肾小球滤过率活体实时监测荧光示踪剂的研究进展

急性肾损伤是一种临床常见的急性疾病. 通过外源性的荧光示踪剂对肾小球滤过率进行非侵入性的实时监测, 对于及时了解易患病人的肾脏功能具有重要的临床价值和应用前景. 本文综合评述了用于活体检测肾小球滤过率的外源性荧光示踪剂的近期研究进展, 重点介绍了荧光示踪剂的设计策略及其活体成像应用效果, 并对相应检测装置的发展进行了阐述, 同时对该领域的挑战与发展前景进行了展望.     

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue

5-Aza-2’-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2’-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM-13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti-proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off-target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.     

CTA联合CTP在预测急性脑梗死预后中的价值

本研究探讨CT血管成像(CTA)联合CT灌注成像(CTP)在预测急性脑梗死预后的价值。选取急性脑梗死患者102例,分为预后良好组和不良组,分析预后良好和不良患者ASPECTS、CTP参数差异。预后不良患者CTA图像ASPECTS评分<3分明显高于预后良好患者(P<0.05);预后不良患者病灶处脑血容量(CBV)和脑血流量(CBF)明显低于预后良好患者(P<0.05),达峰时间(TTP)和平均通过时间(MTT)明显高于预后良好患者(P<0.05);ASPECTS评分联合CBV、CBF及MTT预测预后不良的ROC曲线下面积为0.895(P<0.05),灵敏性和特异性分别为90.00%和84.10%。CTA联合CTP预测急性脑梗死患者预后有一定应用价值。     

Highly sensitive simultaneous quantification of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid in human plasma using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry

Indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid are uremic toxins that accumulate in renal failure and have been reported to decrease the activities of the drug-metabolizing enzyme cytochrome P450 3A and the drug transporter organic anion transporting polypeptides 1B, respectively. In this study, we established and validated an assay for simultaneous quantification of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid in human plasma. The samples were pretreated by solid-phase extraction, and measured by ultra-high-performance liquid chromatography–tandem mass spectrometry. The validation results for this assay were within the acceptable limits recommended by the US Food and Drug Administration, with a lower limit of quantitation of 0.05 μg/mL for both indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. Recovery rates of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid corrected by internal standard were 100.7–101.9 and 100.2–101.3%, respectively. Matrix effects of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid corrected by internal standard were 101.1–105.5 and 97.0–103.8%, respectively. The validated assay was used to analyze indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentrations in the plasma samples of healthy volunteers and patients with chronic kidney disease. All the measured plasma indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentrations were within the calibration ranges. This novel method may contribute to predicting the activities of drug-metabolizing enzymes and drug transporters in individual patients.     

Numerical investigation of shock-induced bubble collapse dynamics and fluid–solid interactions during shock-wave lithotripsy

In this paper we investigate the bubble collapse dynamics under shock-induced loading near soft and rigid bio-materials, during shock wave lithotripsy. A novel numerical framework was developed, that employs a Diffuse Interface Method (DIM) accounting for the interaction across fluid–solid-gas interfaces. For the resolution of the extended variety of length scales, due to the dynamic and fine interfacial structures, an Adaptive Mesh Refinement (AMR) framework for unstructured grids was incorporated. This multi-material multi-scale approach aims to reduce the numerical diffusion and preserve sharp interfaces. The presented numerical framework is validated for cases of bubble dynamics, under high and low ambient pressure ratios, shock-induced collapses, and wave transmission problems across a fluid–solid interface, against theoretical and numerical results. Three different configurations of shock-induced collapse applications near a kidney stone and soft tissue have been simulated for different stand-off distances and bubble attachment configurations. The obtained results reveal the detailed collapse dynamics, jet formation, solid deformation, rebound, primary and secondary shock wave emissions, and secondary collapse that govern the near-solid collapse and penetration mechanisms. Significant correlations of the problem configuration to the overall collapse mechanisms were found, stemming from the contact angle/attachment of the bubble and from the properties of solid material. In general, bubbles with their center closer to the kidney stone surface produce more violent collapses. For the soft tissue, the bubble movement prior to the collapse is of great importance as new structures can emerge which can trap the liquid jet into induced crevices. Finally, the tissue penetration is examined for these cases and a novel tension-driven tissue injury mechanism is elucidated, emanating from the complex interaction of the bubble/tissue interaction during the secondary collapse phase of an entrapped bubble in an induced crevice with the liquid jet.     

低氧血症对轻型颅脑损伤大鼠海马结构二次脑损伤的实验研究

目的 应用低氧血症二次脑损伤大鼠模型,探讨低氧血症对轻型颅脑损伤（mTBI）后海马神经元及轴索组织结构的二 次损伤作用。方法 采用随机数字表法将大鼠分为正常对照组（8 只）、单纯mTBI 组（10 只）、单纯低氧血症组（10只）及低氧血症二次脑损伤组（10只）。在自制旋转装置致大鼠mTBI基础上,利用动物呼吸机获得控制性低氧血症,从而构建低氧血症二次脑损伤模型。脑损伤后1 周,应用HE染色、免疫组化β-APP 染色及电镜观察大鼠海马组织结构病理学变化。结果 HE 染色发现单纯低氧血症组大鼠海马神经元结构完整、排列有序、神经组织结构致密、未见明显神经元丢失及神经组织结构疏松等病理变化,单纯mTBI组及低氧血症二次脑损伤组大鼠均出现海马神经元肿胀、胞质淡染、密度降低、排列不规则及神经组织结构疏松等损伤表现,但低氧血症二次脑损伤组较单纯mTBI组明显。免疫组化β-APP 染色及电镜观察到低氧血症二次脑损伤组大鼠海马存在轴索肿胀扭曲变形、髓鞘板层分 离及轴索球形成等轴索损伤表现。结论 低氧血症二次脑损伤可明显加重mTBI后海马神经元及轴索组织结构的损伤,及早预防、发现和治疗低氧血症对改善mTBI患者预后具有积极意义。     

Nonnegative Moore-Penrose Inverse of Gram Matrices in an Indefinite Inner Product Space

In this paper, we derive necessary and sufficient conditions for the nonnegativity of the Moore-Penrose inverse of a Gram matrix defined in an indefinite inner product space using indefinite matrix multiplication. These conditions include the acuteness of a pair of closed convex cones.     

随机单调算子的满射性及应用

研究Banach空间中的随机单调算子,建立了连续随机单调算子的随机锐角原理、随机满射定理、随机双射定理及Hilbert空间上的一类连续随机算子的新的随机不动点定理,并应用随机强单调算子理论讨论了随机Hammerstein积分方程随机解的存在唯一性.     

Laser ablation inductively coupled plasma mass spectrometry for imaging of copper, zinc, and platinum in thin sections of a kidney from a mouse treated with cis-platin

Platinum complexes are used for the treatment of several types of cancer. High platinum concentrations in the target tissue and low concentrations in dose-limiting tissue structures such as renal tubules are desirable to assure selective toxicity. Microlocal analysis of platinum distribution in tissue sections may thus contribute to the optimization of platinum therapy. Scanning laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) was used to produce images of element distribution in 14-μm thin sections of kidney tissue from a mouse treated with cis-platin 60 min prior to victimization. The sample surface was scanned (raster area 300 mm²) with a focused laser beam (wavelength 266 nm, diameter of laser crater 50 μm, inter line distance 50 μm and laser power density 3 × 10⁹ W cm⁻²) in a cooled laser ablation chamber (about −15 °C) developed for these measurements. The laser ablation system was coupled to a double-focusing sector field ICP-MS. Ion intensities of ⁶³Cu⁺, ⁶⁴Zn⁺, and ¹⁹⁶Pt⁺ were measured within the tissue by LA-ICP-MS. Matrix-matched laboratory standards served for calibration of analytical data. The mass spectrometric analysis yielded an inhomogeneous distribution for Cu, Zn, and Pt in thin kidney sections. Copper was enriched in the capsule and outer cortex, zinc in the inner cortex and the platinum concentration followed a centripetal gradient with clear medullar enrichment. Thus, scanning LA-ICP-MS may be a useful tool in the preclinical development of new and less nephrotoxic platinum complexes.