Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

Cortical mechanisms underlying variability in intermittent theta-burst stimulation-induced plasticity: A TMS-EEG study

ObjectiveTo test the hypothesis that intermittent theta burst stimulation (iTBS) variability depends on the ability to engage specific neurons in the primary motor cortex (M1).MethodsIn a sham-controlled interventional study on 31 healthy volunteers, we used concomitant transcranial magnetic stimulation (TMS) and electroencephalography (EEG). We compared baseline motor evoked potentials (MEPs), M1 iTBS-evoked EEG oscillations, and resting-state EEG (rsEEG) between subjects who did and did not show MEP facilitation following iTBS. We also investigated whether baseline MEP and iTBS-evoked EEG oscillations could explain inter and intraindividual variability in iTBS aftereffects.ResultsThe facilitation group had smaller baseline MEPs than the no-facilitation group and showed more iTBS-evoked EEG oscillation synchronization in the alpha and beta frequency bands. Resting-state EEG power was similar between groups and iTBS had a similar non-significant effect on rsEEG in both groups. Baseline MEP amplitude and beta iTBS-evoked EEG oscillation power explained both inter and intraindividual variability in MEP modulation following iTBS.ConclusionsThe results show that variability in iTBS-associated plasticity depends on baseline corticospinal excitability and on the ability of iTBS to engage M1 beta oscillations.SignificanceThese observations can be used to optimize iTBS investigational and therapeutic applications.     

Altered supraspinal motor networks in survivors of poliomyelitis: A cortico-muscular coherence study

ObjectivePoliomyelitis results in changes to the anterior horn cell. The full extent of cortical network changes in the motor physiology of polio survivors has not been established. Our aim was to investigate how focal degeneration of the lower motor neurons (LMN) in infancy/childhood affects motor network connectivity in adult survivors of polio.MethodsSurface electroencephalography (EEG) and electromyography (EMG) were recorded during an isometric pincer grip task in 25 patients and 11 healthy controls. Spectral signal analysis of cortico-muscular (EEG-EMG) coherence (CMC) was used to identify the cortical regions that are functionally synchronous and connected to the periphery during the pincer grip task.ResultsA pattern of CMC was noted in polio survivors that was not present in healthy individuals. Significant CMC in low gamma frequency bands (30–47 Hz) was observed in frontal and parietal regions.ConclusionThese findings imply a differential engagement of cortical networks in polio survivors that extends beyond the motor cortex and suggest a disease-related functional reorganisation of the cortical motor network.SignificanceThis research has implications for other similar LMN conditions, including spinal muscular atrophy (SMA). CMC has potential in future clinical trials as a biomarker of altered function in motor networks in post-polio syndrome, SMA, and other related conditions.     

Cognitive effort decreases beta,alpha, and theta coherence and ends afterdischarges in human brain

ObjectiveMental activation has been reported to modify the occurrence of epileptiform activity. We studied its effect on afterdischarges.MethodIn 15 patients with implanted electrodes we presented cognitive tasks when afterdischarges occurred. We developed a wavelet cross-coherence function to analyze the electrocorticography before and after the tasks and compared findings when cognitive tasks did or did not result in afterdischarge termination. Six patients returned for functional MRI (fMRI) testing, using similar tasks.ResultsCognitive tasks often could terminate afterdischarges when direct abortive stimulation could not. Wavelet cross-coherence analysis showed that, when afterdischarges stopped, there was decreased coherence throughout the brain in the 7.13–22.53 Hz frequency ranges (p values 0.008–0.034). This occurred a) regardless of whether an area activated on fMRI and b) regardless of whether there were afterdischarges in the area.ConclusionsIt is known that cognitive tasks can alter localized or network synchronization. Our results show that they can change activity throughout the brain. These changes in turn can terminate localized epileptiform activity.SignificanceCognitive tasks result in diffuse brain changes that can modify focal brain activity. Combined with a seizure detection device, cognitive activation might provide a non-invasive method of terminating or modifying seizures.     

未担任临床工作的医院药学人员成为临床药师的必要性与可行性分析

目的： 目前我国临床药师数量短缺现象较为严重，医疗机构中未担任临床工作的药学人员成为临床药师可能是改善我国临床药师人力资源储备的措施之一。本研究旨在分析未担任临床工作的医院药学人员成为临床药师的必要性与可行性。方法： 通过文献研究的方法分析我国未担任临床工作的医院药学人员成为临床药师的必要性与可行性。结果： 医院药学向临床转型是目前的趋势，未担任临床工作的医院药学人员成为临床药师具有药学知识充足、熟悉医院药学工作流程、转型便捷高效等优势，能够弥补临床药学专业教育在人才输送方面存在的不足，具有很强的必要性。此外，未担任临床工作的医院药学人员由于已满足基本的学历要求，且对于成为临床药师的意愿较强，人才来源有保障，加之我国临床药师的培训模式逐渐完善，为我国临床药师培养提供了有利条件，未担任临床工作的医院药学人员成为临床药师具有可行性。结论： 未担任临床工作的医院药学人员成为临床药师具有可行性与必要性，为了促进未担任临床工作的医院药学人员转型成为临床药师，本研究提出了几点建议为政策制定者与医院管理者提供参考。     

基于小波能量谱的先天或风湿性心脏病异常心音分类算法研究

目的为解决先天性心脏病或风湿性心脏病异常心音分辨问题,应用离散小波频带能量对异常心音分类算法进行研究。方法采集22人的正常心音和116人的异常心音,对心音信号做离散小波变换,根据病理性心杂音在频域内的分布范围划分5层频带,计算得到各层频带的能量占比,根据单因素方差分析方法,提出了基于小波能量谱的心音分类指标。结果对正常心音和异常心音的4个听诊区域进行了分类,最优分类准确率为92%。区分动脉导管未闭和其余异常心音的最优分类准确率为81.9%。结论基于小波能量谱的心音分类算法无需对心音信号进行分割,提取特征值少,可准确有效地对心音信号进行分类,相较于传统的心音听诊,算法的引入能够在异常心音临床诊断中提供参考数据。     

The Selection of a Pharmaceutical Salt—The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance

A roadmap for the selection of a pharmaceutical salt form for a development candidate is presented. The free base of the candidate did not have sufficient chemical stability for development. The initially selected salt form turned out to be undevelopable because it was unstable during scale-up synthesis and storage. The rationale for the new solid form screening and the criteria for selection are discussed. Before the final selection, the pH solubility profiles of the 2 new salts, a benzoate and a besylate, were compared. Atypical solubility behavior was observed for the benzoate salt in hydrochloric acid with and without normal saline. A scheme is proposed illustrating how the pKas of the counterion and active pharmaceutical ingredient, the medium composition, and final pH affect the solubility and solution equilibria of the 2 selected salt forms. This scheme also includes the equilibria between solution and solid phases in different pH ranges. The pharmaceutical importance of this research is that it sheds light on how the acidity of the counterion can affect the solubility of the selected salt form in the gastric environment. With a well-designed formulation strategy, this property potentially can be translated to optimal biopharmaceutical performance of the drug product.     

Bottom-Up and Top-Down Approaches to Explore Sodium Dodecyl Sulfate and Soluplus on the Crystallization Inhibition and Dissolution of Felodipine Extrudates

The objectives of this study were to explore sodium dodecyl sulfate (SDS) and Soluplus on the crystallization inhibition and dissolution of felodipine (FLDP) extrudates by bottom-up and top-down approaches. FLDP extrudates with Soluplus and SDS were prepared by hot melt extrusion, and characterized by polarized light microscopy, differential scanning calorimetry, and fourier transform infrared spectroscopy. Results indicated that Soluplus inhibited FLDP crystallization, and the whole amorphous solid dispersions (ASDs) were binary FLDP-Soluplus (1:3) and ternary FLDP-Soluplus-SDS (1:2:0.15～0.3 and 1:3:0.2～0.4) extrudates. Internal SDS (5%-10%) decreased glass transition temperatures of FLDP-Soluplus-SDS ternary ASDs without presenting molecular interactions with FLDP or Soluplus. The enhanced dissolution rate of binary or ternary Soluplus-rich ASDs in the nonsink condition of 0.05% SDS was achieved. Bottom-up approach indicated that Soluplus was a much stronger crystal inhibitor to the supersaturated FLDP in solutions than SDS. Top-down approach demonstrated that SDS enhanced the dissolution of Soluplus-rich ASDs via wettability and complexation with Soluplus to accelerate the medium uptake and erosion kinetics of extrudates, but induced FLDP recrystallization and resulted in incomplete dissolution of FLDP-rich extrudates. In conclusion, top-down approach is a promising strategy to explore the mechanisms of ASDs' dissolution, and small amount of SDS enhances the dissolution rate of polymer-rich ASDs in the nonsink condition.     

不同产地药材牛膝的红外光谱及红外导数光谱鉴别研究

目的 建立不同产地牛膝的红外光谱和红外导数光谱并对其差异性进行分析,为牛膝药材的快速鉴别提供依据。方法 运用傅里叶红外光谱技术结合二阶导数光谱对不同产地的牛膝药材进行鉴别,采用聚类分析和主成分分析对红外光谱数据进行统计分析。结果 牛膝的红外吸收峰主要在3 289、2 975、2 890、1 723、1 630、1 403、1 321、1 241、1 018、927、814、773 cm-1附近,虽然不同产地牛膝所含化学成分具有相似性,但不同产地牛膝红外吸收峰的位置和相对强度存在一定差异;并且在二阶导数红外图谱的1 800~800 cm-1波段中有更加明显差别,可以为其鉴别提供更准确的依据。聚类分析显示不同批次间相似度很高,主成分分析结果表明在1 723、1 630、927、814、651 cm-1等处的吸收峰对区分不同产地牛膝药材的贡献较大,内蒙古自治区赤峰市和河南省焦作市武陟县的牛膝药材综合评分较高。结论 红外光谱法与二阶导数光谱相结合不仅可以提供中药材所含化学成分的相关信息,还可以对其不同产地进行区分,实现对牛膝的快速鉴别。