Metabolism of deltamethrin and cis- and trans-permethrin by human expressed cytochrome P450 and carboxylesterase enzymes

1. The metabolism of the pyrethroids deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes.

2. DLM, CPM and TPM were metabolised by human CYP2B6 and CYP2C19, with the highest apparent intrinsic clearance (CL_int) values for pyrethroid metabolism being observed with CYP2C19. Other CYP enzymes contributing to the metabolism of one or more of the three pyrethroids were CYP1A2, CYP2C8, CYP2C9*1, CYP2D6*1, CYP3A4 and CYP3A5. None of the pyrethroids were metabolised by CYP2A6, CYP2E1, CYP3A7 or CYP4A11.

3. DLM, CPM and TPM were metabolised by both human CES1 and CES2 enzymes.

4. Apparent CL_int values for pyrethroid metabolism by CYP and CES enzymes were scaled to per gram of adult human liver using abundance values for microsomal CYP enzymes and for CES enzymes in liver microsomes and cytosol. TPM had the highest and CPM the lowest apparent CL_int values for total metabolism (CYP and CES enzymes) per gram of adult human liver.

5. Due to their higher abundance, all three pyrethroids were extensively metabolised by CES enzymes in adult human liver, with CYP enzymes only accounting for 2%, 10% and 1% of total metabolism for DLM, CPM and TPM, respectively.

     

63例高级别胶质瘤中IDH1和TERT突变状态的预后价值

目的:探讨异柠檬酸脱氢酶-1（IDH1）和端粒酶逆转录酶（TERT）启动子突变对高级别胶质瘤患者的预后价值。方法:选取2014年9月至2017年6月于我院行手术切除且术后病理提示为高级别胶质瘤的患者63例（WHO Ⅲ级27例，Ⅳ级36例），完善临床资料、随访资料、分子检测结果。应用Sanger测序法检测样本中IDH1和TERT启动子突变情况，根据结果将患者分为不同亚组，通过比较其生存期的差异，分析基因突变与患者预后的关系。结果:63例高级别胶质瘤中，IDH1突变型和野生型患者的中位生存期分别为24和10个月，差异有统计学意义（P＜0.01）；TERT突变型和野生型的中位生存期无明显差异（P＞0.05）。IDH1突变为高级别胶质瘤患者预后良好的因素，TERT突变不能单独提示预后，二者联合分析提示:IDH1突变／TERT突变组预后最好，IDH1野生／TERT突变组预后最差，IDH1突变／TERT野生组预后稍好于IDH1野生／TERT野生组，四组间预后有明显差异。结论:IDH1突变的高级别胶质瘤患者有较好的临床预后，在此基础上，TERT启动子突变检测有助于进一步划分其预后分层。     

Patients Are Knowledge Workers in the Clinical Information Space

Background  Limited research exists on patient knowledge/cognition or “getting inside patients'' heads.” Because patients possess unique and privileged knowledge, clinicians need this information to make patient-centered and coordinated treatment planning decisions. To achieve patient-centered care, we characterize patient knowledge and contributions to the clinical information space. Methods and Objectives  In a theoretical overview, we explore the relevance of patient knowledge to care provision, apply historical perspectives of knowledge acquisition to patient knowledge, propose a representation of patient knowledge types across the continuum of care, and include illustrative vignettes about Mr. Jones. We highlight how the field of human factors (a core competency of health informatics) provides a perspective and methods for eliciting and characterizing patient knowledge. Conclusion  Patients play a vital role in the clinical information space by possessing and sharing unique knowledge relevant to the clinical picture. Without a patient''s contributions, the clinical picture of the patient is incomplete. A human factors perspective informs patient-centered care and health information technology solutions to support clinical information sharing.     

New insights into Wnt signaling alterations in amyotrophic lateral sclerosis: a potential therapeutic target?

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder characterized by upper and lower motor neuron degeneration, which leads to progressive paralysis of skeletal muscles and, ultimately, respiratory failure between 2–5 years after symptom onset. Unfortunately, currently accepted treatments for amyotrophic lateral sclerosis are extremely scarce and only provide modest benefit. As a consequence, a great effort is being done by the scientific community in order to achieve a better understanding of the different molecular and cellular processes that influence the progression and/or outcome of this neuropathological condition and, therefore, unravel new potential targets for therapeutic intervention. Interestingly, a growing number of experimental evidences have recently shown that, besides its well-known physiological roles in the developing and adult central nervous system, the Wnt family of proteins is involved in different neuropathologica conditions, including amyotrophic lateral sclerosis. These proteins are able to modulate, at least, three different signaling pathways, usually known as canonical(β-catenin dependent) and non-canonical(β-catenin independent) signaling pathways. In the present review, we aim to provide a general overview of the current knowledge that supports the relationship between the Wnt family of proteins and its associated signaling pathways and amyotrophic lateral sclerosis pathology, as well as their possible mechanisms of action. Altogether, the currently available knowledge suggests that Wnt signaling modulation might be a promising therapeutic approach to ameliorate the histopathological and functional deficits associated to amyotrophic lateral sclerosis, and thus improve the progression and outcome of this neuropathology.     

Denial of Human Rights: We Must Change the Paradigm of Dementia Care

In far too many instances treatment of persons with dementia has reflected a fundamental denial of basic human rights. At times, these individuals are treated worse than the treatment of animals when the five basic freedoms of animals, described by Pachana in her editorial, are implemented. A number of such examples of dehumanizing (and “de-animalizing”) persons with dementia are presented. A case is made for the position that this is the direct result of the “medicalization” of dementia and “Alzheimer Disease.” This has led to the disenfranchisement of persons with dementia and their caregivers regarding the treatment of dementia, while medical “expertise” has led to a paradigm of learned helplessness while waiting for “the cure.” While the medicalization of dementia has been a financial success in terms of funding failed researcher to find a cure, it has been a catastrophe for the quality of life of persons with dementia and their caregivers. It is time to take control of the treatment of dementia back, and especially to listen to the voices of persons with dementia. It is time to take action NOW – to become disruptive to the current paradigm. The emperor and his cure have no clothes. We deserve better. We must make this change in paradigm our mission, to demand it, and to accept nothing less. Power to the people.     

A Stable Q Compensated Reverse Time Migration Method Based on Excitation Amplitude Imaging Condition

The stability and efficiency, especially the stability, are generally concerned issues in Q compensated reverse time migration (Q-RTM). The instability occurs because of the exponentially boosted high frequency ambient noise during the forward or backward seismic wavefield propagation. The regularization and low-pass filtering methods are two effective strategies to control the instability of the wave propagation in Q-RTM. However, the regularization parameters are determined experimentally, and the wavefield cannot be recovered accurately. The low-pass filtering method cannot balance the selection of cutoff frequency for varying Q values, and may damage the effective signals, especially when the signal-to-noise ratio (SNR) of the seismic data is low, the Q-RTM will be a highly unstable process. In order to achieve the purpose of stability, the selection of cutoff frequency will be small enough, which can cause great damage to the effective high frequency signals. In this paper, we present a stable Q-RTM algorithm based on the excitation amplitude imaging condition, which can compensate both the amplitude attenuation and phase dispersion. Unlike the existing Q-RTM algorithms enlarging the amplitude, the exponentially attenuated seismic wavefield will be used during both the forward and backward wavefield propagation of Q-RTM. Therefore, the new Q-RTM algorithm is relative stable, even for the low SNR seismic data. In order to show the accuracy and stability of our stable Q-RTM algorithm clearly, an example based on Graben model will be illustrated. Then, a realistic BP gas chimney model further demonstrates that the proposed method enjoys good stability and anti-noise performance compared with the traditional Q-RTM with amplitude amplification. Compare the Q-RTM images of these two models to the reference images obtained by the acoustic RTM with acoustic seismic data, the new Q-RTM results match the reference images quite well. The proposed method is also tested using a field seismic data, the result shows the effectiveness of our proposed method.     

颈前入路相关结构三维可视化研究

目的：建立颈前入路相关结构的三维可视化模型。方法：选取首例中国数字化可视人体数据集中第3颈椎上缘至第7颈椎下缘的连续薄层断面图像。运用3D—DOCTOR软件，在计算机上分割重建该手术入路相关的解剖结构并立体显示。结果：成功重建并立体显示第3～7颈椎、椎间盘、脊髓、颈神经、椎动脉、颈长肌、喉（气管）、咽（食管）、颈总动脉（颈内、外动脉）、颈内静脉、迷走神经和胸锁乳突肌等解剖结构的位置关系，建立了颈前入路相关结构的三维可视化模型。结论：在颈部三维可视化模型基础上，参照颈前入路手术步骤可逐层显示该手术相关的重要结构．为该手术的术前训练和模拟提供形态学依据。     

携载rhBMP-2微球的新型可注射自凝固复合人工骨的制备及特性研究

[目的]制备一种具有良好降解性和成骨活性、可注射的自凝固新型骨修复材料。[方法]制备携载rhBMP-2的聚乳酸与聚乙醇酸共聚物（PLGA）微球，并将其与rhBMP-2／磷酸钙骨水泥（CPC）复合，制备出rhBMP-2／PLGA微球／CPC复合人工骨。探讨了材料的特性，包括形貌、固化时间、抗压强度及反映材料体外降解速度的指标一体外降解液Ca、P浓度变化，测定复合材料rhBMP乏的释药速度及体外诱导MSCs细胞成骨分化的能力。[结果]与单纯CPC-rhBMP-2相比，复合材料的固化时间少量增加，抗压强度下降明显。体外降解速度及体外释药明显提高，释放的rhBMP-2具有骨诱导活性。[结论]rhBMP-2／PLGA微球／磷酸钙骨水泥新型复合人工骨是具有良好应用前景的骨修复材料。