Unusual electrophysiological findings in a Chinese ALS 4 family with SETX-L389S mutation: a three-year follow-up

Journal of Neurology - Amyotrophic lateral sclerosis type 4 (ALS4) is a familial form of ALS caused by mutations in the SETX gene. To date, there are seven unrelated ALS4 families with four...     

Controllable stripping of radiolabeled group in vivo to optimize nuclear imaging via NO-responsive bioorthogonal cleavage reaction

A novel “turn-off” strategy for controllable radionuclide clearance is established. 1,4-dihydropyridine (DHP) is used as a conditional linker to connect a radioisotope labeled moiety and nano-agent. A highly specific, sensitive and effective C–C bond cleavage of DHP happens in vivo when treated with nitric oxide which is provided by glyceryl trinitrate (GTN). The radioactive cut-off part from the nanoparticle is observed to be cleared quickly by microSPECT-CT. 3–5 times decreases of radioactivity in the blood, kidneys, intestine, heart and lungs are observed after GTN treatment in a biodistribution assay. The radioactivity redistribution indicates that the radioactive leaving part is indeed cut off and the radionuclide metabolism accelerated. Organ level internal dose assessment reveals the GTN treated groups carry only ½ the radiation dose of the control group. Collectively, a feasible pathway for controllable radionuclide clearance is for the first time provided for high contrast and low radiation nuclear imaging.

A novel “turn-off” strategy was developed for controllable radionuclide clearance in organisms.

Radiolabeled compounds with biological activity, or radiotracers, have been widely used for nuclear imaging and radiation therapy. Compared with other imaging modalities, a unique problem in radiotracer-based imaging is that the radioactivity cannot be simply “turned off”. As a result, it is impossible to carry out multi-scans of the same organ with different tracers in a short period. For instance, there are three kinds of marker receptors (ER, PR, HER2) expressed in breast cancer. Different type of breast cancer expresses a different combination of these three. Therefore, three kinds of radiotracers that aim to bind the corresponding receptors will be used to distinguish individual breast cancer phenotype. The uptake of a second tracer can''t be quantified accurately before the radioactivity of the first tracer decayed to background level, which may need one or two days depending on the half-life of radionuclide. So, it''s necessary to develop a strategy to “quench” the radioactivity. Furthermore, nonspecific binding is inevitable, and the “noise” or “background” from non-specific binding of radiotracers to non-target proteins cannot be easily differentiated from the specific binding component.Therefore, it''s meaningful to develop a kind of reaction that could strip the radiation by control. To achieve this goal, the metabolism of the radioactive part should be accelerated. The biorthogonal cleavage reaction would perfectly meet the needs, if (1) cleavable reactions could happen by the control in vivo; (2) the cut-off part has a relatively fast metabolism; (3) radionuclide is linked on the cut-off part.¹ One of the key issues that bio-orthogonal reactions resolve is to bind two components into one, and make the different metabolic rate of different components synchronized.² As the reaction in the opposite direction of bio-orthogonal reaction, the bio-orthogonal cleavage reaction can extinguish the radiation by diversifying the metabolism of radionuclides and the slow metabolic targeting components.Dihydropyridine (DHP) and its cleavage-triggering partner nitric oxide (NO) can perfectly meet the three conditions. NO, a hydrophobic signal molecule, could spread without any transmembrane transporter, which means NO could spread quickly and spend little energy.^3–5 Many kinds of NO donor drugs are commercially available, such as glyceryl trinitrate (GTN), sodium nitroprusside, etc. In our previous work,⁶ it was demonstrated that the physiological concentration of NO is high enough to cleave the C–C bond of DHP. Furthermore, NO donor drugs could offer a circumstance with higher NO concentration than normal physiological concentration. Therefore, it is possible for the reaction between DHP and NO from donor drugs to occur in vivo. Herein, a NO-triggerred “turn-off” system to extinguish the radiation by cleaving the radionuclides from nanoparticles is present. Benzyl group substituted 1,4-dihydropyridine can be cleaved through controlled NO stimulation by intraperitoneal injection of GTN.Nanoparticles as the major kind of theranostic agents have been developed quickly over these years.^7–11 During the process of synthesis, nanoparticles with similar shape, scale and dispersion properties would be obtained by manipulating conditions precisely. Therefore, the metabolism of nanoparticles in the living body is more predictable than diverse small molecules. Especially, radionuclides labeled nanoparticles not only play roles in diagnosis but also work well on tumor therapy. Enhanced permeability and retention (EPR) effect make nanoparticles wonderful radiotherapy reagents.^12–15 However, nanoparticles mean to be easily captured by the mononuclear phagocyte system (MPS), which makes the nanoparticles mostly enriched in liver besides in tumor.^16–20 Furthermore, metabolism of nanoparticles are quite slow than most of the small molecules, which means the radionuclides labeled on nanoparticles have similar slow metabolism to their carriers. Unnecessarily loaded radiation from the nanoparticles will also harm normal liver cells where the nanoparticles accumulate heavily.     

动态对比增强磁共振对急性脑梗死患者血脑屏障通透性的研究

目的通过动态对比增强(dynamic contrast-enhanced,DCE)MRI定量评估血脑屏障(blood-brain barrier,BBB)的通透性,探讨急性缺血性脑卒中患者BBB通透性的变化及相关影响因素。方法将50例急性缺血性脑卒中患者根据不同治疗方案,分为常规药物组12例,静脉溶栓组19例和取栓组19例,患者在发病72 h内完成DCEMRI(基线时),8例患者发病14 d复查影像检查,发病3个月随访时行改良的Rankin量表(mRS)评分,将mRS评分0~2分为预后良好。使用T1DCE-MRI Extend模型计算BBB通透性指标容积转运常数(Ktrans)值,并计算脑梗死侧与脑梗死对侧Ktrans值的比值(Ki/c)。比较所有患者脑梗死侧与脑梗死对侧、发病14 d复查与基线时、3组Ktrans值和Ki/c值差异,用多因素线性回归分析lg(Ki/c)值的相关影响因素。结果所有患者脑梗死侧Ktrans值较脑梗死对侧明显增高[0.0047(0.0019,0.0087)/min vs 0.0011(0.0003,0.0016)/min,P=0.000];发病14 d复查Ki/c值较基线时明显增高[70.77(13.43,399.43)vs 5.31(3.58,12.64),P=0.012]。常规药物组lg(Ki/c)值为0.42±0.49,静脉溶栓组lg(Ki/c)值为0.77±0.32,取栓组lg(Ki/c)值为0.85±0.41,静脉溶栓组和取栓组lg(Ki/c)值较常规药物组明显升高(P=0.021,P=0.005),静脉溶栓组与取栓组lg(Ki/c)值比较,差异无统计学意义(P=0.534)。常规药物组、静脉溶栓组和取栓组发病3个月预后良好比例比较,差异无统计学意义(66.7%vs 52.6%vs 52.6%,P=0.695)。多因素线性回归分析显示,lg(Ki/c)值与治疗方案(P=0.017)和脑梗死病史(P=0.030)有关。结论急性缺血性脑卒中患者BBB通透性与不同治疗方法、既往脑梗死病史有关,并且发病14 d BBB通透性较72 h内明显增高。     

结合新型冠状病毒肺炎疫情议“三山医院”的建设要领

新型冠状病毒肺炎疫情引起全球关注,病毒的高度传染性致使疫情迅速蔓延和大规模暴发。在应对突发的迅速蔓延的疫情过程中,快速建设一个安全性能高的应急传染病专科医院,对于患者治疗、医护人员防护和疫情的控制十分重要。笔者结合“三山医院”建设的经验和温州医科大学附属第一医院应急传染病治疗中心改造的实际经验,系统地对医院选址、医院规划和设计、暖通系统、给排水系统、医用气体要求及医疗废物处置进行阐述,并对关键环节进行探讨。     

注射用丹参多酚酸联合甲磺酸倍他司汀片治疗后循环缺血性眩晕的疗效

目的 观察注射用丹参多酚酸联合甲磺酸倍他司汀片治疗后循环缺血性眩晕病人的临床疗效。方法 将96例患者随机分为2组,各48例,对照组采取常规治疗,口服甲磺酸倍他司汀片,6 mg/次,3次/d,观察组加用注射用丹参多酚酸治疗,0.13 g加入到0.9%氯化钠注射液250 mL中静滴,1次/d,14 d后比较两组椎基底动脉供血和血流变指标、临床疗效和不良反应。结果 观察组治疗后椎基底动脉血流速度（收缩期峰流速、舒张期末流速、平均流速）和血流变学指标（全血比黏度、血浆比黏度、纤维蛋白原）改善情况明显优于治疗前,且治疗后观察组优于对照组的,差异具有统计学意义（P<0.05）;观察组痊愈率和总有效率均明显高于对照组,差异具有统计学意义（P<0.05）,且两组均无不良反应发生。结论 注射用丹参多酚酸联合甲磺酸倍他司汀片治疗椎后循环缺血性眩晕具良好的疗效,值得临床推广应用。     

粪肠球菌对白假丝酵母菌的体外拮抗作用初探

目的:观测粪肠球菌(EF)在体外对白假丝酵母菌(CA)的生长有无抑制作用.方法:采用直接点种法观察抑菌圈,分别采用反点种菌落计数法和液体共培养法,观察在粪肠球菌作用下白假丝酵母菌菌落数量的变化.结果:①EF在CA和TPY软琼脂上未形成清晰的抑菌圈;②在粪肠球菌软琼脂上的白假丝酵母菌菌落数较对照组明显减少(P＜0.05);③与粪肠球菌共培养的白假丝酵母菌菌落数量减少(P＜0.05).结论:粪肠球菌对白假丝酵母菌的体外生长有抑制作用.     

Nuclear factor of activated T cells as a marker of in vivo low-dose dibenzo[a,h]anthracene exposure

We previously demonstrated that particulate matter ≤2.5 μm (PM2.5) suppresses the immune response in the spleen in vivo. Although PM2.5 includes the polycyclic aromatic hydrocarbon (PAH) such as dibenzo[a,h]anthracene (DBA), it is unclear whether PAH has a direct effect on the responses of splenocytes. In our study, the concentration of DBA used was approximately 0.8 μm , which is much lower than concentrations used in other toxicological studies of DBA. Although exposure to high concentrations of DBA is implicated in carcinogenesis, the effects of low doses of DBA on immune cells in vivo remain unclear. Here, we investigated the effects of low DBA doses on mouse splenocytes in vivo. Mice were administered dimethyl sulfoxide or DBA (0.4 or 0.8 μm ) intratracheally. Twenty-four hours after treatment, the mice were killed and their splenocytes were collected. DBA treatment enhanced mitogen-induced cell proliferation and cytokine production in the mouse splenocytes. Furthermore, DBA enhanced splenic CD4⁺ and CD8⁺ cell proliferation and cytokine production. The nuclear factor of activated T cells (NFAT) was activated in CD4⁺ cells. DBA also activated nuclear factor-kappa B and CCAAT enhancer-binding protein pathways in CD11b⁺ cells. DBA-enhanced splenocyte activation was Toll-like receptor 2-, 4-, 9- and MyD88-independent. These results suggest that NFAT represents a promising marker for evaluation of the effects of DBA on T cells and T-cell-dependent antibody responses.     

Synthesis and preliminary evaluation of a 99mTc‐labeled folate‐PAMAM dendrimer for FR imaging

Folate receptor is an ideal target for tumor‐specific diagnostic and therapeutic. The aim of this study was to synthesize ^99mTc‐labeled folate‐polyamidoamine dendrimer modified with 2‐hydrazinonicotinic acid (^99mTc‐HP ₃FA ) for FR imaging. The ^99mTc‐HP ₃FA conjugate was prepared using N‐tris‐(hydroxymethyl)‐methylglycine and trisodium triphenylphosphine‐3,3′,3″‐trisulfonate as coligands. Physicochemical properties, in vitro cell uptake study, and in vivo micro‐single‐photon emission computed tomography/CT imaging were performed. The radiolabeled ^99mTc‐HP ₃FA conjugate was prepared with high radiolabeling yield, good stability, and water solubility (logP  = ?1.70 ± 0.21). In cell uptake study, the radiolabeled conjugate showed high uptakes in the FR ‐abundant KB cells and could be blocked significantly by excess folic acid. The 7721 cells which served as control group substantially had no uptakes. The results of micro‐single‐photon emission computed tomography/CT imaging exhibited that high accumulation of activity was found in FR ‐overexpressed KB tumor, and the tumor‐to‐muscle ratio was approximately 25.78, while, using free FA as inhibitor, the uptakes of ^99mTc‐HP ₃FA in KB tumor and kidney were obviously inhibited. In summary, a new radiocompound was synthesized successfully with specific FR targeting ability. The feasibility of ^99mTc‐HP ₃FA for early diagnosis of FR ‐positive tumors with non‐invasive single‐photon emission computed tomography imaging was demonstrated and the possibility of imaging‐guided drug delivery based on multifunctional polyamidoamine will be studied in the future.