得良好的经济和社会效益