Targeted Disruption of NF1 in Osteocytes Increases FGF23 and Osteoid With Osteomalacia‐like Bone Phenotype

Neurofibromatosis type 1 (NF1, OMIM 162200), caused by NF1 gene mutations, exhibits multi‐system abnormalities, including skeletal deformities in humans. Osteocytes play critical roles in controlling bone modeling and remodeling. However, the role of neurofibromin, the protein product of the NF1 gene, in osteocytes is largely unknown. This study investigated the role of neurofibromin in osteocytes by disrupting Nf1 under the Dmp1‐promoter. The conditional knockout (Nf1 cKO) mice displayed serum profile of a metabolic bone disorder with an osteomalacia‐like bone phenotype. Serum FGF23 levels were 4 times increased in cKO mice compared with age‐matched controls. In addition, calcium‐phosphorus metabolism was significantly altered (calcium reduced; phosphorus reduced; parathyroid hormone [PTH] increased; 1,25(OH)₂D decreased). Bone histomorphometry showed dramatically increased osteoid parameters, including osteoid volume, surface, and thickness. Dynamic bone histomorphometry revealed reduced bone formation rate and mineral apposition rate in the cKO mice. TRAP staining showed a reduced osteoclast number. Micro‐CT demonstrated thinner and porous cortical bones in the cKO mice, in which osteocyte dendrites were disorganized as assessed by electron microscopy. Interestingly, the cKO mice exhibited spontaneous fractures in long bones, as found in NF1 patients. Mechanical testing of femora revealed significantly reduced maximum force and stiffness. Immunohistochemistry showed significantly increased FGF23 protein in the cKO bones. Moreover, primary osteocytes from cKO femora showed about eightfold increase in FGF23 mRNA levels compared with control cells. The upregulation of FGF23 was specifically and significantly inhibited by PI3K inhibitor Ly294002, indicating upregulation of FGF23 through PI3K in Nf1‐deficient osteocytes. Taken together, these results indicate that Nf1 deficiency in osteocytes dramatically increases FGF23 production and causes a mineralization defect (ie, hyperosteoidosis) via the alteration of calcium‐phosphorus metabolism. This study demonstrates critical roles of neurofibromin in osteocytes for osteoid mineralization. © 2017 American Society for Bone and Mineral Research.     

Hepatoma, arterioportal shunting, and hyperkinetic portal hypertension: therapeutic embolization

Four patients with hepatocellular carcinoma, shunting of blood from the hepatic artery to the portal vein, and hyperkinetic portal hypertension were treated by transcatheter embolization of the hepatic artery. In three acutely bleeding patients variceal hemorrhage was controlled by the embolization. Following embolization hepatofugal portal venous flow became hepatopetal in all four patients. No serious complications were encountered. When hepatoma is complicated by arterioportal shunting and hyperkinetic portal hypertension, occlusion of the fistula by transcatheter embolotherapy can reduce the portal pressure.     

Dynamic magnetic resonance imaging in assessing lung function in adolescent idiopathic scoliosis: a pilot study of comparison before and after posterior spinal fusion

Background  

Restrictive impairment is the commonest reported pulmonary deficit in AIS, which improves following surgical operation. However, exact mechanism of how improvement is brought about is unknown. Dynamic fast breath-hold (BH)-MR imaging is a recent advance which provides direct quantitative visual assessment of pulmonary function. By using above technique, change in lung volume, chest wall and diaphragmatic motion in AIS patients before and six months after posterior spinal fusion surgery were measured.     

Alopecia in association with severe seborrhoeic dermatitis following combination antiretroviral therapy for acute retroviral syndrome

We present a case where alopecia occurred with severe seborrhoeic dermatitis associated with the commencement of combination antiretroviral therapy for acute retroviral syndrome. We postulate that the eruption could represent a novel manifestation in association with immunological response to antiretroviral therapy.     

Synergistic activity of troxacitabine (Troxatyl™) and gemcitabine in pancreatic cancer

Background  

Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl™) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials.     

生物膜与膨体聚四氟乙烯包裹治疗动脉瘤的效果对照

目的:比较生物膜与膨体聚四氟乙烯在动脉瘤包裹的远期治疗效果。方法:实验于2004-12/2006-10年在南方医院神经外科实验室与广东冠昊动物实验中心进行。取成年健康杂种犬10只,采用显微外科技术,将双侧的颈外静脉1.5cm嫁接双侧颈总动脉缺损1.5cm制作梭形动脉瘤模型20枚。左侧10枚应用生物膜(广东冠昊生物科技有限公司产品)包裹治疗,右侧10枚应用膨体聚四氟乙烯(美国戈尔公司周围血管补片)包裹治疗。术后第1,3,6,9,12个月行彩色多普勒超声血动态观察血流动力学变化,第12个月进行数字减影血管造影检测及解剖组织学观察。结果:10只犬全部进入结果分析。①血流动力学观察:生物膜包裹侧瘤腔消失、形态上趋于正常的颈总动脉,管腔均通畅,造影剂快速通过无滞留;血流恢复为层流,频谱特征与颈总动脉一致;1个月时生物膜与瘤壁存在微小间隙,3个月后间隙完全消失,12个月时血管顺应性、弹性与颈总动脉基本相匹配。膨体聚四氟乙烯包裹侧瘤腔消失、管腔通畅6枚,腔内为层流,频谱特征与颈总动脉相似,但速度明显高于远近端颈总动脉;瘤腔轻度缩窄,内壁出现轻度波状充盈缺损,包裹片长度轻度缩短;1个月和3个月各出现2枚血栓性闭塞,经主动脉弓照影不显像。6个月内膨体聚四氟乙烯与瘤壁存在清晰微小间隙,6个月后间隙消失。②组织学观察:生物膜包裹侧外表柔软类似颈总动脉,有较多毛细血管长入但维持原形,瘤腔内膜光滑无增厚,内皮细胞无增生、脱落,未见附壁血栓;生物膜与瘤壁融合、多层次降解,降解间隙内较多新生血管、组织长入,未见炎症细胞。膨体聚四氟乙烯外表僵硬、未见周围组织长入;内膜增厚、不光滑,内皮细胞核密集、部分脱落,薄层血栓附壁;4例见胶冻状长圆柱形杂色血栓。膨体聚四氟乙烯与瘤壁嵌入无降解,未看到明显的毛细血管长入;有极少的成纤维细胞伸入,散在的淋巴细胞浸润及少量巨噬细胞。结论:生物膜具有良好的理化性能与生物相容性,其效果优于膨体聚四氟乙烯,是动脉瘤包裹治疗的理想再生医学工程材料。