Novel Compounds Identified by Structure-Based Prion Disease Drug Discovery Using In Silico Screening Delay the Progression of an Illness in Prion-Infected Mice

The accumulation of abnormal prion protein (PrP^Sc) produced by the structure conversion of PrP (PrP^C) in the brain induces prion disease. Although the conversion process of the protein is still not fully elucidated, it has been known that the intramolecular chemical bridging in the most fragile pocket of PrP, known as the “hot spot,” stabilizes the structure of PrP^C and inhibits the conversion process. Using our original structure-based drug discovery algorithm, we identified the low molecular weight compounds that predicted binding to the hot spot. NPR-130 and NPR-162 strongly bound to recombinant PrP in vitro, and fragment molecular orbital (FMO) analysis indicated that the high affinity of those candidates to the PrP is largely dependent on nonpolar interactions, such as van der Waals interactions. Those NPRs showed not only significant reduction of the PrP^Sc levels but also remarkable decrease of the number of aggresomes in persistently prion-infected cells. Intriguingly, treatment with those candidate compounds significantly prolonged the survival period of prion-infected mice and suppressed prion disease-specific pathological damage, such as vacuole degeneration, PrP^Sc accumulation, microgliosis, and astrogliosis in the brain, suggesting their possible clinical use. Our results indicate that in silico drug discovery using NUDE/DEGIMA may be widely useful to identify candidate compounds that effectively stabilize the protein.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00903-9) contains supplementary material, which is available to authorized users.     

Ethnic variation in deep lateral orbital anatomy and its implications on decompression surgery

Aim: To describe differences in the deep lateral orbital wall (specifically, trigone) between Chinese, Malay, Indian and Caucasian subjects

Methods: Single-centre retrospective Computed Tomogram (CT)-based study; 20 subjects of each ethnicity were used from existing databases, matched for gender, average age and laterality. Subjects below 16 years of age were excluded. DICOM image viewing software CARESTREAM Vue PACS (Carestream Health Inc., USA) and OsiriX version 7.5 (Pixmeo., Switzerland) were used to measure deep lateral wall length, thickness and volume, as well as orbital depth and statistical analyses performed using Statistical Package for Social Sciences version 21 (IBM, USA).

Results: In each group, there were 12 males (60%) and average age was not significantly different (p = 0.682–0.987). Using Chinese subjects as a reference, in Chinese, Malay, Indian and Caucasian subjects, mean trigone thickness was 13.68, 14.02, 11.60 (p < 0.001) and 13.80 mm, curved total wall length 45.23, 42.29 (p = 0.048), 41.91 (p = 0.020) and 45.00 mm, curved trigone length 23.03, 22.61, 17.19 (p = 0.011) and 18.76 mm (p = 0.030) and trigone volume 3120.97, 3221.01, 1613.66 (p < 0.001), 2498.46 mm³ (p = 0.059) respectively. Similarly, perpendicular orbital depth was 27.54, 24.97, 22.12 (p = 0.001) and 25.93 mm and diagonal orbital depth was 34.19, 33.27, 29.48 (p = 0.01) and 34.63 mm respectively.

Conclusions: Indian and, to a lesser extent, Caucasian subjects have smaller trigones compared to their Chinese and Malay counterparts. Indian subjects also have shallower orbits and due care should be taken during decompression surgery.     

眼眶内下壁爆裂性骨折整体修复29例

目的探讨眼眶内下壁骨折整体修复手术方法。设计回顾性病例系列。研究对象29例(29眼)眼眶内下壁骨折患者。方法对29例眼眶内下壁爆裂性骨折者采用整体羟基磷灰石复合人工骨(HA)修复。对比观察手术前后眼球突出度、复视程度,眼眶CT观察术后骨折修复情况。主要指标眼球突出度,复视程度。眼眶CT影像。结果29例眼眶内下壁骨折整体修复术中,加例眼球内陷全部矫正,9例欠矫1～2mm,4例术后复视未完全缓解。结论眼眶内下壁骨折整体修复是一种眼眶骨折修复的新方法,效果好,并发症少。(眼科,2006,15：348-350)     

Enucleation combined with orbital implants for malignant melanoma of the uvea

Advanced malignant melanomas of the uvea unsuited for an eye salvaging approach require enucleation of the tumor containing eye. A series of 68 patients is reported who underwent enucleation combined with insertion of a spherical dura-encased implant after 30 Gray pre-irridiation therapy of the orbit. Postoperative results with special attention to cosmetic outcome and motility of the prosthesis suggest that the insertion of an orbital implant should be preferred to the enucleation with no implant.     

Herpes zoster ophthalmicus and the orbital apex syndrome

Herpes zoster ophthalmicus (HZO) commonly causes isolated ophthalmoplegic syndromes. Visual loss caused by optic neuritis secondary to HZO can be reversible or irreversible. HZO rarely presents as an orbital apex syndrome, when an association with meningo-encephalitis has been reported. We report a case of orbital apex syndrome secondary to HZO treated with systemic steroids and acyclovir. Our patient suffered no systemic complications and displayed a rapid resolution of optic neuropathy. We discuss this case in the light of previous reports and explore the possible pathogenic mechanisms involved.     

Desmoplastic malignant melanoma presenting with orbital involvement

Desmoplastic malignant melanoma (DMM) is a rare variant of spindle cell melanoma. We report a case of DMM of the forehead secondarily involving the orbit. The diagnosis was based on light microscopic features, including prominent peripheral cell nest formation and spindle cell fascicles in densely collagenous stroma. Immunohistochemical studies showed strong uniform staining for S100 antigen throughout the tumour. It was negative for HMB 45, smooth muscle actin, desmin, cytokeratins and Type IV collagen. Electron microscopy showed neither melanosomes nor myelin figures. The clinical and histological characteristics of desmoplastic malignant melanoma, and its differential diagnosis of malignant schwannoma, are discussed. DMM has a poor prognosis, since it tends to invade deeply, recur locally and metastasise readily.     

全主动脉弓替换术中顺行性脑灌注时血流变化观察

目的　利用前瞻性随机对照方法比较全主动脉弓替换术中单侧顺行性脑灌注 (ASCP)和双侧ASCP时视网膜中央动脉、球后血管血流变化和血S1 0 0蛋白浓度变化。方法　 1 6例全主动脉弓替换术患者随机分为单侧AS CP和双侧ASCP组 ,每组各 8例。两组均行术前术后颅脑计算机体层摄影 (CT)。术中采用经眼球超声监测视网膜中央动脉及球后血管血流。术中术后动态测定血S1 0 0蛋白浓度。结果　两组各有 1例出现短暂性神经功能异常。ASCP过程中单侧组右侧视网膜中央动脉可探及血流 ,左侧视网膜中央动脉不可探及 ,双侧组两侧视网膜中央动脉均可探及血流。所有患者球后动脉均可探及血流。两组间各阶段血S1 0 0蛋白浓度无显著性差异 (P >0 .0 5 )。结论　在基底动脉环完整 ,存在有效侧支循环条件下 ,单侧灌注操作较为简便 ,双侧灌注在ASCP期间两侧脑灌注较为均衡 ,但两种灌注方法对S1 0 0蛋白浓度的影响无显著性差异。     

钛板联合羟基磷灰石人工骨眼眶重建

目的：探讨应用钛板联合羟基磷灰石人工骨矫正眼眶骨折眼球内陷的手术方法和疗效。方法：根据术前CT诊断明确的14例14眼眼眶骨折患者，术中用钛钉、钛板将复位的眶缘骨折进行坚强内固定．重建正常的眶缘，然后用羟基磷灰石人工骨材料植入眼眶，以填补眶腔容积的缺损，同时修复重建眶壁。结果：术后随访3～36个月，CT水平和冠状位扫描复查，10例眼球内陷的患者中，8例获得矫正，2例仍存中度内陷；8例复视患者中，7例获得满意改善，1例无效。无植人物感染、移位和脱出，未见视力丧失者。结论：钛板和复合羟基磷灰石人工骨具有很好的生物相容性，在眶壁重建手术中可获得满意的疗效。是眶壁重建术良好的替代材料。     

眼轴线后部眶容积增大与眼球内陷比值的测定研究

目的:通过测量眼眶爆裂性骨折伴有眼眶扩大患者的后部眼眶容积、观察眼球内陷出现的时间及程度,研究后部眶容积扩大与眼球内陷的关系比值,为病情预测和眶内填充手术提供比较精确的参考数据。方法:将96例患者按发病时间分为早期病例组(60例、受伤时间1周以内)和晚期病例组(36例、受伤时间3个月以上),早期组除进行后部眼眶容积测量外,分别于1周、2周、3周测定眼球突出度(相差>1mm为阳性),记录眼球内陷出现时间,用卡方检验进行统计学分析;晚期组测量后部眶容积增大值和眼球内陷量,对其相关性采用Pearson统计方法进行统计学分析,并得出回归方程及相关系数。结果:早期组60例患者中,(58.33%)例患者在1周内出现眼球内陷,4(880%)例在2周内出现内陷,3周时有5(388.33%)例呈现出内陷;2周时出现眼球内陷的例数与1周时有显著性差异(χ2=62.484,P<0.001),2周时出现眼球内陷例数与3周时无差异(χ2=1.563,P>0.05),1周时出现眼球内陷例数与3周时有显著差异(χ2=76.885,P<0.001),后部眶容积增大与眼球内陷的比值约为1.0,两者之间呈正相关(r=0.994,P<0.001),即后部眶容积每增加1ml,产生1.0mm的眼球内陷。结论:眼球内陷通常于伤后2周～3周出现,3个月时趋向稳定;后部眶容积增大与眼球内陷产生比值为1.0,呈正相关;后部眶容积扩大与眼球内陷比值可预测发生眼球内陷的可能性和程度,为手术矫正眼球内陷提供可靠、精确的参考,具有十分重要的临床指导意义。