慢性侵袭性真菌性鼻-鼻窦炎的诊治现状

慢性侵袭性真菌性鼻-鼻窦炎因早期缺乏典型临床症状和特异性影像学特征,被认为是真菌性鼻-鼻窦炎中比较少见的类型。该文就慢性侵袭性真菌性鼻-鼻窦炎的病因、诊断和治疗现状进行综述。     

真菌性鼻-鼻窦炎的研究现状

<正>真菌性鼻-鼻窦炎是鼻科临床常见疾病。近年来,真菌性鼻-鼻窦炎的发病率显著上升,可能与抗生素的广泛使用和环境污染相关,也可能与体检工作的普遍展开、影像学的不断发展使真菌性鼻-鼻窦炎的诊断率提高有关。这种疾病严重损害患者的生活质量,造成巨大的经济损失,应引起重视。1病因关于真菌性鼻-鼻窦炎的病因和发病机制尚没有明确的定论。到目前为止研究表明真菌侵犯鼻腔组织是诱发因素之一,真菌性鼻-鼻窦炎常见的致病菌主要是曲霉,占70%以上^[1],其他有白念珠菌、镰刀菌属、弯孢属、毛霉属和申克孢子丝菌等。     

真菌性鼻鼻窦炎发病相关因素及临床特征分析

目的:探究影响真菌性鼻鼻窦炎发病的有关因素,并分析其临床特征。方法:选取在我院就诊的150例真菌性鼻鼻窦炎患者及150例慢性鼻鼻窦炎患者,回顾性分析2组患者的临床资料,将两者进行对照研究,通过多因素Logistic回归分析和检验的方法,对患者的术前资料进行分析,进而探讨影响真菌性鼻鼻窦炎发病的因素及其临床特征。通过真菌特异性六胺银染色的方法,对150例真菌性鼻鼻窦炎患者进行分型。结果:以年龄(x_1)、病程(x_2)、涕血(x_3)、头痛(x_4)、单侧或双侧病变(x_5)和钙化斑(x_6)为变量,获得了真菌性鼻鼻窦炎发病的Logistic回归预测方程:y=-8.714+1.201 x_1+0.497 x_2+4.576 x_3+1.188 x_4+2.697x_5+4.118 x_6,P=exp(y)/[1+exp(y)]。与慢性鼻鼻窦炎的发病情况对比,发现真菌性鼻鼻窦炎的发生多位女性患者,年龄在40岁以上,病程在3年以内,主要症状为头痛和涕血,影像学检查有单侧病变,且有钙化斑出现(P0.05)。在150例真菌性鼻鼻窦炎患者中,慢性侵袭性46例,非侵袭性104例。结论:真菌性鼻鼻窦炎的发病可以通过其相关因素的Logistic回归预测方程进行预测,其临床表现有明显的特征性。     

地址变更通知

目的：通过对38例真菌性鼻窦炎的诊断、治疗过程的分析,提示本病的临床特点及治疗方法。方法：回顾分析1992年～2002年收治的38例真菌性鼻窦炎的临床资料。结果：38例中,8例采用传统Caldwell-lue手术、30例采用鼻内镜手术．术后病理证实为曲霉菌感染,术后随访2～3个月,术腔黏膜光滑,窦口引流通畅,无复发。结论：真菌性鼻窦炎近年来有增多趋势,有时与恶性肿瘤、慢性鼻窦炎难以鉴别。CT扫描有特征性改变,具有重要诊断价值.鼻内镜手术损伤小,保留功能,正逐渐替代传统手术。     

真菌性鼻窦炎38例临床分析

目的:通过对38例真菌性鼻窦炎的诊断、治疗过程的分析,提示本病的临床特点及治疗方法.方法:回顾分析1992年～2002年收治的38例真菌性鼻窦炎的临床资料.结果:38例中,8例采用传统Caldwell-lue手术、30例采用鼻内镜手术.术后病理证实为曲霉菌感染,术后随访2～3个月,术腔黏膜光滑,窦口引流通畅,无复发.结论:真菌性鼻窦炎近年来有增多趋势,有时与恶性肿瘤、慢性鼻窦炎难以鉴别.CT扫描有特征性改变,具有重要诊断价值.鼻内镜手术损伤小,保留功能,正逐渐替代传统手术.     

真菌性鼻-鼻窦炎的CT影像诊断分析

目的分析真菌性鼻-鼻窦炎的CT影像学特征,并结合临床症状,以提高对其诊断水平。方法收集我院2014～2019年期间经鼻内窥镜手术治疗的84例真菌性鼻-鼻窦炎患者作为研究对象,结合临床症状及主客观评分之间的相关性,回顾性分析经手术、病理证实患者的影像学特征。结果研究对象的影像学特点表现为:本病病灶多发生在上颌窦,且大多数病例累及2个或以上鼻窦;多数为单侧发病,双侧发病的病例较少见;窦腔内均表现为密度不均的软组织影,大多数病变窦腔内可见高密度钙化影,其CT值平均范围71～494 Hu之间;多数腔内可见轻度、局限的窦壁增厚或骨质破坏,仅1例研究对象骨质破坏范围累及颅内;84例真菌性鼻-鼻窦炎患者VAS评分为(8.75±3.51)分,Lund-Mackay评分为(6.27±3.51)分,Lund-Mackay评分与VAS评分呈显著相关(r=0.76,P0.01)。结论鼻窦腔内病灶中的高密度钙化影是真菌性鼻-鼻窦炎的影像学典型特征,影像学表现的严重程度及受累范围与患者的症状程度存在关联,有助于围手术期的综合评估,以提高患者的治愈率及生活质量。     

非侵袭性真菌性鼻窦炎的实验室诊断及致病菌分析

目的探讨非侵袭性真菌性鼻窦炎的实验室诊断方法,分析其致病菌,为鼻窦炎合并真菌感染的临床诊断、治疗提供依据。方法对我院临床及鼻内镜下所诊断的10例真菌性鼻窦炎患者,鼻内镜手术时直接吸取病变的鼻窦黏膜及窦腔内容物,通过直接镜检、真菌培养、传统鉴定及分子生物学鉴定和组织病理学检查对其进行检查。结果 10例病例中,直接镜检阳性者8例;病理学检查可见真菌菌丝或者孢子者8例;接种培养及基因鉴定阳性者5例(感染菌株包括2例烟曲霉复合体、1例杂色曲霉、1例枝孢样枝孢霉、1例帚霉)。不同方法检测出的阳性病例并非完全重叠。结论真菌镜检、真菌培养、真菌分子生物学鉴定、组织病理学检查在诊断真菌感染时可以互补,有助于明确诊断及发现新菌株。     

鼻内镜手术联合咪康唑鼻窦内灌注治疗非侵袭性真菌性鼻窦炎的疗效观察

目的探讨鼻内镜手术联合咪康唑鼻窦内灌注治疗非侵袭性真菌性鼻窦炎的疗效。方法选取住院治疗的非侵袭性真菌性鼻窦炎患者68例,随机将其分为观察组和对照组,每组34例。对照组患者采用鼻内镜手术治疗非侵袭性真菌性鼻窦炎,观察组患者在对照组治疗基础上予以咪康唑鼻窦内灌注。观察并记录两组患者治疗1个月后的临床疗效及药物不良反应,并比较治疗后随访半年与1年复发率。结果治疗1个月后,观察组患者临床总有效率明显高于对照组(χ2=4.22,P0.05)。观察组治疗中有2例患者出现不良反应,症状较轻。治疗后随访半年与1年,观察组患者的复发率分别为3.13%和9.38%,均明显低于对照组的26.92%和34.62%(χ2=4.98或5.57,P0.05)。结论鼻内镜手术联合咪康唑鼻窦内灌注治疗非侵袭性真菌性鼻窦炎的疗效明显优于单纯的鼻内镜手术治疗,安全性较好,且其中远期疗效较好,能减少其术后复发,具有预防其病情复发作用。     

21例变应性真菌性鼻窦炎临床分析

目的探讨变应性真菌性鼻窦炎的诊断以及治疗方法。方法通过临床表现、皮肤激发试验、血清嗜酸性粒细胞、鼻腔真菌涂片、鼻窦CT、鼻内窥镜等专科检查,明确21例变应性真菌性鼻窦炎患者,给予丙酸氟替卡松鼻喷剂喷鼻、151服氯雷他定片10mg（1次／d）、生理海水鼻腔冲洗1～2次／d,治疗1周后,入院行鼻内窥镜鼻息肉切除鼻窦Fess手术,术中彻底清除病变鼻窦内真菌团块或褐色泥砂样真菌泥后,氟康唑氯化钠注射液冲洗窦腔,术后氟康唑氯化钠注射液冲洗清洁术腔,每周1～2次,连续1个月,鼻腔局部继用糖皮质激素3—6个月,获得良好的治疗效果。结果21例变应性真菌性鼻窦炎患者中,单侧鼻窦发病16例,占76．2％,双侧鼻窦发病5例,占23．8％,上颌窦发病16例,占76．2％,上颌窦合并筛窦发病4例,占19．0％,蝶窦发病1例,占4．8％,伴鼻息肉15例,占71．4％,伴有哮喘史8例,占38．1％,术后2例复发,占9．5％。结论变应性真菌性鼻窦炎临床诊断并不困难,治疗以手术为主,但术前糖皮质激素的应用,手术时机选择,术后对鼻腔与鼻窦变应反应的处理,将直接影响预后。     

5例真菌性鼻窦炎临床及实验研究

目的报道5例丝状真菌所致真菌性鼻窦炎病例。方法分析5例鼻窦炎患者临床资料,对患者鼻分泌物或鼻黏膜进行真菌直接镜检和培养,对培养获得菌株进行形态学和分子生物学鉴定。结果结合真菌直接镜检、培养和分子生物学方法,确定致病真菌为茄病镰刀菌、烟曲霉、黄曲霉、波氏假阿利什霉和萝卜镰刀菌。4例患者采用鼻内窥镜手术治疗,1例患者采用伏立康唑、两性霉素B控制病情,效果均良好。结论真菌性鼻窦炎致病真菌多样,分子生物学可做准确鉴定,鼻内镜手术治疗效果良好。     

Fibroblast growth factor receptor 1 (FGFR1) tyrosine phosphorylation regulates binding of FGFR substrate 2alpha (FRS2alpha) but not FRS2 to the receptor

Binding of the fibroblast growth factor (FGF) to the FGF receptor (FGFR) tyrosine kinase leads to receptor tyrosine autophosphorylation as well as phosphorylation of multiple downstream signaling molecules that are recruited to the receptor either by direct binding or through adaptor proteins. The FGFR substrate 2 (FRS2) family consists of two members, FRS2alpha and FRS2beta, and has been shown to recruit multiple signaling molecules, including Grb2 and Shp2, to FGFR1. To better understand how FRS2 interacted with FGFR1, in vivo binding assays with coexpressed FGFR1 and FRS2 recombinant proteins in mammalian cells were carried out. The results showed that the interaction of full-length FRS2alpha, but not FRS2beta, with FGFR1 was enhanced by activation of the receptor kinase. The truncated FRS2alpha mutant that was comprised only of the phosphotyrosine-binding domain (PTB) bound FGFR1 constitutively, suggesting that the C-terminal sequence downstream the PTB domain inhibited the PTB-FGFR1 binding. Inactivation of the FGFR1 kinase and substitutions of tyrosine phosphorylation sites of FGFR1, but not FRS2alpha, reduced binding of FGFR1 with FRS2alpha. The results suggest that although the tyrosine autophosphorylation sites of FGFR1 did not constitute the binding sites for FRS2alpha, phosphorylation of these residues was essential for optimal interaction with FRS2alpha. In addition, it was demonstrated that the Grb2-binding sites of FRS2alpha are essential for mediating signals of FGFR1 to activate the FiRE enhancer of the mouse syndecan 1 gene. The results, for the first time, demonstrate the specific signals mediated by the Grb2-binding sites and further our understanding of FGF signal transmission at the adaptor level.     

Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade

The receptor tyrosine kinase RET functions as the signal transducing receptor for the GDNF (for "glial cell-derived neurotrophic factors") family of ligands. Mutations in the RET gene were implicated in Hirschsprung disease (HSCR), multiple endocrine neoplasia type 2 (MEN 2), and thyroid carcinomas. In this report we demonstrate that the docking protein FRS2 is tyrosine phosphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET. Complex formation between RET and FRS2 is mediated by binding of the phosphotyrosine-binding domain of FRS2 to pY1062, a residue in RET that also functions as a binding site for Shc. However, overexpression of FRS2 but not Shc potentiates mitogen-activated protein (MAP) kinase activation by RET oncoproteins. We demonstrate that oncogenic RET-PTC proteins are associated with FRS2 constitutively, leading to tyrosine phosphorylation of FRS2, MAP kinase stimulation, and cell proliferation. However, loss-of-function HSCR-associated RET mutants exhibit impaired FRS2 binding and reduced MAP kinase activation. These experiments demonstrate that FRS2 couples both ligand-regulated and oncogenic forms of RET, with the MAP kinase signaling cascade as part of the response of RET under normal biological conditions and pathological conditions, such as MEN 2 and papillary thyroid carcinomas.     

Developmental expression patterns of the signaling adapters FRS-2 and FRS-3 during early embryogenesis

Two fibroblast growth factor (FGF) receptor substrates (FRS2 and FRS3) are involved in downstream signaling from activated FGF receptors and neurotrophin-activated Trk receptors. Despite the importance of signaling from these factors in embryogenesis, FRS2 and FRS3 expression patterns during development are unknown. In this study we characterize the expression of FRS2 and FRS3 from E7 to parturition and in adult murine tissues. Both are first detected in whole E8.5 CD1 mouse embryos. FRS2 is detected as early as E7 in the developing syncytiotrophoblast, later in the neural tube (NT) and in many adult and fetal tissues. FRS3 is more restricted in location than FRS2 (fetal NT, heart, stomach, liver and some adult tissues), and is expressed predominantly in the ventricular layer of the developing NT and brains of murine embryos.     

Association of atypical protein kinase C isotypes with the docker protein FRS2 in fibroblast growth factor signaling.

FRS2 is a docker protein that recruits signaling proteins to the plasma membrane in fibroblast growth factor signal transduction. We report here that FRS2 was associated with PKC lambda when Swiss 3T3 cells were stimulated with basic fibroblast growth factor. PKC zeta, the other member of the atypical PKC subfamily, could also bind FRS2. The association between FRS2 and PKC lambda is likely to be direct as shown by yeast two-hybrid analysis. The C-terminal fragments of FRS2 (amino acid residues 300-508) and SNT2 (amino acids 281-492), an isoform bearing 50% identity to FRS2, interacted with PKC lambda at a region (amino acids 240-562) that encompasses the catalytic domain. In vitro kinase assays revealed neither FRS2 nor SNT2 was a substrate of PKC lambda or zeta. Mutation of the alanine residue (Ala-120) to glutamate in the pseudo-substrate region of PKC lambda results in a constitutively active kinase that exhibited more than 2-fold greater binding to FRS2 in vitro than its "closed" wild-type counterpart. Tyrosine phosphorylation of FRS2 did not affect its binding to the constitutively active PKC lambda mutant, suggesting that the activation of PKC lambda is necessary and sufficient for its association with FRS2. It is likely that FRS2 serves as an anchoring protein for targeting activated atypical PKCs to the cell plasma membrane in signaling pathways.     

Molecular networks in FGF signaling: flotillin-1 and cbl-associated protein compete for the binding to fibroblast growth factor receptor substrate 2

Fibroblast growth factor receptor substrate 2 (FRS2α) is a signaling adaptor protein that regulates downstream signaling of many receptor tyrosine kinases. During signal transduction, FRS2 can be both tyrosine and threonine phosphorylated and forms signaling complexes with other adaptor proteins and tyrosine phosphatases. We have here identified flotillin-1 and the cbl-associated protein/ponsin (CAP) as novel interaction partners of FRS2. Flotillin-1 binds to the phosphotyrosine binding domain (PTB) of FRS2 and competes for the binding with the fibroblast growth factor receptor. Flotillin-1 knockdown results in increased Tyr phosphorylation of FRS2, in line with the inhibition of ERK activity in the absence of flotillin-1. CAP directly interacts with FRS2 by means of its sorbin homology (SoHo) domain, which has previously been shown to interact with flotillin-1. In addition, the third SH3 domain in CAP binds to FRS2. Due to the overlapping binding domains, CAP and flotillin-1 appear to compete for the binding to FRS2. Thus, our results reveal a novel signaling network containing FRS2, CAP and flotillin-1, whose successive interactions are most likely required to regulate receptor tyrosine kinase signaling, especially the mitogen activated protein kinase pathway.     

Structural insights into FRS2α PTB domain recognition by neurotrophin receptor TrkB

The fibroblast growth factor receptor (FGFR) substrate 2 (FRS2) family proteins function as scaffolding adapters for receptor tyrosine kinases (RTKs). The FRS2α proteins interact with RTKs through the phosphotyrosine‐binding (PTB) domain and transfer signals from the activated receptors to downstream effector proteins. Here, we report the nuclear magnetic resonance structure of the FRS2α PTB domain bound to phosphorylated TrkB. The structure reveals that the FRS2α‐PTB domain is comprised of two distinct but adjacent pockets for its mutually exclusive interaction with either nonphosphorylated juxtamembrane region of the FGFR, or tyrosine phosphorylated peptides TrkA and TrkB. The new structural insights suggest rational design of selective small molecules through targeting of the two conjunct pockets in the FRS2α PTB domain. Proteins 2014; 82:1534–1541. © 2014 Wiley Periodicals, Inc.     

猴运动前区皮层神经元在顺序行为中的放电活动

本工作猴运动前区（ＰＭ）皮层神经元在视觉图表引导的有序运动行为中的放电活动,并在与记忆信息完成的空间顺序行为（ＭＳＳ）中的活动作了比较。为为训练三只猴同时学会ＦＲＳ和ＭＳＳ任务。对１１１个神经元的统计分析表明,它们在ＦＲＭＳ和ＭＳＳ暗示期中发生放电频率变化的均有一半以上。反应期里有放电频率变化的比例也很高;图形期里,ＦＲＳ中的比例比ＭＳＳ中的高出很多。它们对不同运动顺序呈现明显的选择性。对在动物完     

The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) and other neurotrophins induce a unique prolonged activation of mitogen-activated protein kinase (MAPK) compared with growth factors. Characterization and kinetic and spatial modeling of the signaling pathways underlying this prolonged MAPK activation by BDNF will be important in understanding the physiological role of BDNF in many complex systems in the nervous system. In addition to Shc, fibroblast growth factor receptor substrate 2 (FRS2) is required for the BDNF-induced activation of MAPK. BDNF induces phosphorylation of FRS2. However, BDNF does not induce phosphorylation of FRS2 in cells expressing a deletion mutant of TrkB (TrkBDeltaPTB) missing the juxtamembrane NPXY motif. This motif is the binding site for SHC. NPXY is the consensus sequence for phosphotyrosine binding (PTB) domains, and notably, FRS2 and SHC contain PTB domains. This NPXY motif, which contains tyrosine 484 of TrkB, is therefore the binding site for both FRS2 and SHC. Moreover, the proline containing region (VIENP) of the NPXY motif is also required for FRS2 and SHC phosphorylation, which indicates this region is an important component of FRS2 and SHC recognition by TrkB. Previously, we had found that the phosphorylation of FRS2 induces association of FRS2 and growth factor receptor binding protein 2 (Grb2). Now, we have intriguing data that indicates BDNF induces association of the SH2 domain containing protein tyrosine phosphatase, Shp2, with FRS2. Moreover, the PTB association motif of TrkB containing tyrosine 484 is required for the BDNF-induced association of Shp2 with FRS2 and the phosphorylation of Shp2. These results imply that FRS2 and Shp2 are in a BDNF signaling pathway. Shp2 is required for complete MAPK activation by BDNF, as expression of a dominant negative Shp2 in cells attenuates BDNF-induced activation of MAPK. Moreover, expression of a dominant negative Shp2 attenuates Ras activation showing that the protein tyrosine phosphatase is required for complete activation of MAPKs by BDNF. In conclusion, Shp2 regulates BDNF signaling through the MAPK pathway by regulating either Ras directly or alternatively, by signaling components upstream of Ras. Characterization of MAPK signaling controlled by BDNF is likely to be required to understand the complex physiological role of BDNF in neuronal systems ranging from the regulation of neuronal growth and survival to the regulation of synapses.     

FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors

The docking protein FRS2 was implicated in the transmission of extracellular signals from the fibroblast growth factor (FGF) or nerve growth factor (NGF) receptors to the Ras/mitogen-activated protein kinase signaling cascade. The two members of the FRS2 family, FRS2alpha and FRS2beta, are structurally very similar. Each is composed of an N-terminal myristylation signal, a phosphotyrosine-binding (PTB) domain, and a C-terminal tail containing multiple binding sites for the SH2 domains of the adapter protein Grb2 and the protein tyrosine phosphatase Shp2. Here we show that the PTB domains of both the alpha and beta isoforms of FRS2 bind directly to the FGF or NGF receptors. The PTB domains of the FRS2 proteins bind to a highly conserved sequence in the juxtamembrane region of FGFR1. While FGFR1 interacts with FRS2 constitutively, independent of ligand stimulation and tyrosine phosphorylation, NGF receptor (TrkA) binding to FRS2 is strongly dependent on receptor activation. Complex formation with TrkA is dependent on phosphorylation of Y490, a canonical PTB domain binding site that also functions as a binding site for Shc (NPXpY). Using deletion and alanine scanning mutagenesis as well as peptide competition assays, we demonstrate that the PTB domains of the FRS2 proteins specifically recognize two different primary structures in two different receptors in a phosphorylation-dependent or -independent manner. In addition, NGF-induced tyrosine phosphorylation of FRS2alpha is diminished in cells that overexpress a kinase-inactive mutant of FGFR1. This experiment suggests that FGFR1 may regulate signaling via NGF receptors by sequestering a common key element which both receptors utilize for transmitting their signals. The multiple interactions mediated by FRS2 appear to play an important role in target selection and in defining the specificity of several families of receptor tyrosine kinases.