半乳糖凝集素10在不同类型鼻息肉中的表达及其发病机制中的作用北大核心CSCD

目的检测半乳糖凝集素10(Galectin-10)在不同程度嗜酸粒细胞浸润的鼻息肉中的表达差异,探讨Galectin-10是否可作为嗜酸粒细胞性鼻息肉(eosinophilic chronic rhinosinusitis with nasal polyps,ECRSwNP)的新型标志物,及其在ECRSwNP发病机制中的作用。方法纳入2018年11月至2019年4月在南昌大学第二附属医院住院行鼻内镜手术的患者共36例进行回顾性分析,其中男20例,女16例;年龄为14~74岁。36例患者分为3组:ECRSwNP组11例;非嗜酸粒细胞性鼻息肉(noneosinophilic chronic rhinosinusitis with nasal polyps,non-ECRSwNP)组15例;对照组单纯鼻中隔偏曲患者10例。采用HE染色对CRSwNP进行组织学评估并将其分为ECRSwNP和non-ECRSwNP。根据患者有无变应性鼻炎,将CRSwNP患者分为AR组及非AR组(non-AR),将CRSwNP与对照组根据是否属于特应性状态分为特应性状态阳性组(Atopy)及阴性组(non-Atopy)。免疫组织化学测定Galectin-10在ECRSwNP、non-ECRSwNP及对照组组织中的阳性定位及半定量表达、蛋白免疫印迹(Western Blot)检测Galectin-10蛋白分别在3组中的表达水平、实时荧光定量反转录聚合酶链反应检测Galectin-10 mRNA在3组中的不同表达;分析Galectin-10的表达与临床因素,如合并变应性鼻炎(allergic rhinitis,AR)、特应性状态是否相关。运用IBM SPSS 19.0及Graphpad prism 7.0对实验数据进行处理与作图。结果免疫组织化学染色结果提示Galectin-10主要位于嗜酸粒细胞,与non-ECRSwNP组(0.028±0.004)和对照组(0.025±0.004)相比,ECRSwNP组中Galectin-10的半定量表达(0.051±0.003)更高,差异有统计学意义(t值分别为3.862、5.137,P值均<0.01),non-ECRSwNP组与对照组相比,差异无统计学意义(t=0.560,P>0.05)。Western Blot法检测Galectin-10蛋白的表达发现,与non-ECRSwNP组和对照组相比,ECRSwNP组中Galectin-10蛋白的表达更高,差异有统计学意义(t值分别为25.351、27.376,P值均<0.01),non-ECRSwNP组与对照组相比,差异无统计学意义(t=1.071,P>0.05)。Galectin-10 mRNA在3组中的表达:与non-ECRSwNP组(1.188±0.054)和对照组(1.020±0.142)相比,ECRSwNP组Galectin-10 mRNA表达量(2.413±0.303)较高,差异有统计学意义(t值分别为3.973、4.156,P值均<0.05),non-ECRSwNP组与对照组相比,差异无统计学意义(t=1.110,P>0.05)。采用免疫组织化学方法检测组间Galectin-10蛋白的半定量表达差异,结果显示AR组与non-AR组比较,Galectin-10的表达差异无统计学意义(P值均>0.05),特应性状态阳性组(Atopy)与特应性状态阴性组(non-Atopy)相比,Galectin-10的表达差异无统计学意义(P值均>0.05)。结论Galectin-10在ECRSwNP中表达升高,但是在AR与non-AR以及在特应性状态阳性组(Atopy)与特应性状态阴性组(non-Atopy)患者间差异无统计学意义,提示Galectin-10可作为ECRSwNP的新型生物标志物,并可能在非变态反应诱发的ECRSwNP发病机制中具有意义。     

伴鼻息肉的慢性鼻-鼻窦炎的免疫调节特点

伴鼻息肉的慢性鼻-鼻窦炎（chronic rhinosinusitis with nasalpolyps,CRSwNP）是一种由于鼻黏膜上皮和免疫系统功能紊乱所致鼻腔和鼻黏膜的炎症,典型特征是诱导较强的Th2型免疫应答、嗜酸性粒细胞的优势浸润和调节性T细胞的功能障碍。其中,IL-25和IL-33可能是介导鼻息肉组织中上皮细胞间嗜酸性粒细胞浸润和诱导Th2型免疫应答的关键细胞因子。探讨伴鼻息肉的慢性鼻-鼻窦炎的免疫调节异常机制,将有助于寻找新的治疗靶点。本文对CRSwNP的免疫调节特点做一综述,提出CRSwNP以诱导Th2型免疫反应和调节性Th细胞功能障碍为特征。     

Galectin-9及其受体Tim-3在慢性鼻窦炎中的表达及临床意义

目的研究半乳糖凝集素9(Galectin-9)及其受体T细胞免疫球蛋白及粘蛋白结构域分子3(T cell immunoglobulin and mucin domain-3, Tim-3)在慢性鼻窦炎(chronic rhinosinusitis, CRS)患者鼻黏膜中的表达与对照组的差异,探讨Galectin-9及其受体Tim-3与CRS发病的关系。方法选取2019年1～9月住院确诊为CRS的患者为实验组(A组),选同期住院的单纯鼻中隔偏曲患者作为对照组(B组),所有患者均在手术中取窦口鼻窦复合体区黏膜作为标本。经实时荧光定量PCR(qPCR)、HE染色及免疫组化检测各组鼻黏膜中Galectin-9与Tim-3的表达及分布情况。分析比较各组间的差异,阐述Galectin-9及其受体Tim-3与CRS发病的关系。结果 Galectin-9及Tim-3在实验组及对照组鼻黏膜中均有表达,且实验组Galectin-9及Tim-3的表达明显高于对照组,差异有统计学意义(P0.05)。结论 CRS患者鼻黏膜中Galectin-9与Tim-3表达量较单纯鼻中隔偏曲患者鼻黏膜中高,提示Galectin-9及其受体Tim-3与CRS的炎症反应有关,可能参与CRS的炎症调节过程。     

夏科雷登结晶与慢性鼻-鼻窦炎的关系

夏科雷登结晶是一种由嗜酸性粒细胞裂解后所释放的半乳糖凝集素-10形成的蛋白质结晶，主要存在于慢性鼻-鼻窦炎、哮喘、变应性鼻炎等伴Th2型免疫细胞浸润疾病的病变部位中，其含量的变化可作为评估病情的指标之一。通过清除或溶解该结晶，可以减轻这类疾病的症状，这一发现为慢性鼻-鼻窦炎的治疗提供了新的治疗思路。本文就夏科雷登结晶的研究历史、新进展及其对慢性鼻-鼻窦炎治疗的意义做一综述。     

上皮屏障在慢性鼻窦炎伴鼻息肉中的研究进展

慢性鼻窦炎伴鼻息肉(CRSwNP)是耳鼻咽喉科的常见病,以鼻腔和鼻窦黏膜的高度异质性慢性炎症为特征。近年来,由于其发病率不断升高且易反复发作,预后较差,严重影响患者的生活质量,增加社会医疗经济负担。鼻黏膜上皮细胞构成的上皮屏障作为“守门员”,是鼻腔抵御病原体、过敏原等入侵的第一道防线。它通过启动防御机制、激活各类理化因子和调节免疫反应等维护宿主鼻腔黏膜的健康稳态。研究表明,上皮屏障功能障碍与CRSwNP的发生密切相关,也是目前CRSwNP领域的研究热点之一。因此,深入探究调控CRSwNP上皮屏障功能障碍的潜在分子生物学机制至关重要。本文将对上皮屏障在CRSwNP形成过程中的功能、作用机制和破坏因素等方面的研究进展作一综述,以期为阐明CRSwNP的病理机制提供见解,为其诊断和治疗的研究提供新方向。     

慢性鼻窦炎伴鼻息肉合并哮喘患者临床特征及转录组分析

目的　探讨慢性鼻窦炎伴鼻息肉（c h r o n i c rhinosinusitis with polyps,CRSwNP）合并哮喘（asthma,AS）患者的临床特征,并比较C R S w N P 合并A S 组（CRSwNP+AS组）组与CRSwNP不伴AS组（CRSwNPAS组）的转录组表达差异。方法　纳入北京协和医院于2016年2月～2018年2月收治的CRSwNP患者201例,比较CRSwNP+AS与CRSwNP-AS患者的临床特征差异,通过RNA-Seq分析二者转录组差异。结果　CRSwNP+AS占22.9%,CRSwNP-AS占77.1%。与CRSwNP-AS相比,CRSwNP+AS在嗜酸性粒细胞型鼻息肉、合并过敏性鼻炎或阿司匹林不耐受的比例、筛窦CT评分及CT总分、外周血及组织嗜酸性粒细胞计数及百分比上均显著高于 CRSwNP-AS组。RNA-Seq结果显示,与CRSwNP-AS组相比,CRSwNP+AS组上调的基因主要与2型免疫炎症反应及组织重塑有关,如CLCA1、COL6A5、IGHE、CCL7、CCL24、CCL26、CCR3、IL-5、IL13等。结论　CRSwNP+AS患者临床表现更重,鼻息肉组织嗜酸性粒细胞浸润更高,2型免疫反应相关基因表达更高。     

TH2细胞因子在2型慢性鼻窦炎伴鼻息肉中的作用机制研究进展

慢性鼻窦炎(chronic rhinosinusitis with nasal polyps, CRS)根据其发病机制可分为2型和非2型炎症内型,其中2型炎症对应于嗜酸性粒细胞浸润为主的慢性鼻窦炎伴鼻息肉(chronic rhinosinusitis with nasal polyps, CRSwNP)。典型的2型CRSwNP患者通常对目前的治疗有耐药性,表现出较高的复发率。尽管生物制剂在其治疗上取得了一定的成功,但靶向单一TH2细胞因子并不能完全消除大多数患者的2型疾病,故靶向阻断TH2细胞因子及其下游的信号转导通路可能是针对内型治疗的一种新思路。论文对各2型细胞因子(IL-4、IL-5、IL-9、IL-13、IL-25和IL-33)在2型CRSwNP中与其特异性受体相互结合后激活的细胞内信号通路进行综述,旨在为治疗2型CRSwNP提供新的靶点。     

半乳糖凝集素3和9与变应性疾病

半乳糖凝集素是凝集素超家族中的一个家族,家族个体成员的多价性在发挥不同生物学效应中起重要作用,具有参与炎性反应、细胞凋亡、细胞黏附等多种生物学功能.近年来研究表明,半乳糖凝集素家族个体成员Galectins-3、9可能与变应性炎性反应发病机制密切相关.本文就半乳糖凝集素3、9的结构、分布、生物学功能,在变应性疾病中的表达及其可能的发病机制的研究进展予以综述,希望能为变应性疾病的防治开辟新的思路.     

度普利尤单抗在慢性鼻窦炎伴鼻息肉治疗中的研究进展

慢性鼻窦炎(CRS)是一种常见的鼻窦黏膜炎症性疾病,复杂的发生机制造就了CRS的高度异质性,部分患者无法从目前标准的药物治疗和手术中得到缓解。CRS具有不同的炎症内型和临床表型,慢性鼻窦炎伴鼻息肉(CRSwNP)一直是治疗难点,其症状相对较重还常合并哮喘,易对常规药物和手术的疗效不佳并伴有较高的复发风险。近年来,度普利尤单抗(dupilumab)在成人顽固性CRSwNP中疗效显著,其通过阻断Ⅱ型炎症中关键驱动因子IL-4和IL-13的信号传导,达到治疗作用。目前度普利尤单抗对国人CRSwNP治疗研究尚无报道。本文将对度普利尤单抗治疗CRSwNP的研究进展进行综述,以期为其在CRSwNP中的进一步应用研究提供参考。     

巨噬细胞在慢性鼻窦炎伴鼻息肉中的研究进展

慢性鼻窦炎伴鼻息肉（chronic rhinosinusitis with nasal polyps，CRSwNP）是鼻和鼻窦黏膜的慢性炎症反应，其发病机制至今还不清楚。与其他内在型相比，Th2型CRSwNP患者常规治疗后更容易复发，鼻黏膜内金黄色葡萄球菌的定植数多，金黄色葡萄球菌感染诱导Th2炎症反应，进一步加重炎症反应。巨噬细胞在病原微生物清除方面发挥了重要作用，但在Th2失调的炎症环境下巨噬细胞吞噬和杀菌能力明显下降，可能与Th2型CRSwNP患者黏膜内金葡菌持续性存在密切相关。本文就巨噬细胞的亚型、分化和功能进行综述，寄希望于巨噬细胞的研究能有效减少病原菌定植，控制鼻黏膜内持续性炎症反应。     

Galectin-3, an endogenous lectin,as a tool for monitoring cell differentiation in head and neck carcinomas with implications for lectin-glycan functionality

OBJECTIVE: Galectin-3 is an endogenous lectin that reacts with glycan epitopes of membrane and extracellular glycoproteins, including integrins, fibronectin, laminin and tetraspanins. Its expression, and also the presentation of its glycoligands, is controlled in a differentiation-dependent manner in squamous epithelia. The aim of this study was to monitor the carbohydrate-dependent binding of labeled galectin-3 to primary head and neck squamous cell carcinomas (from the tonsil, base of the tongue and larynx) and lymph node metastases. MATERIAL AND METHODS: Double labeling (using antibodies against desmoplakin-1, Ki-67 and cytokeratins) at the single-cell level was employed to cytologically characterize cells reacting with galectin-3. RESULTS: Galectin-3 binds a non-proliferating pool of tumor cells. Colocalization of galectin-3 binding sites with desmosomal proteins may indicate a role for this endogenous lectin in the formation of intercellular contacts of the desmosomal type. Cytokeratin-10-positive tumor cells also presented galectin-3-reactive binding sites on the surface; however, cytokeratin-10-free cells were also recognized by this lectin. CONCLUSION: These findings intimate that galectin-3 may represent a new tool for monitoring the degree of cell differentiation in carcinomas originating from the transformation of squamous cell epithelia.     

变应性鼻炎小鼠鼻黏膜中半乳糖凝集素3和9的表达

目的 探讨小鼠鼻黏膜内半乳糖凝集素3(galectin-3)和半乳糖凝集素9(galectin-9)的表达水平及其与变应性鼻炎的关系.方法 20只BALB/c小鼠随机分为变应性鼻炎组(AR组)和对照组,每组10只.AR组分别于第1天和第14天腹腔注射含卵清蛋白10μg及氢氧化铝2 mg的生理盐水悬液0.1ml,第21天起鼻腔给予1%卵清蛋白局部激发,持续7 d;对照组用生理盐水代替卵清蛋白.通过免疫组织化学染色和逆转录-聚合酶链反应(RT-PCR)检测鼻黏膜中galectin-3和galectin-9 的表达,同时采用酶联免疫吸附测定法(ELISA)检测外周血中自细胞介素4(IL-4)、白细胞介素5(IL-5)及γ干扰素(IFN-γ)的表达.结果 AR组和对照组均有galectin-3和galectin-9蛋白及mRNA的表达,AR组表达强度高于对照组,差异具有统计学意义(t值分别为11.18、9.261、7.667和6.971,P值均＜0.05).与对照组相比,AR组小鼠外周血中IL-4和IL-5含量均有不同程度的增高(t值分别为7.202和8.121,P值均＜0.05),而IFN-γ含量则下降(t=-11.94,P＜0.05).galectin 3和galectin 9 mRNA的表达强度与外周血中IL-4、IL-5的含量呈正相关(r值分别为0.667、0.847、0.720及0.736,P值均＜0.05),与IFN-γ含量呈负相关(r值分别为-0.528和-0.817,P值均＜0.05).结论 galectin 3和galectin 9可能在变应性鼻炎的发病过程中发挥一定作用.     

Expression patterns of galectin-1 and galectin-3 in nasal polyps and middle and inferior turbinates in relation to growth regulation and immunosuppression

BACKGROUND: The term nasal polyposis describes benign growth processes in the nasal and sinus mucosa, which are mainly located in the middle meatus and never in the inferior meatus. As a step to define the biochemical determinants relevant for growth regulation, we focused on endogenous lectins known for anti-apoptotic (galectin-3) and immunomodulatory (galectin-1) activities. DESIGN: Using computer-assisted microscopy, we performed an immunohistochemical investigation defining the quantitative parameters of expression of galectin-1 and galectin-3 in 10 nasal polyps, 10 middle turbinates, and 10 inferior turbinates, all of which were obtained from surgical resection. RESULTS: Our data show that galectin-3 expression is markedly (P<.001) higher in nasal polyps than in turbinates. No relation to the allergic status was discovered. Galectin-1 expression is higher in nasal polyps than in middle turbinates (P<.001) in nonallergic patients compared with allergic ones (in glandular epithelium, P =.009; in connective tissue, P =.006). The lowest galectin-1 expression was observed in the middle turbinate. CONCLUSIONS: These data are in line with a positive influence of galectin-3 on growth and an immunoregulatory role of galectin-1, mimicking an increased expression dependent on glucocorticoid.     

Allergic fungal rhinosinusitis

Allergic fungal rhinosinusitis is a phenotype of chronic rhinosinusitis with nasal polyposis, characterized by type 1 hypersensitivity to fungi, eosinophilic mucin with fungal hyphae in sinus secretions, and propensity for mucocele formation and bone erosion. Although its differentiation from other forms of chronic polypoid rhinosinusitis with eosinophilic mucin is sometimes problematic, type 1 hypersensitivity is a component of the disease process. Medical and surgical management can be augmented by immunotherapy directed toward the patient's specific allergen sensitivities. The primary rationale for immunotherapy is to control the allergic diathesis that may be contributing to the patient's chronic sinus inflammation.     

New paradigm for the roles of fungi and eosinophils in chronic rhinosinusitis

PURPOSE OF REVIEW: Chronic rhinosinusitis represents a challenge with its poorly understood pathophysiology and limited treatment options. Potential roles of fungi and eosinophils in the etiology and pathophysiology of chronic rhinosinusitis are summarized. RECENT FINDINGS: Previously, the fungal role in chronic rhinosinusitis was limited to the rare subgroup, allergic fungal rhinosinusitis. Critical examination of earlier diagnostic criteria for allergic fungal rhinosinusitis reveals limitations. By using updated diagnostic standards and novel sensitive techniques to detect fungi, a higher number of patients can now be diagnosed with fungal rhinosinusitis. A novel non-IgE-mediated immunologic mechanism in chronic rhinosinusitis patients links the predominant eosinophilic inflammation to certain fungi. Overall, these new findings have implications for surgical and medical approaches, including anti-inflammatory and antifungal medications. SUMMARY: Several classification schemes and diagnostic criteria describe chronic rhinosinusitis and make comparisons difficult. Preselection of patient groups within the chronic rhinosinusitis population and the lack of sensitive diagnostic techniques have prevented a full understanding of the syndrome complex of chronic rhinosinusitis. New results suggest a broader role for fungi in the pathophysiology of chronic rhinosinusitis, linking the eosinophilic inflammation to the presence of certain molds in the nasal and paranasal cavities. Although fungi are commonly found in nearly everyone, only chronic rhinosinusitis patients respond to them with an eosinophilic inflammation. These findings support a shift in the etiologic understanding of chronic rhinosinusitis away from a bacteriologic infectious pathogenesis to a fungal-driven inflammatory pathophysiology. Herein, the authors review earlier studies and describe an updated view on an old paradigm.     

Staphylococcus aureus and endoscopic sinus surgery

PURPOSE OF REVIEW: The current recommendation for the choice of empiric antibiotic therapy of chronic rhinosinusitis is based on the bacteriology of acute rhinosinusitis. Staphylococcus aureus has been found consistently in cultures from patients with chronic rhinosinusitis. New studies have examined the role of Staphylococcus aureus in the pathogenesis and clinical course of chronic rhinosinusitis, both before and after surgical therapy. The consequence of antibiotic resistance, on the course of chronic rhinosinusitis and its treatment, has also been examined. RECENT FINDINGS: Several recent studies have confirmed past literature demonstrating a high incidence of sinus cultures positive for Staphylococcus aureus growth in patients with chronic rhinosinusitis. Moreover, one study reported that Staphylococcus aureus is common in patients with persistent chronic rhinosinusitis after endoscopic sinus surgery. These studies, however, have not shown that this bacterium is a significant factor in the development of chronic rhinosinusitis or a predictor of the severity of symptoms. Other studies did not support the notion of increased antibiotic resistance in chronic rhinosinusitis, although there is some evidence that antibiotic resistance may lead to refractory cases of the disease. The standard treatment, of multiple courses of empiric antibiotics followed by surgery, was not shown to increase the prevalence of methicillin-resistant Staphylococcus aureus. SUMMARY: A review of recent literature shows a high incidence of positive cultures for Staphylococcus aureus from the sinuses of patients with chronic rhinosinusitis, both before and after surgery, but has not produced convincing evidence that Staphylococcus aureus has a significant role in the pathogenesis or clinical course of the disease.     

波形蛋白在不同类型慢性鼻-鼻窦炎中的表达及意义

目的:探讨波形蛋白(VM)在不同类型的慢性鼻-鼻窦炎中的表达和分布情况及意义。方法:将慢性鼻-鼻窦炎患者分为嗜酸粒细胞性鼻息肉(10例)、非嗜酸粒细胞性鼻息肉(12例)和不伴息肉的单纯慢性鼻-鼻窦炎(10例),将鼻中隔偏曲的肥大下鼻甲(10例)作为对照组。用免疫组织化学染色检测各组中VM的表达。并运用免疫荧光双染检测VM阳性的细胞是否同时表达上皮的连接标记上皮性钙黏蛋白,用来鉴别VM在上皮中的表达是否属于上皮来源的细胞。结果:伴和不伴息肉的慢性鼻-鼻窦炎各组以及对照组的上皮与间质中均出现VM的阳性表达。但VM阳性的细胞主要分布于黏膜的间质包括成纤维细胞、血管内皮细胞和其他间充质细胞。伴息肉的慢性鼻-鼻窦炎组VM的表达较其他组下调(P<0.05)。VM阳性的细胞为上皮来源的细胞,上皮层的VM阳性细胞尤其见于各种类型的鼻-鼻窦炎。结论:VM不仅分布于鼻黏膜的间质而且分布于黏膜上皮,这一现象尤其见于慢性鼻-鼻窦炎,且这些VM阳性的细胞不是白细胞,可能是上皮-间充质细胞转分化的结果。VM与鼻-鼻窦炎的组织学特征密切相关,可能在慢性鼻-鼻窦炎的发病过程中发挥重要的作用。     

慢性鼻-鼻窦炎黏膜重塑研究进展

黏膜重塑在慢性鼻-鼻窦炎的发生、发展进程中起着十分重要的作用,其与难治性鼻窦炎的关系密切。慢性鼻-鼻窦炎的机制与病因复杂,现有研究表明不同亚型慢性鼻-鼻窦炎其黏膜重塑的特点不同,主要表现为组织免疫学特点及黏膜重塑相关细胞因子表达不同。本文就不同亚型慢性鼻-鼻窦炎黏膜重塑的特点以及炎症与黏膜重塑之间的关系做一综述。     

Interleukin-1 beta, interleukin-5, interleukin-6, interleukin-8, and tumor necrosis factor-alpha in chronic sinusitis: response to systemic corticosteroids

Recently, the role of various cytokines in the pathogenesis of chronic rhinosinusitis has come under investigation. Various studies have reported increased levels of interleukin-3, interleukin-4, interleukin-5, interleukin-13, and granulocyte macrophage-colony stimulating factor in the sinonasal mucosa of patients with chronic rhinosinusitis. The present study investigated the levels of pro-inflammatory cytokines, including interleukin-1 beta (IL-1 beta), interleukin-5 (IL-5), interleukin-6 (IL-6) interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha), in the sinonasal mucosa of patients with chronic rhinosinusitis, and evaluated the response of these cytokines to oral corticosteroids. Chronic rhinosinusitis subjects (n = 15) and control subjects (n = 9) underwent nasal endoscopy and biopsy of the sinonasal mucosa. Chronic rhinosinusitis subjects were subsequently treated with a 10-day tapering dose of prednisone followed by a second sinonasal endoscopic exam and biopsy. Mucosal biopsy specimens were immunostained for IL-1 beta, IL-5, IL-6, IL-8, and TNF-a. In chronic rhinosinusitis subjects, mucosal levels of IL-1 beta, IL-6, IL-8, and TNF-alpha were significantly elevated when compared with control subjects, and levels of IL-5 demonstrated a strong trend toward elevation. In posttreatment chronic rhinosinusitis subjects, levels of IL-6 were significantly decreased when compared with pretreatment levels, and TNF-alpha levels demonstrated a significant trend toward reduction. These findings support the hypothesis that the inflammatory response in chronic rhinosinusitis is associated with elevated levels of pro-inflammatory cytokines, and suggest that oral corticosteroids may exert a beneficial effect by significantly reducing the levels of IL-6 and TNF-alpha.