Interactions of phenethylamine‐derived psychoactive substances of the 2C‐series with human monoamine oxidases

Psychoactive substances of the 2C‐series (2Cs) are phenethylamine‐derived designer drugs that can induce psychostimulant and hallucinogenic effects. Chemically, the classic 2Cs contain two methoxy groups in positions 2 and 5 of the phenyl ring, whereas substances of the so‐called FLY series contain rigidified methoxy groups integrated in a 2,3,6,7‐tetrahydrobenzo[1,2‐b:4,5‐b’]difuran core. One of the pharmacological features that has not been investigated in detail is the inhibition of monoamine oxidase (MAO). Inhibition of this enzyme can cause elevated monoamine levels that have been associated with adverse events such as agitation, nausea, vomiting, tachycardia, hypertension, or seizures. The aim of this study was to extend the knowledge surrounding the potential of MAO inhibition for 17 test drugs, which consisted of 12 2Cs (2C‐B, 2C‐D, 2C‐E, 2C‐H, 2C‐I, 2C‐N, 2C‐P, 2C‐T‐2, 2C‐T‐7, 2C‐T‐21, bk‐2C‐B, and bk‐2C‐I) and five FLY analogs (2C‐B‐FLY, 2C‐E‐FLY, 2C‐EF‐FLY, 2C‐I‐FLY, and 2C‐T‐7‐FLY). The extent of MAO inhibition was assessed using an established in vitro procedure based on heterologously expressed enzymes and analysis by hydrophilic interaction liquid chromatography–high resolution tandem mass spectrometry. Thirteen test drugs showed inhibition potential for MAO‐A and 11 showed inhibition of MAO‐B. In cases where MAO‐A IC₅₀ values were determined, values ranged from 10 to 125 μM (7 drugs) and from 1.7 to 180 μM for MAO‐B (9 drugs). In the absence of detailed clinical information on most test drugs, it is concluded that a pharmacological contribution of MAO inhibition cannot be excluded and that further studies are warranted.     

股骨近端防旋髓内钉治疗老年股骨转子间骨折内固定失败原因分析

目的分析股骨近端防旋髓内钉（proximal femoral nail antirotation，PFNA）内固定治疗老年股骨转子间骨折的失败原因。方法回顾分析 2015 年 5 月—2017 年 6 月采用 PFNA 内固定治疗的 136 例股骨转子间骨折患者临床资料。其中男 106 例，女 30 例；年龄 60～80 岁，平均 75.5 岁。骨折按 Evans-Jensen 分型，Ⅰ型 45 例，Ⅱ型 50 例，Ⅲ型 23 例，Ⅳ型 13 例，Ⅴ型 5 例。受伤至手术时间 2～4 d，平均 3 d。根据手术前后 X 线片，总结 PFNA 内固定失败患者的骨折类型（稳定型和不稳定型）、骨折复位质量（根据 Baumgaertner 等的标准评定）、外侧壁及后内侧骨皮质完整性，分析失败原因。结果136 例患者术后均获随访，随访时间 7～18 个月，平均 13.6 个月。术后发生 PFNA 内固定失败 17 例（12.5%），其中稳定型骨折 3 例、不稳定型骨折 14 例；骨折复位质量优 2 例、良 5 例、差 10 例；外侧壁完整 10 例、缺损 7 例；后内侧骨皮质完整 9 例、缺损 8 例。内固定失败原因分析：① 股骨转子间后内侧骨皮质缺失致术后 12 周出现髋内翻 8 例，其中 7 例继续非负重观察，术后 6 个月骨折愈合；1 例术后发生螺旋刀片切出，行人工全髋关节置换术。② 外侧壁缺损致内固定失败 7 例，其中 2 例术后发生螺旋刀片退钉，非负重观察，于骨折愈合后取出内固定物；2 例发生旋转畸形，旋转均不超过 15°，未作特殊治疗，术后 6 个月骨折端愈合；3 例术中致股骨转子间外侧壁破裂，非负重观察，术后 6 个月骨折愈合。③ 术中主钉远端螺钉锁偏 2 例，其中 1 例为术中及时发现并重新植钉，1 例于术后 3 d 摄片发现并伴股骨干裂隙骨折，均非负重观察，术后 1 年后骨折端愈合。结论股骨转子间骨折类型（尤其是不稳定型骨折）、股骨近端外侧壁完整性、后内侧骨皮质是否缺损是 PFNA 治疗老年股骨转子间骨折成败的内在危险因素，术中对外侧壁有效保护及良好的骨折复位质量是术者必须重视的外在因素。     

股骨近端防旋髓内钉内固定治疗老年不稳定型股骨转子间骨折中螺旋刀片位置的研究

目的探讨股骨近端防旋髓内钉（proximal femoral nail anti-rotation，PFNA）内固定治疗老年不稳定型股骨转子间骨折术中螺旋刀片位置对疗效的影响。方法回顾分析 2010 年 1 月—2017 年 1 月经 PFNA 内固定治疗的 131 例老年不稳定型股骨转子间骨折患者临床资料。其中 72 例患者正位 X 线片显示螺旋刀片位于股骨颈中间（A 组）、59 例位于股骨颈中下 1/3（B 组）。两组患者性别、年龄、骨密度、骨折分型、合并内科疾病及受伤至手术时间等一般资料比较，差异均无统计学意义（P>0.05），具有可比性。比较两组并发症发生情况、髋关节功能 Harris 评分、骨折愈合情况以及尖顶距（tip-apex distance，TAD）、尾钉高度。 结果两组患者术后均获随访，随访时间 11～14 个月，平均 12.1 个月。术后患者切口均Ⅰ期愈合，均无相关并发症发生。两组骨折均达临床骨性愈合，愈合时间组间比较差异无统计学意义（Z=−0.190，P=0.849）。术后 6 个月，A 组 TAD 为（2.23±0.07）cm、尾钉高度为（1.72±0.14）cm，B 组分别为（2.85±0.12）、（0.53±0.26）cm，两组间差异有统计学意义（t=−47.643，P=0.000；t=31.031，P=0.000）。术后 6 个月，A 组髋关节功能获优 48 例、良 15 例、可 9 例，B 组获优 38 例、良 16 例、可 5 例，组间差异无统计学意义（Z=−0.075，P=0.941）。 结论PFNA 内固定治疗老年不稳定型股骨转子间骨折时，结合适宜的 TAD，螺旋刀片置于股骨颈中间或中下 1/3 均可获得较好疗效。     

骨牵引器与牵引床辅助闭合复位内固定治疗股骨转子间骨折的疗效比较

目的与传统牵引床复位比较，探讨下肢骨牵引器用于股骨转子间骨折闭合复位股骨近端防旋髓内钉（proximal femoral nail antirotation，PFNA）内固定的疗效及优势。方法回顾分析 2016 年 10 月—2018 年 3 月经闭合复位 PFNA 内固定治疗且符合选择标准的 86 例股骨转子间骨折患者临床资料。其中，44 例术中采用骨牵引器辅助复位（试验组），42 例采用牵引床辅助复位（对照组）。两组患者性别、年龄、致伤原因、骨折侧别、AO 分型以及骨质疏松程度比较，差异均无统计学意义（P>0.05），具有可比性。比较两组患者术前体位摆放时间、手术时间、术中透视次数、术中出血量、骨折愈合时间、术中及术后并发症发生情况，以及术后髋关节功能 Harris 评分。 结果两组患者均顺利完成手术。与对照组相比，试验组患者体位摆放时间、手术时间均缩短，术中透视次数、术中出血量均减少，差异有统计学意义（P<0.05）。两组患者均获随访，试验组随访时间 12～21 个月，平均 14.2 个月；对照组 12～22 个月，平均 14.3 个月。术后 8 例（试验组 3 例、对照组 5 例）发生下肢肌间静脉血栓形成，5 例（试验组 2 例、对照组 3 例）术后 1 年内发生内固定失效。除内固定失效患者外，其余患者骨折均愈合；试验组骨折愈合时间为（11.6±2.9）周，对照组为（12.4±3.6）周，差异无统计学意义（t=1.250，P=0.214）。术后 1 年，试验组 Harris 评分为（86.2±5.9）分，对照组为（84.1±6.1）分，差异无统计学意义（t=1.768，P=0.080）。 结论与牵引床相比，骨牵引器辅助股骨转子间骨折闭合复位 PFNA 内固定能明显缩短术前体位摆放时间及手术时间、减少术中透视次数，提高手术效率且获得相似疗效。     

Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway

Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors (ICIs) have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity. Particularly, the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S. Food and Drug Administration (FDA)-approved anti-programmed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies. However, the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity. Indeed, the cyclic guanosine monophosphate-adenosine monophosphate synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS‒STING‒TBK1) axis is now appreciated as the major signaling pathway in innate immune response across different species. Aberrant signaling of this pathway has been closely linked to multiple diseases, including auto-inflammation, virus infection and cancers. In this perspective, we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS‒STING‒TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy. Meanwhile, highlights on the clinical candidates, limitations and challenges, as well as future directions in this field are also discussed. Further, small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.     

Cellular response to the deposition of diesel exhaust particle aerosols onto human lung cells grown at the air–liquid interface by inertial impaction

The pathogenesis of disease resulting from exposure to diesel exhaust particles (DEP) is often studied using cultured lung cells. Frequently, researchers expose cells to DEP by spiking a suspension of particles in liquid onto the apical surface. This is not representative of in vivo exposure, where aerosols are deposited onto cell surfaces at the air–liquid interface (ALI). Inertial impaction provides an opportunity to deliver high doses of particles with aerodynamic diameters >∼1 μm to the surface of cells in seconds in a reproducible and predictable manner.A custom device was constructed to deposit DEP aerosols onto the surface of Calu-3 and A549 cells grown at the ALI. The pro-inflammatory and toxic cellular response to exposure to the deposited DEP aerosols was measured and compared to the response of cells exposed to DEP as suspensions. Calu-3 cells showed evidence of an oxidative stress response for both exposure types, while there was strong evidence to suggest that the method of aerosol delivery was harmful to the A549 cells.     

A comparative clinical and functional assessment of cortical button versus suture anchor in distal biceps brachii tendon repair

Purpose

The studies comparing the fixation methods being used for the ruptured distal biceps brachii tendon reinsertion show similar outcomes of cortical button and suture anchors usage, however, longer follow-up studies remain necessary. The goal of this study was to compare the clinical and functional three-year outcomes of the cortical button in contrast to the suture anchor fixation.

Kidney Transplantation in Elderly Recipients: A Single-Center Experience

In this retrospective single-center study we evaluated the outcome after kidney transplant in recipients older than 65 years in terms of patient and graft survival and causes of death.

The N‐terminal domain of GPR61, an orphan G‐protein‐coupled receptor,is essential for its constitutive activity

G‐protein‐coupled receptor 61 (GPR61) is an orphan receptor that is abundantly expressed in the brain, which suggests its involvement in various physiological functions in the central nervous system. It couples with Gs and shows constitutive activity. To investigate the role of the N‐terminal segment in the constitutive activity of GPR61, we measured [³⁵S]GTPγS binding using a GPR61‐Gs fusion protein and derivatives that had a deletion or alanine mutation in the N‐terminal segment. We found that deletion of the N‐terminal 25 amino acids and the V19A mutation in GPR61 impaired its constitutive activity. Moreover, the loss of the constitutive activity of the mutants could be restored by adding a fusion protein containing a C‐terminal CD8 single transmembrane domain and the N‐terminal 48‐amino‐acid segment of GPR61, i.e., CD8‐48. We conclude that the N‐terminal domain of GPR61 is required for maintaining its constitutive activity and functions as a tethered intramolecular ligand. © 2008 Wiley‐Liss, Inc.