幽门螺杆菌毒力蛋白CagA诱导AGS细胞IL-8mRNA表达的研究

目的 研究AGS细胞的白细胞介素8(IL-8)mRNA表达与野生型幽门螺杆菌(H.pylori)和cagA基因突变株感染的关系.方法 采用RT-PCR法检测野生株西方型(WSS-type)H.pylori 26695和东方型(ESS-type)H.pylori HPK5、cagA基因突变株(cagA disrupted mutant strain)26695CA 和HPK5CA,按照细菌与细胞比例( multiplicity of infection,MOI) 150感染AGS 细胞的 IL-8 mRNA 动态(time-course)含量.同步感染试验排除菌株动力(motility)可能影响感染早期IL-8表达水平.结果 H.pylori诱导AGS细胞IL-8 mRNA表达.野生株西方型26695感染AGS细胞3小时后,IL-8 mRNA呈现时间依赖性(time-dependent)升高,持续升高至48小时;野生株东方型HPK5时间依赖性(time-dependent)表现为感染3小时后升高,随后降低,12小时再次出现峰值,随后又降低;突变株26695CA感染3小时后升高,持续至48小时,峰值表现在6小时和12小时;而突变株HPK5CA 感染3小时后未升高,6小时迅速达峰值,随后降低,48小时又出现峰值.结论 虽然cagA基因是诱导细胞表达IL-8 mRNA的重要因子,但并非是唯一因素,其他信号通路也参与IL-8 mRNA表达.     

Relationship of Helicobacter pylori CagA(+) status to gastric juice vitamin C levels

BACKGROUND: To date it is not known whether gastric juice vitamin C levels are influenced by Helicobacter pylori CagA(+) strains. The aim of the present study, therefore, was to study the impact of H. pylori CagA status on gastric juice vitamin C levels. MATERIALS AND METHODS: We studied 30 H. pylori(+) patients, and the results were compared with 10 endoscopically and histologically normal H. pylori(-) subjects (control group) who were similar to the H. pylori(+) group in terms of age and sex. In all patients, gastric juice vitamin C levels were determined and the severity of gastritis was graded on a scale of 0 (absent) to 3 (severe). CagA was determined by immunoblotting the sera from patients against H. pylori antigens. RESULTS: Among 30 H. pylori(+) patients, 20 were CagA(+) and 10 CagA(-). In the entire group of H. pylori(+) patients, the median gastric juice vitamin C levels (mg L-1) were 16.35 (range 3.5-33.6) and were significantly lower (P < 0.001) than in the control group of H. pylori(-) patients [35.5 (23.1-50.2)]. In addition, in the entire group of H. pylori(+) patients there was a highly significant (P < 0.0001) inverse correlation between the gastritis activity score and the gastric juice vitamin C levels. In the group of H. pylori CagA(+) patients, the median levels of gastric juice vitamin C were 13.8 (3.5-31.2) and were significantly lower than the corresponding levels in both the H. pylori CagA(-) group [24.8 (22-33.6), P < 0.01] and the H. pylori(-) control group [35.5 (23.1-50.2), P < 0.001], the last groups being similar. Furthermore, the gastritis activity median score in the H. pylori CagA(+) group [2 (1-3)] was significantly higher (P < 0.05) than in the H. pylori CagA(-) group [1 (1-2)]. CONCLUSION: These data indicate that infection with CagA(+) H. pylori strains significantly lowers the gastric juice vitamin C levels in comparison with CagA(-) H. pylori strains, which might have a significant impact on gastric carcinogenesis.     

Association of CagA-Dositive infection with Helicobacter pylori antibodies of IgA class

cagA gene, the best known virulence factor of Helicobacter pylori, codes for an immunodominant CagA protein. In this study, CagA antibodies of the IgG class were measured by immunoblot or enzyme immunoassay in subjects with positive H. pylori serology, and the presence of CagA antibodies was compared with that of H. pylori antibodies of IgA and IgG classes. Serum samples were available for a total of 1481 subjects, including gastroscopied patients with biopsy-verified H. pylori infection, smoking men with a normal or low serum pepsinogen I level indicating atrophic corpus gastritis, and subjects who later developed gastric cancer and their matched controls. CagA antibodies were significantly more prevalent among individuals with elevated H. pylori antibody titres of the IgA class than in those with IgG antibodies only, with the exception of a small subgroup of individuals who later developed gastric cancer. CagA-positive H. pylori strains seem to induce an immune response with a markedly higher frequency of IgA than what is found in inflammation caused by CagA-negative strains. The presence of serum IgA antibodies to H. pylori seems to indicate a higher risk for CagA-positive H. pylori infection and possibly more severe late sequelae of the disease.     

胃肠道相关疾病患者幽门螺杆菌CagA抗体阳性率分析

目的探讨胃肠道相关疾病患者幽门螺杆菌（HP）感染、CagA抗体检测阳性与所患疾病类型间的关系。方法纳入研究的对象包括本院消化内科住院的320例胃肠道相关疾病患者和同期于本院进行体检的健康体检者200例,共520例。采用蛋白质印迹（WB）法和”C-尿素呼气试验对520例上述人群进行HP感染的检测,采用WB检测CagA抗体,并对检测结果进行比较分析。结果320例患者和200例健康体检者”c-尿素呼气试验阳性率分别为60．9％（195／320）和55％（110／200）,WB检测HP抗体的阳性率分别为68．4％（219／320）和61．0％（122／320）。2种方法检测HP感染的阳性率差异无统计学意义（P〉O．05）;患者和健康体检者HP感染的阳性率差异无统计学意义（P〉0．05）。慢性胃炎、胃及十二指肠溃疡、食管炎、胃癌患者及健康体检者CagA抗体的阳性率分别为43．1％、66．7％、51．3％、70．0％、21．5％;不同胃相关疾病患者CagA抗体阳性率的差异无统计学意义（P〉O．05）;不同胃肠道相关疾病患者CagA抗体阳性率均高于健康体检者（P〈O．05）。结论CagA是HP分泌的重要毒力因子之一,感染的HP大多数为CagA阳性菌株,抗体阳性较阴性者更易放生严重的组织炎症和损伤,同胃肠道相关疾病的发生密切相关。     

CagA+幽门螺杆菌与胃黏膜上皮细胞凋亡的分子研究

目的：观察CagA^ Hp对胃黏膜上皮细胞凋亡的影响，进而探讨CagA^ Hp增加胃癌发生危险性的机制。方法：以TUNEL染色法研究30例CagA^ Hp阳性患者Hp根除前后胃黏膜上皮细胞凋亡的情况；通过免疫组织化学法和RT－PCR检测凋亡相关基因bcl-2和bax的表达。结果：CagA^ Hp阳性患者胃黏膜上皮细胞凋亡指数为13．42％，Hp根除后，胃黏膜上皮细胞凋亡指数降为4．8％，较治疗前明显减少（P＜0．01），而CagA^ Hp仍为阳性患者胃黏膜上皮细胞凋亡指数无明显减少（P＞0．05）；bcl-2蛋白表达阳性的CagA^ Hp阳性患者Hp根除后，胃黏膜上皮细胞bcl-2蛋白表达阳性明显增多（P＜0．01），且胃黏膜上皮细胞bcl-2的mRNA表达明显增强（P＜0．01），而CagA^ Hp仍为阳性患者胃黏膜上皮细胞bcl-2蛋白表达和mRNA表达无明显增强（P＞0．05）；bax蛋白表达阳性的CagA^ Hp阳性患者Hp根除后，胃黏膜上皮细胞bax蛋白表达阳性明显减少（P＜0．01），且胃黏膜上皮细胞bax的mRNA表达明显减少（P＜0．01）；而CagA^ Hp仍为阳性患者胃黏膜上皮细胞bax蛋白表达和mRNA表达无明显减少（P＞0．05）。结论：诱导胃黏膜上皮细胞凋亡是CagA^ Hp参与胃癌发生的机制之一，CagA^ Hp通过下调bcl-2的表达、促进bax的表达诱导胃黏膜上皮细胞凋亡。     

幽门螺杆菌cagA、vacA、iceA基因与儿童结节性胃炎的关系

目的：探讨幽门螺杆菌（HP）cagA、VaCA、iceA基因与儿童结节性胃炎的关系。方法：收集2007年5月-2008年1月行胃镜检查确诊Hp感染的22例结节性胃炎和22例非结节性胃炎患儿的胃粘膜组织,分别用聚合酶链反应（PCR）检测cagA、vacA和iceA基因。病理检查了解胃窦粘膜炎症程度。结果：结节性胃炎组中cagA基因单独检出率为68．2％,VaCAs1／ml单独捡出率为13．6％,vacAs1／m2单独检出率为45．5％,iceA1单独检出率为72．7％,iceA2单独检出率为18．2％．非结节性胃炎组中cagA基因单独检出率为68．2％,vacAs1／ml单独检出率为22．7％,vacAs1／m2单独检出率为27．3％。iceA1单独检出率为63．6％．iceA2单独检出率为22．7％。不同基因型菌株在结节性胃炎和非结节性胃炎中的检出率无统计学意义（P〉0．05）。在轻度、轻一中度、中度慢性结节性胃炎中,cagA型茵株检出率分别为66．7％、50％、75Voo,vacA s1／ml型菌株检出率分别为11．1％、0%、25%,VaCAs1／m2型菌株检出率分别为55．6％、25％、37．5％,iceA1型菌株检出率分别为88．9%、50％、75%．iceA2型菌株在轻度、轻一中度、中度慢性结节性胃炎中的检出率分别为0％、50％、25％,不同基因型菌株与结节性胃炎胃窦粘膜炎症的严重程度无关（P〉0．05）。结论：cagA、vacA、iceA基因与结节性胃炎、胃粘膜的炎症严重程度无关。提示除菌株因素外．宿主因素、环境因素在结节性胃炎的形成过程中可能发挥了重要作用。     

Association between Helicobacter pylori cytotoxic type I CagA-positive strains and migraine with aura

Recent studies have suggested an association between Helicobacter pylori infection and migraine. However, various strains of the bacterium are present, some endowed with greater pathogenicity. In particular, H. pylori type I CagA-positive strains induce a higher release of proinflammatory substances by the gastric mucosa that could trigger systemic vasospasms. The aim of the present study was to assess the prevalence of H. pylori CagA-positive strains in subjects with migraine. One hundred and seventy-five patients affected by migraine (49 with aura, 126 without aura) were consecutively enrolled and matched for sex, age, social background and geographical origin with 152 controls. Helicobacter pylori infection was assessed through 13C-urea breath test. Specific serological IgG against CagA were detected through ELISA. The prevalence of H. pylori infection was similar in migraine patients and in controls (40% vs. 39%, respectively). Among migraine patients, prevalence of infection was not related to presence or absence of aura (45% vs. 37%, respectively). However, among infected subjects, a significantly higher prevalence of CagA-positive strains was observed in patients affected by migraine with aura when compared with those affected by migraine without aura (41% vs. 19%, P < 0.01) and with controls (41% vs. 17%, P < 0.01). CagA-positive H. pylori strains were found to be strongly associated with migraine with aura. A higher inflammatory response of the gastric mucosa to more virulent strains could release substances that may act as triggers of vasospasm in peculiar cerebral arterial districts, probably implicated in the 'aura' phenomenon.     

消化性溃疡患者CagA-Hp感染与血清IL-8、IL-10的相关性研究

目的：探讨消化性溃疡（PU）患者伴有CagA-Hp感染与其血清IL-8、IL-10之间的关系。方法：取H.pylori阳性PU患者100例，其中CagA-Hp抗体阳性患者50例，CagA-Hp抗体阴性患者50例，采用ELISA法分别测定其血清IL-8和IL-10水平。结果：消化性溃疡患者中CagA-Hp抗体阳性组血清IL-8和IL-10显著高于CagA-Hp抗体阴性组。CagA-HpIgG抗体阳性患者中，胃溃疡与十二指肠球溃疡患者血清中IL-8和IL-10水平与溃疡发生的部位无关。     

幽门螺杆菌感染及其毒力因子和胃十二指肠疾病关系的研究

目的 探讨幽门螺杆菌（Hp)感染病人中Hp细胞毒相关蛋白（CagA)、细胞空泡毒素（VacA)抗体在胃十二指肠疾病的比例，并评估不同类型幽门螺杆菌感染对胃窦粘膜炎症程度的影响。方法 应用免疫印迹法测定Hp感染者病人体内的CagA、VacA抗体。结果 73％的Hp感染者病人中出现CagA抗体，61％Hp感染者病人中出现VacA抗体。CagA抗体和VacA抗体在各疾病之间差异无显著性（P＞0．05）。在胃溃疡、十二指肠溃疡和复合性溃疡三类病人中，具CagA和VacA双阳性的比例较CagA和VacA双阴性的比例差异有显著性（P＜0．05）。胃窦萎缩病变在CagA和VacA双阳性的病人中比CagA和VacA双阴性的病人严重（P＜0．05）。结论 具有高毒力因子（CagA和VacA)的Hp是胃肠疾病病人感染的常见菌株，具有CagA和VacA的Hp可能在诱导胃粘膜发展到萎缩病变过程中起重要作用。但不能作为特异性指标来判断胃十二指肠疾病。     

儿童幽门螺杆菌相关性胃十二指肠疾病的三联治疗临床研究

目的分别用以雷尼替丁和胶体枸橼酸铋为主,另外加两种抗生素的2组低剂量短疗程三联疗法治疗儿童幽门螺杆菌(HP)相关性胃炎,评价不同治疗方案的疗效并探讨根除HP感染与胃炎好转的关系。方法HP相关性胃十二指肠疾病患儿55例,随机分为A、B2组,接受三联治疗。A组用胶体枸橼酸铋6～8mg/(kg·d),每日2次;阿莫西林30mg/(kg·d),每日3次;克拉霉素10～15mg/(kg·d),每日2次。B组用雷尼替丁3～5mg/(kg·d),每日睡前服1次;阿莫西林30mg/(kg·d),每日3次;克拉霉素10～15mg/(kg·d),每日2次。2组均治疗2周停药,停药满4周以上行13C尿素呼气试验及血清抗HPIgG抗体检测。结果治疗后HP根除率A组为63.3%,B组为88%(χ2=4.373,P<0.05)。两组患儿腹痛症状缓解时间A组为(5.1±3.0)d,B组为(4.3±3.5)d(P>0.05)。两组副反应均较轻,如腹泻、腹胀、恶心、纳差等胃肠症状,个别患者出现皮疹,均无肝肾、造血系统副作用,且于停药后均很快缓解,未影响治疗。2组血清抗HPIgG抗体阴转情况:A组1个月为56.7%,3个月73.3%,6个月90.0%,12个月96.7%;B组1个月为88%,3个月96.0%,6个月100.0%。结论儿童HP相关性胃炎经根除HP的治疗,可使胃炎好转。以雷尼替丁为主的联合克拉霉素和阿莫西林组成的三联疗法治疗儿童HP相关性胃十二指肠疾病具有疗程短、疗效高、副反应小和HP根除率高等优点。血清抗HPIgG抗体检测可以作为监测HP根除效果的观测指标。     

成人特发性血小板减少性紫癜与幽门螺杆菌CagA蛋白的关系

目的了解成人特发性血小板减少性紫癜(idiopathic thrombocytopenic purpura,ITP)与幽门螺杆菌(helicobacter pylori,Hp)CagA蛋白的关系。方法采用14C尿素呼吸试验对正常成人和ITP患者进行Hp检测后,对Hp阳性的ITP患者进行CagA蛋白抗体检测。依据急性ITP,慢性ITP,难治性ITP对ITP患者进行分类。结果 223例正常患者中123例Hp阳性,感染率为55.2%,而CagA蛋白抗体阳性为42例,占34.1%。278例ITP患者中Hp阳性176例,感染率63.3%,其中CagA蛋白抗体阳性83例,占47.2%,ITP患者的Hp感染率与正常人相似,但CagA蛋白抗体阳性率显著高于正常人(P<0.05)。Hp感染率及CagA蛋白抗体阳性率在急性ITP患者中分别为62.2%和46.4%,慢性ITP为63.2%和47.0%,难治性ITP为64.7%和48.5%,比较显示不同类型的ITP患者Hp感染率及CagA抗体阳性率差异无统计学意义(P>0.05)。结论纳入研究的ITP患者的Hp感染率与正常人相似,但CagA蛋白抗体阳性率明显高于正常人,提示CagA蛋白在成人ITP的发生发展中具有一定作用。进一步分析也显示不同类型的ITP患者Hp感染率及CagA蛋白阳性率差异无统计学意义。     

幽门螺杆菌血清分型与上消化道疾病的关系

目的 探讨幽门螺杆菌(helicobacter pylori,Hp or H.pylori)分型与消化道不同疾病的关系。方法 入选198例Hp阳性的胃镜检查患者，采用免疫印迹法进行Hp的血清学分型，并取胃窦黏膜经HE染色观察胃窦黏膜病理组织学变化。结果 198例患者中检出HpI型菌株173例(87．4％)，Ⅱ型菌株25例(12．6％)。I型较II型Hp感染者胃镜下消化性溃疡、胃癌的比例更高，P=0.012；与胃炎组比较，十二指肠球部溃疡组、胃癌组的I型感染者更高（P值分别为0.026、0.048），而与胃溃疡组无显著差别(P=0.125)。病理组织学改变I型较II型Hp感染者的结果更为严重（P=0.038）。结论 临床上消化道疾病患者Hp感染以I型菌株最为多见。Hp感染的分型诊断有助于对胃、十二指肠疾病类型及病情的判断，I型菌株感染者需要更为积极的治疗。     

Phospholipase C activity of Helicobacter pylori is not associated with the presence of the cagA gene

BACKGROUND: Knowledge about the possible role of phospholipase C (PLC) activity of microbial pathogens in the development of disease is increasing. Recently attention has focused on investigating PLC activity elaborated by Helicobacter pylori, but the role of this enzyme in H. pylori pathogenesis is still unknown. The aim of this study was to correlate PLC-activity of H. pylori on the basis of the cagA status with the clinical diagnosis of the patients. MATERIALS AND METHODS: Helicobacter pylori was isolated from patients with gastritis (G; n = 38), duodenal ulcer (DU; n = 15), gastric ulcer (GU; n = 11) and gastric cancer (GC; n = 12). Polymerase chain reaction primers DZ3/R009 which amplified a 1350-bp fragment were used to detect the cagA gene. PLC activity was determined using p-nitrophenylphosphorylcholine as substrate. RESULTS: Of the strains, 60% were cagA(+) and 40% were cagA(-). All strains showed PLC activity (2.20 +/- 0.91 U mg(-1) protein). PLC activity showed no association with the cagA status: cagA(+) (2.21 +/- 1.03 U mg(-1) protein), cagA(-) (2.18 +/- 0.79 U mg(-1) protein). Patients with GU had the highest PLC activity (2.77 +/- 1.26 U mg(-1) protein) and patients with GC had the lowest activity (1.8 +/- 0.57 U mg(-1) protein). CONCLUSIONS: Although PLC activity was present in all strains tested, it may only have pathological importance in patients with GU. However, the extent of PLC activity was independent of the presence of the cagA gene.     

幽门螺旋杆菌中CagA、VacA毒素与糜烂性胃炎的关系及其临床应用价值

目的 探讨血清幽门螺旋杆菌中细胞毒素(CagA)、空泡毒素(VacA)与糜烂性胃炎的危险因素关系及其临床应用价值.方法 选取2020年1-12月于该院治疗的56例糜烂性胃炎患者作为糜烂性胃炎组,54例慢性胃炎患者作为慢性胃炎组,另选同期体检健康者60例作为健康对照组.运用免疫印迹法对幽门螺旋杆菌(HP)进行抗体分型检测...     

Detection and evaluation of salivary antibodies to Helicobacter pylori in dyspeptic patients

Helicobacter pylori infection is one of the most prevalent infections in humans. The high prevalence and the association with peptic ulceration and gastric cancer require simple and non-invasive methods for the diagnosis of the infection. Detection of salivary anti-H. pylori IgG antibodies has advantages compared with those on serum. In this study, salivary immunoglobulin G response to H. pylori was evaluated in 100 consecutive dyspeptic patients by enzyme-linked immunosorbent assay (ELISA), in comparison with culture and histopathologic examination of gastric biopsy specimens obtained at endoscopic procedures and assessed the accuracy of salivary diagnosis of the infection. The overall sensitivity and specificity of the test were 87 and 73%, respectively. These results suggest that saliva testing for H. pylori antibodies could be used reliably for screening dyspeptic patients in general practice, especially in children in whom venesection is more difficult.     

Analysis of serum gastrin-17 and Helicobacter pylori antibody in healthy Chinese population

BackgroundGastrin‐17 (G‐17) and Helicobacter pylori (H pylori) antibody are widely used in the screening of gastric diseases, especially in gastric cancer. In this study, we aimed to evaluate the value of G‐17 and H pylori antibody in gastric disease screening.MethodsHealthy males and females (1368 and 1212, respectively) aged between 21‐80 years were recruited for the study. Serum G‐17 value was measured using ELISA, and H pylori antibodies were measured using Western blotting. Statistical analyses were performed using the chi‐square, Mann‐Whitney U, and Kruskal‐Wallis H tests.ResultsSerum G‐17 level was higher in the H pylori‐positive group than in the negative group. Serum G‐17 level was higher in the type 1 H pylori‐positive group than in the type 2 H pylori‐positive group. Further, serum G‐17 level was higher in females than in males and showed significant differences among different age‐groups, with changes in trend proportional to the age. The positive rate of H pylori infection in all the subjects was 58.29% and did not show a significant difference between males and females. However, it showed significant differences among different age‐groups, with the changing trend proportional to the age.ConclusionAnalysis of serum G‐17 level and H pylori antibody typing is valuable in gastric disease screening. Every laboratory should establish its own reference interval for G‐17 level.     

血清特异性免疫复合物在幽门螺杆菌感染诊断中的意义

目的:建立一种血清幽门螺杆菌(Helicobacterpylori,Hp)特异性免疫复合物的检测方法,并评价其在Hp感染诊断中的作用。方法:利用抗Hp单克隆抗体捕获Hp特异性免疫复合物,再用酶标羊抗人免疫球蛋白对其进行检测,并对其特异性和敏感性进行分析,同时与临床常用的血清特异性抗体检测、快速尿素酶试验、涂片镜检、14C尿素呼气试验和细菌培养5种方法进行了比较,并对药物根除效果进行了评价。结果:血清可溶性Hp抗原检测方法敏感性和特异性分别为86.0%和96.0%,此方法明显优于血清特异性抗体检测、快速尿素酶试验、涂片镜检和细菌培养,与14C尿素呼气试验差异无显著性,药物治疗前后血清Hp特异性免疫复合物含量差异无显著性。结论:血清Hp特异性免疫复合物检测方法是一种简便、高敏感性和特异性的检测Hp感染的方法,但不能用于Hp感染药物根除效果的评价。     

快速免疫色层法-库力斯伯法测定血清幽门螺杆菌抗体(附167例检测结果)

目的 :研究快速免疫色层法—库力斯伯法 (Flex Pack TMHp)试验对中国人血清幽门螺杆菌 (Hp)抗体测定的临床价值。方法 :用库力斯伯法测定 167例上消化道症状患者血清中的 Hp抗体 ,并与组织学检查对照。结果 :库力斯伯法测定的敏感度为 94 .68% ;特异度为 89.0 4 % ;阳性预告值为91.75 % ;阴性预告值为 92 .86% ;与组织学检查的符合度为 92 .2 2 %。结论 :库力斯伯法测定准确、快速 (4分钟 )、简便、无需专门的仪器或设备 ,可应用于临床及 Hp感染的流行病学调查。     

扬州地区不同人群幽门螺杆菌感染现状分析

目的了解扬州地区不同人群中幽门螺杆菌(Hp)感染情况及临床分布特点。方法选取该院的门诊、住院患者及体检者共2 917例,利用Hp尿素酶抗体检测试剂盒(胶体金法)快速检测三类人群的Hp感染情况,并对结果进行统计学分析。结果 2 917例受试者Hp总体检出率为32.9%(959/2 917),门诊、住院患者及体检人群的Hp检出率分别是33.1%、34.5%和30.0%且男女性别间比较差异均无统计学意义(P0.05);总体来看,Hp的检出率随受检者年龄的增加而增高。未成年组(少年及儿童)Hp检出率最低,为16.0%(285/1 529);青壮年人群居中,Hp检出率为34.0%(221/650);中老年人群Hp检出率最高,为61.38%(453/758)。研究发现,59.8%的消化道疾病患者Hp检测阳性,其中以消化性溃疡(74.4%)和胃癌(70.6%)的Hp检出率最高,部分血液病、心脑血管病患者及其他疾病患者也有较高Hp的检出率。结论扬州地区Hp感染分布随年龄增加而增高,与性别无关。消化道疾病(尤其消化性溃疡与胃癌)患者存在高Hp感染率,其他疾病与Hp关系不可忽略并有待进一步探索。