我国不同地区阿片类镇痛药物在癌痛治疗中的使用情况及个人经济负担

摘 要 目的：了解我国不同地区阿片类镇痛药的使用情况与趋势,评估癌痛治疗吗啡临床需要量及满足临床需要的程度,评价个人药费可负担性,为我国合理使用阿片类镇痛药,提高癌痛控制水平和患者生活质量提出政策建议。方法：采用回顾性分析方法,分析2006~2016年我国7个片区的阿片类镇痛药使用强度（MUD）及其各阶段年复合增长率（CAGR）。基于我国7个片区肿瘤登记数据和国际疼痛标准治疗指南,测算2015年不同地区的吗啡需要量。将药品价格以DDD值标化为限定日费用(DDC),采用改进后的WHO/HAI标准调查法评价阿片类镇痛药用于癌痛治疗的个人药费可负担性。结果：全国MUD从2006年的1.45DDD/10万人天增长至2016年的6.93DDD/10万人天,整体增长率呈现为前高后低。不同地区间MUD差异较大,且MUD极差有逐年加大趋势。2016年MUD最大地区为华南（9.67DDD/10万人天）,最小为西北（3.28DDD/10万人天）。2015年,全国吗啡等效当量实际使用量仅占癌痛治疗吗啡需要量的21.5%,华东（26%）和华南（36%）等地区高于西南（11%）和西北（12%）。各类阿片类镇痛药的DDC范围为10.80～848.88元,除吗啡注射剂外,其余药品的疗程自付费用均大于1 d的日均可支配收入。结论：我国阿片类镇痛药用于癌痛治疗整体使用不足,且不同经济水平的地区使用差异较大,癌痛患者长期使用镇痛药物治疗的个人药费负担较重。应全面加快推行癌痛规范化治疗示范病房和疼痛门诊,完善相应保障体系,合理引导广大城乡居民可负担的癌痛治疗药品价格,降低个人费用负担,提高癌症患者生存质量,使更多癌痛患者得到经济有效的治疗。     

DCE-MRI减影技术及DWI序列在原发性肝癌局部介入术后评估的应用研究

目的探讨磁共振动态增强减影技术及DWI序列在原发性肝癌经局部介入治疗术后疗效评估中的应用价值。方法收集56例经临床或病理证实为原发性肝癌的患者,同时满足1)接受过射频消融、微波消融、动脉内碘油栓塞等局部介入治疗术后≥6个月;2)治疗后病灶MRI表现为平扫T1高信号,且病灶直径≥1cm。共纳入符合标准的74个病灶,根据mRECIST标准,将所有病灶分为完全坏死组(42个病灶)和复发残留组(32个病灶)。由两位腹部影像诊断医师对MRI常规动态增强、动态增强减影及DWI(联合ADC)图像分别进行肉眼分析并对疗效判断的信心度进行评分,采用方差分析比较三种技术医师信心度水平差异;分别计算病灶在MRI常规动态增强与增强减影后动脉期、静脉期图像上的对比信噪比(CNR),采用t检验比较减影前后差异;测量所有病灶ADC值并对比完全坏死组与复发残留组之间差异。P<0.05为差异有统计学意义。结果完全坏死组1)诊断医师对常规动态增强、动态增强减影、DWI(联合ADC)三种技术肉眼判断肿瘤完全性坏死的信心度评分无显著差异;2)MRI动态增强动脉期减影前、后病灶CNR值无显著差异;静脉期减影后病灶CNR值明显大于减影前。复发残留组1)三种技术判断病灶内仍有活性肿瘤组织残留或复发的医师信心度评分由高到低为动态增强减影>常规动态增强>DWI(联合ADC);2)MRI动态增强动脉期、静脉期减影后病灶CNR值均显著大于减影前。复发残留组病灶平均ADC值明显低于完全性坏死组。结论与常规动态增强相比,减影技术结合DWI及ADC图像的定量分析,可以更加准确评估原发性肝癌局部治疗疗效。     

Time Interval of Two Injections and First-Dose Dependent of Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomal Gambogenic Acid: The Contribution of PEG-Specific IgM

Repeated injection of PEGylated liposomes can cause the disappearance of long circulating property because of the induction of anti-PEG IgM antibody referred to as “accelerated blood clearance (ABC) phenomenon.” Although ABC phenomenon typically occurs when entrapped drugs are chemotherapeutic agent with low cytotoxic, there is little evidence of accelerated blood clearance of PEGylated herbal-derived compound on repeated injection. Herein, we investigated the blood concentration of PEGylated liposomal gambogenic acid (PEG-GEA-L), a model PEGylated liposomal herbal extract, on its repeated injection to rats. We found time interval between injections had considerable impact on the magnitude of ABC phenomenon induced by PEG-GEA-L. When time interval was prolonged from 3 days to 7 days, ABC phenomenon could be attenuated. Furthermore, its magnitude was enhanced accompanied by a marked rise in the accumulation of PEG-GEA-L in the liver and spleen in a first-dose–dependent manner. Consistently, the level of anti-PEG IgM significantly increased with the first dose of PEG-GEA-L and decreased with the extended time interval between injections, which implies anti-PEG IgM is a major contributor to the ABC phenomenon. Notably, the increased expression of liver anti-PEG IgM was accompanied by an increased expression of efflux transporters in the induction process of the ABC phenomenon.     

Synergistic Inhibition on Acetylcholinesterase by the Combination of Berberine and Palmatine Originally Isolated from Chinese Medicinal Herbs

Alzheimer’s disease is a multi-factorial neurodegenerative disorder devastatingly affecting the aged population worldwide. Previous studies have shown that medicinal herbs used in traditional Chinese medicine might be benefit to Alzheimer’s disease patients. Berberine and palmatine, two isoquinoline alkaloids found in several medicinal herbs, were used for memory enhancement in China. In this study, the inhibitory effects of combined berberine and palmatine on acetylcholinesteras were evaluated using recombinant human acetylcholinesterase. Our results showed that the combination of berberine and palmatine inhibited acetylcholinesterase in a mixed competitive pattern. By the median-effect principle, the calculated combination index of the combination was less than 1, suggesting that berberine and plamatine inhibited acetylcholinesterase synergistically. Furthermore, the drug-reducing index of berberine and palmatine were 2.98 and 2.66, respectively. Taken together, the results showed that the combination of the two alkaloids might potentially be developed as a more effective therapeutic strategy for Alzheimer’s disease patients.     

Interleukin-33 alleviates psoriatic inflammation by suppressing the T helper type 17 immune response

Psoriasis is a chronic inflammatory skin disease with unclear pathogenesis. Interleukin-33 (IL-33) is highly expressed in patients with psoriasis, but its role in psoriasis is unknown. The aim of this study was to investigate the possible role of IL-33 in the pathogenesis and treatment of psoriasis. IL-33 expression was determined using enzyme-linked immunosorbent assay, real-time fluorescent quantitative polymerase chain reaction and immunohistochemical staining. CD4⁺ T cells were sorted using magnetic beads and treated with or without IL-33. Imiquimod (IMQ) was used to induce psoriatic inflammation in mice. The frequency of immune cells was determined using flow cytometry. The cytokine level in mouse skin was measured using cytometric bead array. Our results showed that IL-33 was highly expressed in the lesional skin and serum of patients with moderate-to-severe plaque psoriasis. IL-33 inhibited the expression of IL-17 in CD4⁺ T cells of psoriasis patients. Subcutaneous injection of IL-33 alleviated the IMQ-induced psoriatic inflammation in mice, reduced tumor necrosis factor-α and IL-23 expression, and decreased the proportion of T helper type 17 (Th17) cells in the skin-draining lymph nodes in the mice. Our results suggest that IL-33 plays a protective role in the pathogenesis of psoriasis by suppressing Th17 cell differentiation and function. The potential therapeutic effect of IL-33 in treating psoriasis warrants further investigation.     

Advances and novel developments in allergic rhinitis

Allergic rhinitis (AR) is an upper airway disease with high prevalence in the world, and therefore needs to be thoroughly investigated and treated accordingly. Although the mechanisms underlying the pathology and treatment of AR have been widely studied, many aspects of AR are still unclear and warrant further investigations. The purpose of the present review was therefore to report recently published papers, which highlight the novel mechanisms and treatments of AR. These include role of environment, important proteins and cells, and some other factors in the pathogenesis of AR; as well as the role of immunotherapy and biologics in the treatment of AR.     

人黄韧带细胞骨化发生过程中的自噬

文题释义： 黄韧带骨化症：是由于脊柱黄韧带发生骨向分化而形成的一种韧带骨化疾病,常导致椎管狭窄,造成脊髓受压,并产生不可逆损害,出现肢体感觉障碍,严重的将导致瘫痪。目前对黄韧带骨化病因学研究取得了一定的进展,但其具体的发病机制仍未完全明确。 自噬：因外界或自身环境的改变,细胞器和胞内蛋白通过溶酶体进行分解消化并重新利用,从而达到适应外界环境、维持细胞内环境稳定的过程,是真核细胞特有一种表现形式。 MAPK信号通路：是生物体内重要的信号转导系统之一,它可以被物理应激、炎性细胞因子、生长因子以及细胞复合物等一系列细胞外信号或刺激激活,从而参与介导细胞生长、发育、分裂以及分化等多种生理及病理过程。在哺乳动物细胞中MAPK信号通路的主要信号分子包括ERK1/2、JNK以及P38等。 背景：黄韧带骨化发生的病理机制尚不清楚,临床上无有效的药物或非手术治疗的方法。目前研究发现,骨桥蛋白与自噬在成骨过程中均发挥重要作用,二者在黄韧带骨化中的作用尚不清楚。 目的：通过对骨桥蛋白和自噬在黄韧带骨化发生机制的研究,尝试找出药物治疗的潜在作用靶点。 方法：①黄韧带骨化病、胸椎骨折或单纯腰椎间盘突出症患者行后路全椎板切除减压获取黄韧带,将标本分为骨化组和非骨化组,每组各取8例标本,通过免疫组化染色观察骨桥蛋白、骨钙素及自噬指标Beclin-1、LC3、P62的表达;②通过组织块贴壁法进行黄韧带细胞的分离培养,并用不同质量浓度的骨桥蛋白干预不同时间来构建体外黄韧带细胞骨化模型;③非骨化组黄韧带细胞用不同浓度的自噬抑制剂3-甲基腺嘌呤干预后,再用100 μg/L骨桥蛋白诱导,应用Western blot检测骨化指标碱性磷酸酶、骨钙素的表达变化;④用100 μg/L骨桥蛋白干预非骨化黄韧带细胞,并在0,15,30,60,120 min终止骨化诱导过程,应用Western blot检测MAPK信号通路中重要分子ERK1/2、JNK、P38的磷酸化情况;⑤非骨化组黄韧带细胞用ERK1/2特异的磷酸化阻滞剂U0126阻断ERK1/2通路磷酸化后,再用100 μg/L骨桥蛋白诱导,应用Western blot检测碱性磷酸酶以及骨钙素的表达变化。 结果与结论：①骨化黄韧带和非骨化黄韧带组织骨钙素、骨桥蛋白的免疫组化均呈阳性表达;骨化黄韧带组织中Beclin-1呈阳性表达,而LC3及P62未见明显阳性结果;非黄韧带骨化组织中Beclin-1、LC3、P62均呈阳性表达;②与非骨化组比较,骨化组黄韧带细胞中碱性磷酸酶和骨钙素的表达增加;骨桥蛋白可诱导黄韧带骨化,骨桥蛋白的作用具有浓度相关性和时间相关性;③自噬强弱与骨化程度呈负相关,即自噬越明显,骨化作用越弱;④骨桥蛋白能使MAPK信号通路磷酸化,并具有一定的时间相关性;抑制MAPK磷酸化过程后,骨桥蛋白仍然能够诱导黄韧带细胞的骨化;⑤结果表明,黄韧带骨化发生过程中,信号通路上ERK1/2、骨桥蛋白、骨钙素、碱性磷酸酶分子的上下游关系为：ERK1/2→骨桥蛋白→骨钙素/碱性磷酸酶。 ORCID: 0000-0003-0008-9802(许国峰) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

基于同轴细胞打印双网络生物墨水优化及类血管支架的打印

文题释义：双网络生物墨水：生物墨水是指可以用于生物3D打印机的材料,具有类似细胞外基质的理化性质,可用于制造与人体器官相似的组织。双网络生物墨水内部具有两种交联网络,能使体外构建的组织具有良好的机械性能,适用于不同的应用场景。 同轴细胞打印：生物3D打印也叫细胞打印,是指操控细胞生物墨水体外构建活性组织的过程。同轴细胞打印是生物3D打印的延伸和发展,通过结合多层同轴针头可以直接快速制备含有内部连通网络的组织工程支架。 背景：细胞体外培养情况下无法在远离营养物质200 μm以上的区域存活,血管网络构建对组织工程领域厚组织和器官再生至关重要,同轴细胞打印为体外构建类血管通道提供了一种新的方式。 目的：优化生物墨水的同轴细胞打印性能,制备具有类血管结构的组织工程支架。 方法：通过间歇式巴氏灭菌制备无菌海藻酸钠溶液,冷冻保存;以脱胶蚕丝为原料制备无菌丝素蛋白冻干粉,密封保存;将丝素蛋白冻干粉加入解冻的海藻酸钠溶液中,再加入人脐静脉内皮细胞,作为生物墨水;将生物3D打印机的外轴连接生物墨水,内轴连接交联剂,同轴打印类血管支架材料,进行光学相干层析成像扫描、扫描电镜观察;拉伸测试海藻酸钠与丝素蛋白/海藻酸钠同轴打印环形试件(不含细胞)的弹性模量。采用冷冻保存7 d的海藻酸钠溶液与人脐静脉内皮细胞制作同轴打印支架,冷冻保存7 d的海藻酸钠溶液、人脐静脉内皮细胞与密封保存6个月的丝素蛋白冻干粉制作同轴打印支架,培养24 h后死活染色观察细胞存活率。设计打印串联与并联结构的类血管支架,培养1,3,7,10,14 d后检测细胞增殖情况。 结果与结论：①光学相干层析成像扫描显示,该混合生物墨水最高打印高度为9层,整体厚度约为4.4 mm;扫描电镜显示,类血管支架的中空纤维丝外壁呈无规则条状卷曲,存在微米级内部连通孔隙结构,中空纤维丝内壁具有更致密的孔隙结构;②丝素蛋白/海藻酸钠同轴打印环形试件的弹性模量大于单纯海藻酸钠同轴打印环形试件(P < 0.05);③采用保存7 d海藻酸钠溶液制作的支架细胞存活率为(86.7±3.4)%,加入丝素蛋白冻干粉支架的细胞存活率为(98.1±1.2)%,说明冷冻保存7 d的海藻酸钠溶液未染菌,丝素蛋白的保质期可达6个月;④并联结构类血管支架培养7,10,14 d的细胞增殖活性高于串联结构的类血管支架(P < 0.05);⑤结果表明,实验制备的类血管支架材料具有良好的生物相容性与机械性能。 ORCID: 0000-0002-5556-6672(张一帆) 中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程     

The effect of thick fibers and large pores of electrospun poly(ε-caprolactone) vascular grafts on macrophage polarization and arterial regeneration

The vascular grafts prepared by electrospinning often have relatively small pores, which limit cell infiltration into the grafts and hinder the regeneration and remodeling of the grafts into neoarteries. To overcome this problem, macroporous electrospun polycaprolactone (PCL) scaffolds with thicker fibers (5–6 μm) and larger pores (∼30 μm) were fabricated in the present study. In vitro cell culture indicated that macrophages cultured on thicker-fiber scaffolds tended to polarize into the immunomodulatory and tissue remodeling (M2) phenotype, while those cultured on thinner-fiber scaffolds expressed proinflammatory (M1) phenotype. In vivo implantation by replacing rat abdominal aorta was performed and followed up for 7, 14, 28 and 100 d. The results demonstrated that the macroporous grafts markedly enhanced cell infiltration and extracellular matrix (ECM) secretion. All grafts showed satisfactory patency for up to 100 days. At day 100, the endothelium coverage was complete, and the regenerated smooth muscle layer was correctly organized with abundant ECM similar to those in the native arteries. More importantly, the regenerated arteries demonstrated contractile response to adrenaline and acetylcholine-induced relaxation. Analysis of the cellularization process revealed that the thicker-fiber scaffolds induced a large number of M2 macrophages to infiltrate into the graft wall. These macrophages further promoted cellular infiltration and vascularization. In conclusion, the present study confirmed that the scaffold structure can regulate macrophage phenotype. Our thicker-fiber electrospun PCL vascular grafts could enhance the vascular regeneration and remodeling process by mediating macrophage polarization into M2 phenotype, suggesting that our constructs may be a promising cell-free vascular graft candidate and are worthy for further in vivo evaluation.     

颈腮区手术中耳大神经的临床解剖学观察

目的 研究耳大神经的应用解剖学,为颈腮区相关手术提供临床解剖资料。方法 选取安徽医科大学第一附属医院耳鼻咽喉头颈外科2010年11月—2013年10月45例（52侧）头颈腮腺区手术病例进行前瞻性研究,在手术中观察耳大神经出肌点的位置、行程、分支点、分支及其与颈外静脉之间的关系。其中全颈淋巴结清扫术25例（32侧）、腮腺恶性肿瘤手术4例、咽旁间隙肿瘤16例。结果 耳大神经多于胸锁乳突肌后缘中点上下10mm范围内穿出占94．2％（49／52）,并多以单干形式上行,在胸锁乳突肌前缘、腮腺尾部以及下颌角下方10mm左右分成前、中、后3个终支。耳大神经伴行于颈外静脉的后方上行（间距不超过20mm）。结论 耳大神经解剖变异较大,其主干与颈外静脉关系密切,手术时尽可能避免耳大神经损伤。