Serotonin-2A receptor and catechol-O-methyltransferase polymorphisms in panic disorder

Catechol-O-methyltransferase (COMT) and serotonin receptor 2A (5HTR2A) polymorphisms have been investigated for their possible role in panic disorder (PD). The aim of this study was to investigate the genotype distribution of the COMT val158met and 5HTR2A 102T/C polymorphisms in PD. COMT val158met is a polymorphism at codon 158 that results in variations in COMT enzymatic activity with high- (H) and low-activity (L) alleles. The 5HTR2A 102T/C polymorphism comprises a T-to-C mutation at position 102. The effects of symptom severity, gender, and age of onset were also investigated. The participants were 105 outpatients with PD and 130 controls. The severity of the symptoms of PD was assessed by the Panic and Agoraphobia Scale (PAS). Polymorphisms of the 5HTR2A and COMT genes were identified using polymerase chain reaction and restriction fragment length polymorphism analysis. A significant relationship was found between the COMT Val158Met polymorphism and PD. No significant differences were found in genotype distributions or allele frequencies of the 5HTR2A polymorphisms between the PD and control groups. There were no significant relationships between the COMT and 5HTR2A polymorphisms and age of onset, gender, presence of agoraphobia, or PAS scores in the PD group (p > 0.05).     

Hippocampal injury and neurobehavioral deficits are improved by PD 81,723 following hyperglycemic cerebral ischemia

We investigated the effects of PD 81,723, an allosteric enhancer for the adenosine A(1) receptor subtype, on hippocampal injury and Morris water maze (MWM) performance following hyperglycemic cerebral ischemia and reperfusion (4-VO, 10 min) in the rat. PD 81,723 (3 or 10 mg/kg) or the equivalent volume of saline was administered intraperitoneally 30 min prior to ischemia. Moderate hyperglycemia was achieved by administration of D-glucose (3g/kg, i.p.) 15 min prior to induction of ischemia. Morris water maze trials were performed on the 6th, 7th, and 8th days after the ischemic insult. The rat brains were sectioned (8 microm), stained with cresyl violet/acid fuchsin, and evaluated for hippocampal ischemic injury by an experimenter blinded to the treatment conditions. At the higher dose, PD 81,723 (10 mg/kg) had no effect on hippocampal injury or MWM performance following hyperglycemic ischemia compared to corresponding saline-treated animals. In contrast, a lower dose of PD 81,723 (3 mg/kg) resulted in significant (P < 0.05, n = 8) reduction of hippocampal injury following hyperglycemic ischemia. Furthermore, corresponding Morris water maze performance (latency, learning index, and cumulative distance swum) was significantly improved by PD 81,723 (P < 0.05, n = 8). The results of the present study suggest that, in the presence of PD 81,723, an A(1) allosteric enhancer, endogenously produced adenosine is sufficient to exert significant neuroprotection during hyperglycemic ischemia. Moreover, the present study provides further evidence for a neuromodulatory role of adenosine during hyperglycemic ischemia.     

罗替戈汀透皮贴剂的研究进展

罗替戈汀为选择性多巴胺D1/D2/D3受体激动剂,其透皮贴剂是第一个非麦角类多巴胺受体激动剂贴剂。罗替戈汀贴剂24h有效,能对帕金森病人持续提供多巴胺能刺激,目前获得FDA和EMA批准上市。对罗替戈汀贴剂研究情况进行简要综述。     

Prognostic value of SUVmax measurements obtained by FDG-PET in patients with non-small cell lung cancer receiving chemotherapy

[¹⁸F]Fluorodeoxyglucose (FDG) uptake has been shown to correlate well with tumor proliferation rates. In patients with non-small cell lung cancer (NSCLC) receiving chemotherapy, we analyzed the relationships between the maximum standardized uptake value (SUVmax) obtained by FDG positron emission tomography (FDG-PET) and other clinical factors, and examined whether or not SUVmax could predict progression-free survival (PFS) and/or overall survival (OS). This retrospective study involved 62 consecutive NSCLC patients (35 male and 27 female: median age, 65 years). All patients underwent FDG-PET examination before treatment. As the first-line treatment, the patients received chemotherapy with (n = 15) or without (n = 47) radiotherapy. Survival curves were obtained by the Kaplan-Meier method, and differences in survival between subgroups were analyzed by the log-rank test and the Cox proportional hazards model. Significant correlations were observed between SUVmax and gender (P = 0.006), histology (P < 0.001), smoking status (P = 0.049), stage (P = 0.015), and treatment modality (P = 0.008), but not other factors, including age (P = 0.402) and performance status (P = 0.421). The median SUVmax was 5.1 (25-75th percentile: 3.45-7.0) in patients with adenocarcinoma and 8.3 (25-75th percentile: 6.9-9.9) in those with other types of NSCLC. Adenocarcinomas showed significantly lower SUVmax than the other tumor types (P < 0.001). Cox analysis adjusting for possible confounding factors, including gender, smoking status, histology and stage, demonstrated that the hazard ratios increased as the SUVmax increased in terms of both PFS (P = 0.008) and OS (P = 0.045), indicating that SUVmax predicts outcome independently of other clinical factors, such as histology and stage. Our findings indicate that FDG-PET examination can provide information useful for prognostication in NSCLC.     

Thorough QT study of the effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese and Caucasian subjects

Aims

The aims of this study were three-fold and were to (i) investigate the effect of food (fasted and fed state) on the degree of QT prolongation caused by moxifloxacin under the rigorous conditions of a TQT study, (ii) differentiate the effects on QT_c that arise from changes in PK from those arising as a result of electrophysiological changes attributable to raised levels of C-peptide [11] offsetting in part the I_Kr blocking properties of moxifloxacin and (iii) characterize the QT_cF profile of oral moxifloxacin (400 mg) in healthy Japanese volunteers compared with Caucasian subjects.

Methods

The study population consisted of 32 healthy non-smoking, Caucasian (n = 13) and Japanese (n = 19), male and female subjects, aged between 20–45 years with a body mass index of between 18 to 25 kg m⁻². Female volunteers were required to use an effective contraceptive method or be abstinent. Subjects with ECGs which were deemed unsuitable for evaluation in a TQT study were excluded. ECGs were recorded in triplicate with subsequent blinded manual adjudication of the automated interval measurements. Electrocardiograms in the placebo arm were recorded twice in fasted and fed condition.

Results

The results demonstrated a substantial change in the typical moxifloxacin effect on the ECG. The effect on ΔΔQT_c in the fed state led to a significant delay and a modest reduction compared with the fasted state correcting both conditions with the corresponding placebo data. The largest QT_cF change from baseline in the fed state was observed at 4 h with a peak value of 11.6 ms (two-sided 90% CI 9.1, 14.1). In comparison, the largest QT_cF change observed in the fasted state was 14.4 ms (90% CI 11.9, 16.8) and occurred at 2.5 h post-dose. The PK of moxifloxacin were altered by food and this change was consistent with the observed QT_cF change. In the fed state plasma concentrations of moxifloxacin were considerably and consistently lower in comparison with the fasted state, and this applied to both ethnicities. The concentration–effect analysis revealed that there was no change in slope and confirmed that the difference in this analysis was caused by a change in the PK profile of moxifloxacin. Comparisons of the moxifloxacin effect in the fed state compared with fasted placebo also revealed a pharmacodynamic effect whereby a meal appears to antagonize the effects of moxifloxacin on the lengths of the QT_c interval.

Conclusions

Our findings demonstrate that the food effect by itself leads to a shortening of the QT_c interval offsetting in part the effects of a 400 mg single dose of oral moxifloxacin. The typical moxifloxacin PK profile is also altered by food prior to dosing reducing the C_max and delays the peak effects on QT_c up to several hours thereby reducing the overall magnitude of the effect and delaying the peak QT_c prolongation. The contribution of the two effects was clearly discernible. Given that moxifloxacin is sometimes given with food in TQT studies, consideration should be given to adequate baseline corrections and appropriate sampling time points. In this study the PK–PD relationship was similar for Japanese and Caucasian subjects in the fed and fasted conditions, thereby providing further evidence that the sensitivity to the QT_c prolonging effects of fluoroquinolones was likely to be independent of ethnicity. The small differences observed between the two subpopulations were not statistically significant. However, future studies should give consideration to formal ethnic comparisons as a secondary outcome parameter as very little is known about the relationship between ethnicity and drug effects on cardiac repolarization.     

Chir99021联合PD0325901对小鼠胚胎干细胞中miRNAs差异表达的影响

目的：通过研究Chir99021联合PD0325901对小鼠胚胎干细胞中miRNAs差异表达的影响,为揭示胚胎干细胞的自我更新和分化的机制提供更多线索。方法采用miRNA基因芯片技术检测Chir99021联合PD0325901处理组和PD0325901处理组miRNAs的表达谱差异。选取3倍以上及通过查文献与胚胎干细胞自我更新相关的1.5倍以上3倍以下的miRNAs,采用实时荧光定量PCR法验证,利用miRDB、Miranda两个数据库交叉预测差异表达的靶基因,并应用KEGG Pathway进行靶基因功能富集分析。结果与PD0325901单独处理相比,Chir99021联合PD0325901处理组有47种miRNAs上调1.5倍以上,75种miRNAs下调1.5倍以上;用实时荧光定量PCR验证差异表达的miRNAs,结果显示13个miRNAs与芯片结果相符。靶基因预测分析显示,miR-466a-5p、miR-466d-5p处于重要位置,Plcb1、Prkcb处于关键基因位置。结论 Chir99021可引起小鼠胚胎干细胞中的miRNAs差异表达,差异表达的miRNAs可能通过调控Plcb1、Prkcb基因而影响胚胎干细胞的自我更新。     

接受连续性静脉-静脉血液滤过患者左氧氟沙星抗感染方案的优化

目的:对ICU肾衰竭接受连续性静脉-静脉血液滤过(continuous veno-venous haemofiltration,CVVH)治疗患者左氧氟沙星给药方案进行优化。方法:根据左氧氟沙星药效学及药动学参数等实验数据资料,应用蒙特卡洛模拟法计算累积反应分数(CFR),推荐最佳给药方案。结果:ICU肾衰竭接受CVVH治疗的患者,治疗肺炎克雷伯菌和肺炎链球菌感染时左氧氟沙星的最佳方案分别为500 mg qd iv和200 mg qd iv;ICU肾功能正常患者,对肺炎链球菌感染时左氧氟沙星的最佳方案为750 mg qd iv。对于肾衰竭或肾功能正常患者,当感染铜绿假单胞菌和金黄色葡萄球菌时,左氧氟沙星4种静注给药方案(200,300,500,750 mg qd)治疗效果均不佳,建议联合治疗或更换药物。结论:与ICU肾功能正常患者对比,ICU肾衰竭接受CVVH治疗患者使用左氧氟沙星时应根据不同病原菌感染考虑降低给药剂量。     

Comparison of the plaque assay and 50% tissue culture infectious dose assay as methods for measuring filovirus infectivity

Two common methods of quantifying filovirus infectivity, a plaque assay and 50% cell culture infectious dose (TCID₅₀) endpoint dilution assay, were compared. The two assays were performed side by side using the same virus stock sample to determine the correlation between the results of the two assays. The TCID₅₀ assay appeared to be more sensitive but slightly more variable, and there was a tenfold difference in the numerical results of these methods of enumeration. The advantages and disadvantages of both assays are discussed. Both methods are useful and practicable in filovirus research, and this comparison will be hugely beneficial to the filovirus research community as it seeks to become more united. Further work in this area should be performed to ensure consistency in filovirus research.     

辛伐他汀联合阿昔莫司对高脂血症患者颈动脉粥样斑块的影响

【目的】观察辛伐他汀联合阿昔莫司对颈动脉粥样硬化斑块的影响。【方法】117例高脂血症并颈动脉粥样硬化斑块患者并随机分为三组：辛伐他汀组（39例）,在常规治疗基础上加辛伐他汀40mg,每晚1次;阿昔莫司组（39例）,在常规治疗基础上加阿昔莫司,250mg,每天2次;联合治疗组（39例）,在常规治疗基础上加阿昔莫司,每天2次,辛伐他汀40mg,每晚1次。患者均连续服药6个月,并均于服药前和服药后第6个月检查颈动脉粥样硬化斑块大小、血脂水平。【结果】三组患者治疗前后相比较血脂下降、颈动脉斑块消退差异均有显著性（P〈0．05）,其中联合用药组血脂变化、颈动脉斑块消退治疗后最为明显,与其他组比较差异有显著性（P〈0．05）。【结论】辛伐他汀联合阿昔莫司能够更有效地消退颈动脉斑块,其效果优于单独应用辛伐他汀或阿昔莫司。