不同屈光度近视青少年儿童黄斑区血管密度和视网膜厚度的比较

目的:通过光学相干断层扫描血管成像技术(OCTA)观察与比较不同屈光度近视青少年儿童黄斑区血管密度和视网膜厚度的变化,并探讨其相关性。方法:前瞻性横断面研究。纳入6~18岁青少年儿童115例230眼。根据等效球镜度数(SE)分为4组:正视组16例32眼,低度近视组47例94眼,中度近视组34例68眼,高度近视组18例36眼。RTVueXR扫描黄斑区6mm×6mm范围,系统自动分区,分为以黄斑中心小凹为中心,直径分别为1mm的中心凹(fovea)环、1~3mm的内环(parafovea)、3~6mm的外环(perifovea),且每个圆环被进一步划分为颞(T)、上(S)、鼻(N)、下(I)4个象限,定量分析各分区浅层、深层毛细血管密度和视网膜厚度。结果:正视、低度、中度和高度近视组黄斑区整体浅层毛细血管密度依次显著减低,分别为(44.4±3.5)%、(44.8±3.8)%、(44.3±3.8)%、(42.6±4.5)%(F=2.963,P=0.033),内环颞侧浅层毛细血管密度分别为(46.1±3.5)%、(46.8±5.1)%、(46.2±4.3)%、(43.8±5.5)%(F=3.436,P=0.018);四组黄斑区整体深层毛细血管密度随着近视度数增加亦显著降低,分别为(49.9±4.1)%、(48.4±4.7)%、(47.9±5.5)%、(45.3±4.7)%(F=4.806,P=0.003),外环深层毛细血管密度分别为(49±4.4)%、(47.2±5.2)%、(46.6±6)%、(43.6±5.1)%(F=5.495,P=0.001)。四组黄斑区整体视网膜厚度分别为293.9±12.9、295.5±13.0、290.9±12.0、284.5±10.7μm(F=6.606,P<0.001)。内环颞侧、鼻侧浅层毛细血管密度与SE呈正相关(r=0.221、0.219,P=0.001、0.001),外环颞侧、上方、鼻侧、下方深层毛细血管密度与SE呈正相关(r=0.172、0.200、0.250、0.296,P=0.011、0.003、<0.001、<0.001);黄斑区除中心凹外其余区域视网膜厚度与SE均呈正相关(P<0.05)。结论:随着青少年儿童近视度数的增加,黄斑区浅层毛细血管密度降低,以内环颞侧为甚;深层毛细血管密度降低,以外环范围内为甚;视网膜厚度降低,以内环和外环范围为甚。青少年儿童近视随着屈光度增加,会导致黄斑区结构和血流循环的变化,在高度近视眼中改变尤为显著。     

泪腺腺样囊性癌生物标志物的研究进展

泪腺腺样囊性癌是泪腺最常见的恶性上皮肿瘤,具有易复发、易转移及预后差的特点,目前临床治疗方式主要有手术切除、放疗、化疗等,但其生存率仍低。因此,进一步研究泪腺腺样囊性癌的发病机制和寻找泪腺腺样囊性癌的生物标志物尤为迫切。本文将对泪腺腺样囊性癌的生物标志物的研究进展作一综述。     

光学相干断层扫描血管造影对DR诊断价值的Meta分析

目的：应用光学相干断层血管造影(OCTA)评估糖尿病视网膜病变(DR)患者中心凹无血管区(FAZ)和血管密度(VD)的变化。

方法：对OCTA在DR诊断中的应用文献进行系统回顾。搜索Medline、Embase、Web of Science、PubMed、中国知网数据库、万方数据库以查找相关研究,检索时间从建库截止到2020-09-20。仅检索中英文文献。两名研究者分别独立提取文献资料,包括浅层视网膜毛细血管层血管线性密度(VD_SCP)、深层视网膜毛细血管层血管线性密度(VD_DCP)、浅层FAZ面积和周长。绘制森林图、漏斗图,并采用Begg检验和敏感性分析,确保结果的准确性。

结果：共检索得24篇文献,纳入2 305眼。结果显示,糖尿病患者与健康对照组各指标均有差异(VD_SCP：WMD=-5.78,95% CI：-7.67～-3.88,P<0.05; VD_DCP：WMD=-5.08,95% CI：-6.49～-3.67,P<0.05; FAZ周长：WMD=0.57,95% CI：0.36～0.78,P<0.05; FAZ面积：WMD=0.08,95% CI：0.06～0.10,P<0.05)。

结论：DR患者FAZ面积更大,周长更长,与DR患者对比,对照组FAZ的VD较高。虽然目前OCTA的实际适用性仍然存在问题,但随着技术的不断发展和改进,OCTA在DR中的诊断价值可能会变得明显。     

犬迷走神经性心房颤动模型的建立

目的制作犬迷走神经性心房颤动模型,评价可行性和持续性。方法针状电极分别插入颈部双侧迷走神经干,以3V-5V的电压/10Hz-20Hz的频率,刺激双侧迷走神经,在心率出现明显下降后,给予频率为10Hz-20Hz,电压为3V-5V的快速脉冲起搏刺激右心房,诱发心房颤动。结果迷走神经刺激的平均电压/频率为4.4V±0.7V/16.8Hz±3.3Hz,心率由基础的(171±26)次/分降为(97±8)次/分;在给予平均电压/频率为3.5V±0.6V/11.5Hz±2.2Hz的右心房起搏刺激后,36只杂种犬中31只(86.1%)成功诱发出持续性心房颤动,且在保持迷走神经刺激下,持续时间超过90分钟。结论本实验建立的犬迷走神经性心房颤动模型容易诱发,持续时间长,为评估抗心率失常药物对心房颤动的作用提供可靠的方法。     

Applications of the isolated-check visual evoked potential in primary open angle glaucoma with or without high myopia

AIM: To determine whether the different diameters of a specific intraocular lens (IOL) have significantly different optimised SRK/T A constants and whether these new A constants can improve refractive outcomes. METHODS: Data were collected prospectively from Jan 2011 - Dec 2012 on all patients undergoing routine cataract surgery at a district general hospital in the UK. Patients were divided into three groups according to the size of the Akreos AO MI60 IOL used. A constant for the SRK/T formula were optimised according to the size of the IOL. These optimised A constants were then used to select future refractive outcomes. RESULTS: Totally 2398 cataract operations were performed during the study period of which 1131 met the inclusion criteria. The three optimised A constants for the different sized IOLs were 118.98, 119.13 119.32. The difference between them was highly significant (P≤0.0001). Two optimised A constants for three sizes of IOL led to an improvement in refractive outcomes (from 93.4% to 94.6% of refractive outcomes within 1.00 D of predicted spherical equivalent). The optimised A constant for the largest IOL was based on a small number of cases and was not used. CONCLUSION: Optimising the A constant for the three distinct sizes of the Bausch & Lomb Akreos MI60 lens lead to three significantly different A constants. In our practice, using two different optimised A constants for three different sized IOLs give the least refractive error, however, using three optimised A constants may give better results with a larger dataset.     

Strain-induced structural phase transition,electric polarization and unusual electric properties in photovoltaic materials CsMI3 (M = Pb,Sn)

The structural phase transition, ferroelectric polarization, and electric properties have been investigated for photovoltaic films CsMI₃ (M = Pb, Sn) epitaxially grown along (001) direction based on the density functional theory. The calculated results indicate that the phase diagrams of two epitaxial CsPbI₃ and CsSnI₃ films are almost identical, except critical transition strains varying slightly. The epitaxial tensile strains induce two ferroelectric phases Pmc2₁, and Pmn2₁, while the compressive strains drive two paraelectric phases P2₁2₁2₁, P2₁2₁2. The larger compressive strain enhances the ferroelectric instability in these two films, eventually rendering them another ferroelectric state Pc. Whether CsPbI₃ or CsSnI₃, the total polarization of Pmn2₁ phase comes from the main contribution of B-position cations (Pb or Sn), whereas, for Pmc2₁ phase, the main contributor is the I ion. Moreover, the epitaxial strain effects on antiferrodistortive vector, polarization and band gap of CsMI₃ (M = Pb, Sn) are further discussed. Unusual electronic properties under epitaxial strains are also revealed and interpreted.

The structural phase transition, ferroelectric polarization, and electric properties have been investigated for photovoltaic films CsMI₃ (M = Pb, Sn) epitaxially grown along (001) direction based on the density functional theory.     

The protective effects of GLP-1 receptor agonist lixisenatide on oxygen-glucose deprivation/reperfusion (OGD/R)-induced deregulation of endothelial tube formation

Acute myocardial infarction (AMI) is a complication of atherosclerosis that takes place in coronary arteries. Cardiac endothelial cells play a significant role in the pathogenesis of AMI. Oxygen-glucose deprivation/reperfusion (OGD/R) is widely used as a model to simulate AMI in vitro. Recently, antidiabetic GLP-1 receptor agonists have been shown to exert pleiotropic effects that modulate cardiovascular complications. In this study, we investigated the vascular effect of lixisenatide. We show that pre-treatment of endothelial cells with lixisenatide protected them from OGD/R-induced cytotoxicity and improved their viability. Pre-treatment with lixisenatide ameliorated OGD/R-induced ROS accumulation and disturbed endothelial tube formation. At the molecular level, lixisenatide mitigated OGD/R-induced reduced eNOS expression and NO production but further promoted the expression of the anti-oxidant regulators Nrf2 and HO-1. Mechanistically, we confirmed that the PI3K/Akt pathway is essential for mediating the effects of lixisenatide, and blockage of PI3K/Akt using the inhibitor LY294002 abolished the ameliorative effect of lixisenatide on ROS production and impaired tube formation. These data indicate that lixisenatide possesses a beneficial effect on the vasculature in a model of ischemia-induced endothelial injury. We conclude that the GLP-1 receptor agonist lixisenatide has pleiotropic properties that can modulate vascular function independent of its anti-glycemic effect.

Acute myocardial infarction (AMI) is a complication of atherosclerosis that takes place in coronary arteries.     

Synthetic progress toward the marine natural product zamamiphidin A

An asymmetric synthetic approach to the octahydrofuro[3,4-b]pyridine framework of marine natural product zamamiphidin A has been described. The key steps include an asymmetric Michael addition of (R)-N-tert-butanesulfinyl imidate with enamidomalonate to install the C10 stereocenter, an intramolecular alkoxide exchange/Michael addition/hydrogenation sequence to construct the bicyclic ring system.

An asymmetric synthetic approach to the octahydrofuro[3,4-b]pyridine framework of marine natural product zamamiphidin A has been described.

Marine natural products have been recognized as an important source of potential lead compounds.¹ Recently, the growing attention on innovative drug discovery has propelled the identification of numerous marine-derived bioactive compounds with superior chemical novelty.² In 2013, Kobayashi and co-workers isolated a new macrocyclic diamine alkaloid zamamiphidin A (1, Fig. 1A) from an Okinawan marine sponge Amphimedon sp. (SS-1231),³ along with its biogenetically related manzamine alkaloids such as ircinic acid (2) and manzamine A (3). In the isolation work, the authors also demonstrated that compound 1 exhibited moderate antibacterial activity against Staphylococcus aureus (MIC, 32 μg mL⁻¹).³ Architecturally, zamamiphidin A was characterized by an unprecedented heptacyclic framework, comprising a highly fused pentacyclic caged core, two 11-membered rings and seven contiguous stereocenters including one all-carbon quaternary center. More specifically, the fusion of 7-oxa-2-azabicyclo[2.2.1]heptane (4, Fig. 1B), azabicyclo[3.3.1]nonane (5) and octahydrofuro[3,4-b]pyridine (6) fragments as well as the presence of quaternary ammonium salt render zamamiphidin A unique among other macrocyclic diamine alkaloids.⁴ To the best of our knowledge, the chemical synthesis of 1 has yet to be disclosed. Herein, we report our recent synthetic efforts toward zamamiphidin A (1).Open in a separate windowFig. 1Structures of (A) zamamiphidin A (1), its related manzamine alkaloids (2 and 3) and (B) fragments 4–6 of 1.From a retrosynthetic perspective (Scheme 1), we envisioned that zamamiphidin A would arise from the advanced intermediate 7 through late-stage formation of two 11-membered rings.^4,5 Central to the synthesis of the target molecule (1) would be the construction of the pentacyclic and cage-like backbone 7. Structural analysis suggested the diazapentacyclic core of 7 could be simplified as a fully substituted tetrahydrofuran moiety containing two amine functionalities at C3 and C10 (Scheme 1, in blue), which thus could be traced back to the precursor 10. Specifically, disconnecting the C1–N2 bond in 7 revealed ketone 8; and the azabicyclo[3.3.1]nonane unit in 8 could be formed by a Mannich reaction and an intramolecular Dieckmann condensation from bicycle 9. Disassembly of the piperidine ring in 9 through an intramolecular Michael addition led back to the functionalized tetrahydrofuran 10. Based on our previous studies,⁶10 could be easily traced back to the chiral malonate 12 bearing a pendant N-tert-butanesulfinyl imidate motif, relying on an intramolecular alkoxide exchange to forge the tetra-hydrofuran ring (11 to 10) and a Davis oxidation to install the C9 hydroxyl group (12 to 11). In turn, 12 could be accessed via a diastereoselective Michael addition of N-tert-butanesulfinyl imidate 13 to enamidomalonate 14.Open in a separate windowScheme 1Retrosynthetic analysis of zamamiphidin A.Our synthetic approach started from the preparation of the chiral malonate 12 (Scheme 2). First, condensation of the known primary amine 15⁷ with dimethyl methoxymethylenemalonate (16) in refluxing toluene delivered enamine 17 (92% yield), which was subsequently protected with Boc to give compound 14. The key asymmetric Michael addition of (R)-N-tert-butanesulfinyl imidate 13 to enamidomalonate 14 proceeded smoothly by employing LiHMDS as base,^6,8–10 providing adduct 12 as the major diastereomer in 72% yield (d.r. = 7 : 1 at C10). We supposed that the addition would preferentially take place through Ts-18 to avoid the significant steric repulsion between the tert-butyl group of 13 and the N-Boc side chain of 14, thus favoring the generation of 12. The configuration of the newly generated C10 stereocenter in 12 could be confirmed later by further transformations (vide infra). As far as we knew, this example represents the first asymmetric conjugate addition of N-tert-butanesulfinyl metalloenamines by using enamidomalonate as the Michael acceptor, which would be useful for the preparation of β-amino acid.¹¹Open in a separate windowScheme 2Synthesis of the chiral malonate 12.With malonate 12 available, we next sought to construct the octahydrofuro[3,4-b]pyridine ring system of zamamiphidin A (Scheme 3). To this end, our first task was to introduce a hydroxyl group at C9 in 12. After exploring various oxidative conditions such as Mn(OAc)₃/AcOH,¹² IBX/DMSO/H₂O,¹³ and O₂/I₂/NaOAc,¹⁴ we found that a Davis protocol¹⁵ (Davis'' oxaziridine/NaH/THF, −50 °C) was successful to convert 12 to 11 with 82% yield. Formation of the tetrahydrofuran ring from 11 proceeded in the presence of Et₃N/toluene at reflux temperature via an intramolecular alkoxide exchange, resulting in 19 (71% yield). Desilylation of 19 with HF afforded the primary alcohol 20 (85% yield). The latter then underwent a two-step synthetic sequence including oxidation of the hydroxyl group to aldehyde and Wittig olefination of the resulting aldehyde with methyl(triphenylphosphoranylidene)acetate (21), providing enoate 10 in 64% overall yield. Upon treating 10 with NaH in the presence of HMPA at −20 °C, an intramolecular Michael addition reaction occurred to enable the coupling of C4 and C4a, leading to the formation of the bicyclic intermediate 22 (72% yield). The structure of 22 was determined through extensive interpretation of the NMR data of its deprotected derivative 23. Unfortunately, we found that the configuration of the newly formed C4a stereocenter was opposite to that in the natural product zamamiphidin A. Inversion of the C4a stereochemistry through generation of the C4–C4a double bond (22 to 24) followed by hydrogenation (24 to 25) was investigated. When compound 22 was treated with LDA and PhSeCl followed by oxidation and spontaneous elimination under the conditions of H₂O₂/pyridine/CHCl₃, the above reaction gave a complex mixture, with only 5–10% yield of the desired product 24 isolated. We attempted to improve this transformation by employing various bases (e.g., LiHMDS, NaHMDS, KHMDS, LiTMP) and different oxidants (e.g., m-CPBA, NaIO₄, AcOOH), which all proved to be unsuccessful. These failures impeded further transformations.Open in a separate windowScheme 3Synthesis of the tricyclic compound 28.On the other hand, we investigated the construction of the oxazolidine ring starting from the bicyclic intermediate 22 (Scheme 3). Thus, reduction of the imine double bond in 22 with borane dimethyl sulfide afforded sulfinamide 26 in 55% yield. Subjecting 26 to the conditions of HCl/MeOH¹⁶ followed by treatment of the resulting primary amine with 2-hydroxypyridine in refluxing toluene¹⁷ furnished an unexpected tricyclic compound 28. The structure of 28 was determined unambiguously through X-ray crystallographic analysis, which again confirmed the C4a stereochemistry generated in the aforementioned intramolecular Michael addition reaction (10 to 22). Formation of the undesired 28 was due to the lactamization occurred at C18 rather than at C1 that was initially envisaged to establish the oxazolidine ring. These results indicated that the correct configuration of C4a might be crucial for the subsequent synthesis.In our revised synthetic approach, a propiolate group was employed to replace the originally used enoate for the Michael addition. We envisioned that hopefully reduction of the double bond generated in the Michael addition of the corresponding propiolate would secure the right configuration at the C4a position. As shown in Scheme 4, the known propargyl alcohol 29 was prepared on a decagram scale from 3-butyl-1-ol over two steps.¹⁸ After acylation of 29 and subsequent deprotection of the TBS group with TBAF, the resulting primary alcohol 30 was converted into phthalimide 31via a Mitsunobu reaction in the presence of phthalimide/PPh₃/DIAD (64% overall yield for three steps). Deacylation of 31 followed by silylation of the resulting primary alcohol with TBSCl/Et₃N/DMAP provided 32 in 36% yield over two steps. Exposure of 32 to hydrazine hydrate in refluxing methanol resulted in removal of the phthalimide group and delivered a free amine, which was directly condensed with 16 to afford the secondary enamine 33 in 80% overall yield. Further protection of the amino group in 33 with Boc produced intermediate 34. Next, compound 34 underwent a similar three-step transformation to that performed on enamidomalonate 14, involving asymmetric 1,4-conjugate addition with imidate 13, Davis oxidation to install the C9 hydroxyl group (35 to 36), and cyclization with Et₃N to assemble the tetrahydrofuran ring, yielding the intermediate 37 smoothly. To reach propiolate 39, the precursor of the key Michael addition for forming C4–C4a bond, further functional group manipulations of 37 were conducted. These included desilyation with HF (37 to 38), Dess–Martin oxidation, Pinnick oxidation, and esterification (38 to 39). Gratifyingly, upon treating 39 with LDA and HPMA in THF at −20 °C, compound 24 was formed with 42% yield through an intramolecular Michael addition and spontaneous migration of the double bond from C4a–C8a to C4–C4a.Open in a separate windowScheme 4Synthesis of compound 24.With compound 24 in hand, selective reduction of the C4–C4a double bond was carried out under catalytic hydrogenation conditions (RANEY® Ni/H₂) and furnished 25 (70% yield) as a single diastereomer with correct C4 and C4a configurations (Scheme 5). Ensuing reduction of the imine group in 25 using borane dimethyl sulfide delivered the tert-butyl sulfonamide 40 with excellent diastereoselectivity (single isomer, 72% yield). The structures of both 25 and 40 were extensively interpreted by NMR spectroscopy. As a consequence, the configurations at C3, C4, C4a and C10 were found to be consistent with the ones in zamamiphidin A.¹⁹ Furthermore, transformations of 25 or 40 into the core of the target zamamiphidin A were investigated. Subjecting 25 to various conditions (NaH, NaOMe, t-BuOK, LDA, LiHMDS, AlCl₃, TiCl₄, etc.) for a Dieckmann condensation failed to construct the C1–C8a bond and give the desired product 41. Instead, ring-opening of the tetrahydrofuran unit in 25 was observed under some circumstances, leading to the byproduct 42via a retro-Michael reaction.Open in a separate windowScheme 5Synthesis of 25 and attempted further transformations.Meanwhile, attempts to synthesize the tricyclic β-keto ester 43 or lactam 44 from compound 40 were also unsuccessful. Most of these experiments suffered from either no reaction or decomposition of the starting materials.In conclusion, we have established a synthetic approach to the octahydrofuro[3,4-b]pyridine core of the complex natural product zamamiphidin A. The synthesis features an intermolecular asymmetric Michael addition (compounds 34 to 35) to form the first chiral center at C10 and a Michael addition/hydrogenation sequence (compounds 39 to 25) to secure the correct configurations at C4 and C4a. The highly functionalized bicyclic intermediate (i.e., 40) prepared in the present work contains four contiguous stereocenters and all the requisite heteroatoms at the right positions. While further transformations of related intermediates to zamamiphidin A were unfruitful, efforts to develop a feasible strategy for total synthesis of the target molecule are ongoing in our laboratory.     

Bio-cleaning improves the mechanical properties of lignin-based carbon fibers

Production of carbon fibers (CF) using renewable precursors has gained importance particularly in the last decade to reduce the dependency on conventional petroleum-based precursors. However, pre-treatment of these renewable precursors is still similar to that of conventional ones. Little work is put into greener pre-treatments and their effects on the end products. This work focuses on the use of bio-cleaned lignin as a green precursor to produce CF by electrospinning. Bio-cleaned kraft lignin A (Bio-KLA) and uncleaned kraft lignin A (KLA) were used to explore the effect of bio-cleaning on the diameter and mechanical properties of lignin fibers and CF. The effect of electric field, lignin-to-poly(ethylene oxide) (PEO) ratio and PEO molecular weight (MW) were evaluated by 3³ factorial design using Design of Experiment (DOE). The electrospinning process parameters were optimized to obtain a balance between high elastic modulus and small fiber diameter. The model predicted optimized conditions were 50 kV m⁻¹ electric field, 95/5 lignin-to-PEO ratio and 1000 kDa MW of PEO. When compared to KLA, Bio-KLA CFs showed a 2.7-fold increase in elastic modulus, 2-fold increase in tensile strength and 30% decrease in fiber diameter under the same optimum conditions. The results clearly show that bio-cleaning improved the mechanical properties of lignin derived CF.

Waste lignin (KLA) and bio-cleaned lignin (Bio-KLA) precursors, used to produce parameter-optimized-electrospun carbon fibers showed improved mechanical properties for Bio-KLA.