香草酸受体亚型Ⅰ与降钙素基因相关肽和植物凝集素结合位点在大鼠脊神经节内感觉神经元的共存

目的:研究香草酸受体亚型Ⅰ(VR1)在大鼠脊神经节(DRG)内感觉神经元的表达.及与降钙素基因相关肽(CGRP)、植物凝集素(IB4)结合位点的共存,为探讨VR1在伤害性感觉刺激信号传导中的作用提供形态学依据.方法:应用免疫荧光组织化学三标方法结合激光共聚焦扫描显微镜技术观察VR1与CGRP和IB4结合位点在DRG的分布及相互关系.结果:背根节内可见大量中、小型神经元胞体和神经纤维表达VR1,一群独特的VR1阳性特小神经元胞体(直径8～11 μm)呈荧光强阳性.荧光双标显示背根节内许多VR1阳性神经无与CGRP共存或结合IB4,而CGRP/IB4双标神经元数量稀少.有41.1%±3.2%VR1阳性细胞呈CGRP阳性,有54.9%±3.8%VR1阳性神经元结合IB4.VR1强荧光特小神经元胞体未见CGRP阳性标记或结合IB4.VR1/CGRP/IB4三标神经元数量较少,只有1.5%±1.1% VR1阳性神经元同时呈CGRP阳性并结合IB4.结论:背根节内可能存在VR1/CGRP与VR1/IB4两种不同的与伤害性刺激相关的VR1阳性神经元亚群.     

VR1与CGRP和IB4在大鼠结状神经节和岩神经节内的共存

应用免疫荧光组织化学三标方法结合激光共聚焦显微镜技术研究了辣椒素受体(VR1)在大鼠舌咽神经和迷走神经内脏感觉神经节结状神经节(NG)和岩神经节(PG)内的表达,以及与降钙素基因相关肽(CGRP)、植物凝集素(IB4)的共存。结果显示:VR1在NG和PG内中、小型神经元胞体和神经纤维存在广泛的表达。许多VR1阳性神经元呈IB4阳性或与CGRP共存。在NG,CGRP阳性神经元数量较少,约有71.4%±3.8%VR1阳性神经元与IB4共存,只有7.1%±1.2%VR1阳性细胞与CGRP共存。PG内CGRP阳性神经元胞体数量较多,有55.7%±3.1%VR1阳性神经元与IB4共存;有38.7%±2.7%VR1阳性细胞同时呈CGRP阳性。两个神经节内IB4/CGRP双标神经元或VR1/CGRP/IB4三标神经元数量稀少。上述结果提示舌咽神经和迷走神经内脏感觉神经节内存在VR1/IB4和VR1/CGRP两种不同的与伤害性刺激相关的VR1阳性神经元亚群。     

5-HT1A受体亚型与P物质、Ⅰ型囊泡膜谷氨酸转运体和甘丙肽在大鼠背根神经节神经元中的共表达

为探讨5-HT1A受体亚型参与感觉信息调控的机制,本文利用免疫荧光组织化学双重染色技术观察了该受体亚型与P物质(SP)、I型囊泡膜谷氨酸转运体(VGLUT1)和甘丙肽(Gal)在大鼠背根神经节(DRG)神经元内的共存状况。结果表明:5-HT1A受体亚型阳性神经元占DRG神经元总数的46.2%,阳性神经元以大型及小型神经元为主。在DRG内观察到了5-HT1A/SP、5-HT1A/VGLUT1以及5-HT1A/Gal双标神经元。其中5-HT1A/SP双标神经元占5-HT1A受体亚型阳性神经元的34.6%,占SP阳性神经元的72.0%;5-HT1A/VGLUT1双标神经元占5-HT1A受体亚型阳性神经元的24.1%,占VGLUT1阳性神经元的18.5%;5-HT1A/Gal双标神经元占5-HT1A免疫阳性神经元的17.6%,占Gal免疫阳性神经元的63.8%。5-HT1A/SP和5-HT1A/Gal双标神经元主要为DRG的小型神经元,而5-HT1A/VGLUT1双标神经元主要为大、中型神经元。上述结果提示,5-HT1A受体亚型可能通过调节SP、谷氨酸以及Gal在初级传入终末及外周神经末稍的释放发挥其感觉信息的调节作用。     

小鼠脊神经节内P2X2、P2X3受体与降钙素基因相关肽和植物凝集素结合位点的共存

目的:研究小鼠脊神经节内ATP受体P2X2、P2X3与降钙素基因相关肽(CGRP)、植物凝集素IB4(IB4)结合位点的共存。方法:在成年c57/6小鼠脊神经节,用免疫组织化学荧光三标方法结合激光共聚焦显微镜技术观察。结果:脊神经节内可见大量P2X2、P2X3阳性细胞和纤维;P2X2阳性细胞多为大型和小型神经元,P2X3阳性细胞多为小型神经元;有34.2%±3.9%P2X2阳性细胞含有CGRP;但只有4.6%±1.1%P2X3阳性神经元含有CGRP。许多感觉神经元结合IB4;有62.4%±4.3%P2X2和89.5%±4.1%P2X3阳性神经元分别结合IB4。未观察到P2X2/CGRP/IB4或P2X3/CGRP/IB4三标神经元。结论:小鼠脊神经节内P2X2、P2X3的表达与IB4结合位点之间密切相关,部分P2X2受体与CGRP共存。     

背根神经节内代谢型谷氨酸受体2与酸敏感性离子通道3和辣椒素受体1的共存研究(英文)

代谢型谷氨酸受体(mGluR)2/3在伤害性信息从外周向脊髓传递的过程中发挥着重要作用。以往研究证明在大鼠中mGluR2参与了机械性超敏和热超敏的形成,因此本研究拟采用免疫荧光组织化学染色技术揭示背根节(DRG)中mGluR2和酸敏感性离子通道3(ASIC3),一个多觉机械性感受器,或者和热伤害性感受器辣椒素受体(TRPV1)的共存情况。结果显示:mGluR2主要存在于DRG神经元的胞浆中。计数结果显示DRG中35.85%的神经元呈mGluR2免疫阳性。在这些阳性神经元中,82.61%为小细胞(直径小于30μm);5.79%为中等细胞(直径为30～50μm);11.59%为大细胞(直径大于50μm)。进一步在免疫荧光双重标记切片上可观察到分别有42.45%和79.78%的小型mGluR2阳性神经元同时表达ASIC3或TRPV1免疫阳性。以上结果提示mGluR2主要存在于DRG中的小神经元中,这些神经元通常被认为是外周Aδ-或C-纤维传入的伤害性感觉神经元,在这类神经元中mGluR2与ASIC3或TRPV1均有大量共存,提示这些共存可能与机械性或热超敏的产生或者维持有着重要的联系。     

大鼠咽黏膜内ATP受体P2X3阳性感觉纤维的分布

目的 研究大鼠咽黏膜内三磷酸腺苷(ATP)受体P2X₃阳性感觉纤维的分布,为探究ATP在咽黏膜感觉信号传导中的作用提供形态学依据。 方法 成年Wistar大鼠12只,应用免疫荧光组织化学双标技术结合激光扫描共焦显微镜。 结果 1.在咽黏膜各部位均可观察到P2X₃阳性感觉纤维,纤维分为两类：一类为串珠样游离神经纤维;另一类纤维在黏膜内发出分支并形成复杂的树枝状末梢,纤维分支在黏膜内形成神经丛。2.可见许多降钙素基因相关肽（CGRP）阳性纤维缠绕在P2X₃阳性树枝状末梢周围,并有少量的串珠样P2X₃阳性纤维与CGRP共存。3.在岩神经节内可观察到许多P2X₃或CGRP免疫阳性神经元,其中有少量神经元同时呈P2X₃/CGRP免疫阳性。 结论 大鼠咽黏膜内不同类型的感觉纤维均表达ATP受体P2X₃阳性,提示ATP可能与咽黏膜伤害性刺激和其他生理性刺激向中枢的传递有关。     

蛋白酶激活受体4在内脏高敏感性疼痛调节机制的研究进展

研究发现位于初级感觉神经元的蛋白酶激活受体4(PAR4)是参与外周疼痛和炎症机制的重要调节受体。越来越多的证据显示PAR4活化在内脏高敏感性疼痛的调节中起着重要作用,其机制可能是作用于肥大细胞和感觉神经元TRPV1受体,进而抑制内脏高敏感性疼痛反应,这为内脏痛的治疗提供了新的靶点。本文以肠易激综合征为基础,对PAR4调控肥大细胞和TRPV1介导内脏高敏感机制的研究进展进行了综述。     

5-羟色胺3A受体在成年小鼠海马中间神经元中的分布

目的:利用成年5-HT3AR-BACEGFP转基因小鼠,研究5-羟色胺3A受体(5-HT3AR)在海马中间神经元中的分布情况。方法:成年5-HT3AR-BACEGFP转基因小鼠经心脏灌注固定后,利用免疫荧光双标记方法,并结合激光共焦显微镜扫描技术,观察5-HT3AR在成年5-HT3AR-BACEGFP转基因小鼠海马中不同中间神经元内的表达和分布情况。结果:5-HT3AR在成年小鼠整个海马中都有分布,且主要在CA1区、CA2/CA3区和齿状回有大量5-HT3AR免疫阳性细胞;激光共聚焦显微镜下观察到5-HT3AR阳性产物在细胞核、细胞浆和树突上均有表达;免疫荧光双标实验结果表明5-HT3AR阳性产物在CB(calbindin),CR(calretinin),Reelin,Som(somatostatin),NPY(neuropeptide Y)和VIP(vasoactive intestinal peptide)免疫阳性神经元中表达,但在PV(parvalbumin)免疫阳性神经元中不表达。定量结果显示:几乎所有的VIP阳性神经元均表达5-HT3AR阳性,约3/4的CR阳性神经元表达5-HT3AR,约1/2的CB、Reelin、NPY和Som阳性神经元表达5-HT3AR阳性;约1/4的5-HT3AR阳性神经元中表达Reelin,1/5的表达Som,5-HT3AR/CB和5-HT3AR/CR双标神经元各占5-HT3AR阳性神经元的1/10左右。结论:5-HT3AR-BACEGFP转基因小鼠能够作为研究海马中5-HT3AR功能及其在中间神经元中的作用机制研究的工具鼠。     

小鼠背根神经节慢性压迫引起的痛敏化机制

目的 探讨背根神经节慢性压迫（CCD）引起的低剂量辣椒素诱发痛敏化机制。 方法 将光滑L型钢柱插入小鼠的L4椎间孔，对背根神经节（DRG）造成持续压迫，建立小鼠CCD模型。于CCD术前1 d及术后第1、3、5、7 d向小鼠胫骨前区皮下注射不同浓度的辣椒素（0.01、0.1、1 g/L）10 μl后采用行为学检测动物的痛行为学表现并录像，以寻找CCD术后辣椒素诱发痛行为差异最显著的浓度。利用Pirt-GCaMP3转基因小鼠，胫骨前区皮下注射最佳浓度辣椒素，利用激光扫描共焦显微镜在体记录DRG神经元对外周体表感受野辣椒素刺激的反应。利用免疫荧光染色技术观察正常及CCD模型压迫5 d后DRG内辣椒素受体（TRPV1）的表达变化。 结果 行为学检测结果显示，与正常小鼠相比，低浓度（0.1 g/L）辣椒素在CCD模型小鼠上引起的诱发痛显著提升（n=8; 术后1 d，P<0.01；术后5 d，P<0.05；术后7 d，P<0.05；术后3 d，P> 0.05）。在体激光扫描共焦成像结果表明，在记录的398（n=4）个正常小鼠L4 DRG神经元中，对皮下注射0.1 g/L辣椒素有反应的神经元为75个，在382（n=6）个CCD术后5 d的小鼠L4 DRG神经元中，对皮下注射0.1 g/L辣椒素有反应的神经元为169个，差异有显著性（P<0.01）。免疫荧光染色结果显示，在653（n=10）个正常神经元中，TRPV1阳性的细胞数为148，在611（n=6）个CCD神经元中，TRPV1阳性的细胞数为237，差异有显著性（P<0.01）。 结论 在小鼠CCD模型中，受到压迫DRG神经元TRPV1表达上调，导致相应的体表感受区域对辣椒素诱发痛敏化。     

囊泡膜谷氨酸转运体与ASIC3或TRPV1在大鼠结状神经节内的共存研究(英文)

为了探讨囊泡膜谷氨酸转运体(VGluTS)与酸敏感离子通道亚基3(ASIC3)或瞬时感受器电位香草酸亚型1(TRPV1)样阳性产物在大鼠迷走神经结状神经节(nodoseganglia,NG)内的分布和共存,本研究采用免疫荧光组织化学双重标记技术,在激光共聚焦显微镜下观察了大鼠NG内VGluT1或VGluT2分别与ASIC3或TRPV1的共存情况。结果显示:(1)在NG内,VGluT2、ASIC3和TRPV1主要见于中、小型神经元的胞浆内,大型神经元少见,而VGluT1阳性神经元数量较少,主要见于大型或中型神经元;(2)部分VGluT2阳性神经元同时显示ASIC3或TRPVl免疫活性,其中VGluT2/ASIC3双标神经元分别占VGluT2阳性神经元的43.06%,占ASIC3阳性神经元的58.74%;而VGluT2/TRPVl双标神经元分别占VGluT2或TRPVl阳性神经元的5617%和51.12%;(3)VGluTI与ASIC3或TRPV1双标神经元的数量很少,不到1%。以上结果提示,VGluT2主要存在于NG内中、小型神经元,这些神经元通常被认为是内脏伤害性信息的初级感受神经元,因而VGluT2分别与ASIC3或TRPVl的共存表明它们可能与内脏伤害性信息的产生和传递密切相关。     

Mediators and cytokines in persistent allergic rhinitis and nonallergic rhinitis with eosinophilia syndrome

Background: Patients with nonallergic rhinitis with eosinophilia syndrome (NARES) show typical symptoms of persistent allergic rhinitis (PAR). The aim of the present study was to compare nasal cytokine patterns between NARES and PAR. Methods: Nasal secretions of 31 patients suffering from NARES, 20 patients with PAR to house dust mite and 21 healthy controls were collected using the cotton wool method and analyzed for interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β) by Bio-Plex Cytokine Assay as well as eosinophil cationic protein (ECP) and tryptase by UniCAP-FEIA. Results: NARES and PAR presented elevated levels of tryptase, while ECP was markedly increased solely in NARES compared to both the controls and PAR. Elevated levels of IL-1β, IL-17, IFN-γ, TNF-α and MCP-1 were found in NARES compared to the controls as well as PAR. MIP-1β was elevated in NARES and PAR, while IL-4, IL-6 and G-CSF showed increased levels in NARES, and IL- 5 was elevated in PAR only. Conclusions: In patients with NARES and PAR, eosinophils and mast cells appear to be the pivotal cells of inflammation, reflected by high levels of tryptase and ECP as well as IL-5 and GM-CSF as factors for eosinophil migration and survival. The elevated levels of proinflammatory cytokines in NARES may indicate the chronic, self-perpetuating process of inflammation in NARES which seems to be more pronounced than in PAR. IL-17 might be a factor for neutrophilic infiltration or be responsible for remodeling processes in NARES.     

The role of protease‐activated receptors PAR‐1 and PAR‐2 in the repair of 16HBE 14o− epithelial cell monolayers in vitro

Background We recently reported that repair following mechanical wounding of epithelial cell layers in vitro is dependent on fibrin formation and the activity of locally expressed coagulation cascade proteins. Serine proteases of the coagulation cascade are an important group of protease‐activated receptor (PAR) activators and PAR‐1 to 4 are expressed by the normal bronchial epithelium. Objective We tested the hypothesis that activation of PAR‐1 and PAR‐2 by coagulation cascade proteases stimulates epithelial repair via effects on fibrin formation. Methods Using mechanically wounded 16HBE 14o^? epithelial cell layers in culture, we investigated the effect of PAR‐1 and PAR‐2 agonist peptides, control partially scrambled peptides and PAR‐neutralizing antibodies on the rate of repair and fibrin formation. Coagulation factors in culture supernatants were measured by immunoblot. RT‐PCR was used to investigate PAR‐1, PAR‐2 and PGE2 receptor (EP‐1 to EP‐4) expression in this model and qRT‐PCR to quantify responses to wounding. Additionally, we investigated the effect of exogenously added factor Xa (FXa) and neutrophil elastase and the influence of PGE2 and indomethacin on the repair response. Results PAR‐1 and PAR‐2 peptide agonists stimulated the rate of repair and enhanced the formation of a fibrin provisional matrix to support the repair process. Conversely, PAR‐neutralizing antibodies inhibited repair. Under serum‐free culture conditions, 16HBE 14o^? cells expressed EP‐2 and EP‐3, but not EP‐1 or EP‐4, receptors. Wounding induced an increased expression of EP‐3 but did not alter EP‐2, PAR‐1 or PAR‐2 expression. In the absence of PAR agonists, there was no evidence for a role for PGE2 in fibrin formation or the repair process. Indomethacin attenuated fibrin formation in wounded cultures only in the presence of the PAR‐2 peptide. FXa stimulated epithelial repair while neutrophil elastase reduced the levels of coagulation factors and inhibited repair. Conclusion Locally expressed serine proteases of the coagulation cascade activate PAR‐1 and PAR‐2 to enhance fibrin formation and bronchial epithelial repair. Cite this as: D. Ewen, S.L. Clarke, J.R. Smith, C. Berger, G. Salmon, M. Trevethick and J.K. Shute, Clinical & Experimental Allergy, 2010 (40) 435–449.     

Lysozyme levels in the nasal secretions of patients with perennial allergic rhinitis and recurrent sinusitis.

BACKGROUND: The association of perennial allergic rhinitis (PAR) with recurrent sinusitis (RS) is well recognized. Anatomic abnormalities at the osteomeatal complex or ciliary dysfunction may play a significant role in some patients. However, for most patients with allergy, the determinants of RS are unknown. OBJECTIVE: To determine whether altered concentrations of antimicrobial peptides and proteins, such as lysozyme, lactoferrin, human beta-defensin-2 (HBD-2), and human neutrophil peptides 1 to 3 (HNP-1 to 3), contribute to the development of RS in patients with PAR. METHODS: Nasal secretions were collected by vacuum aspiration from 15 individuals with PAR+RS, 16 with PAR alone, and 16 controls. Lysozyme and lactoferrin levels were determined in nasal secretions by using quantitative enzyme-linked immunosorbent assay, and HBD-2 and HNP-1 to 3 levels were determined in nasal secretions by using semiquantitative Western blot analysis. Eosinophil-derived neurotoxin (EDN) levels were measured by using enzyme-linked immunosorbent assay as a marker of nasal eosinophilia in all 3 groups. RESULTS: Levels of EDN were elevated significantly in patients with PAR+RS compared with controls. Lysozyme levels were decreased significantly in patients with PAR+RS compared with PAR alone or controls. Mean lysozyme levels were significantly lower in patients with EDN levels greater than 1,000 ng/mL vs those with levels of 1,000 ng/mL or less in the PAR+RS group. There were no statistically significant differences in lactoferrin, HBD-2, and HNP-1 to 3 levels among the 3 groups. CONCLUSIONS: The presence of eosinophils and their products and reduced lysozyme concentrations may be critical factors that predispose the airways of patients with PAR to RS.     

Desloratadine therapy for symptoms associated with perennial allergic rhinitis.

BACKGROUND: Perennial allergic rhinitis (PAR) has a substantial negative social and economic impact. Recent studies emphasize the potential seriousness of PAR and the need for improved treatment of this condition. OBJECTIVE: To confirm the efficacy and safety of the H1-antihistamine desloratadine in reducing the symptoms of PAR in a randomized, double-blind, placebo-controlled trial. METHODS: Patients with PAR (N = 1,179) from 67 US/international centers received desloratadine, 5 mg once daily, or identical placebo tablets. The primary efficacy measure was the change from baseline to week 4 in average morning and evening reflective total symptom scores (TSSs). Secondary end points included changes from baseline in total nasal and nonnasal symptom scores and peak nasal inspiratory flow (PNIF) rates. RESULTS: Desloratadine was significantly more effective than placebo in reducing morning and evening reflective TSSs for each week and during weeks 1 through 4 (P = .001). Mean changes in TSSs during the 4-week study were -3.9 (26.6% reduction) and -3.2 (22.3% reduction) for the desloratadine and placebo groups, respectively (P = .001, desloratadine vs placebo). With desloratadine therapy, significant improvements were also seen in secondary efficacy end points compared with placebo use (total nasal and nonnasal symptom scores: P < or = .04). Improvements in mean morning PNIF were significantly greater in the desloratadine-treated group than in the placebo group (P = .03). CONCLUSIONS: These results confirm and extend previous findings that desloratadine is safe and is associated with a statistically significant reduction in nasal and nonnasal symptoms in patients with PAR. Objective nasal airflow, evaluated by PNIF, was statistically significantly improved after desloratadine treatment.     

Association between response to decongestion testing and sensitizations and allergic inflammation.

BACKGROUND: Rhinomanometry is used to measure nasal airflow, which is frequently impaired in allergic rhinitis (AR). Decongestion testing consists of spraying an intranasal vasoconstrictor drug to evaluate recovery of nasal airflow. OBJECTIVE: To evaluate the relationships among type and number of sensitizations, nasal airflow recovery after topical vasoconstrictor drug use, and allergic inflammation. METHODS: A total of 123 patients (112 men and 11 women; mean +/- SD age, 22.9 +/- 5.7 years) were studied: 40 with perennial AR (PAR), 43 with mixed AR (MAR), and 40 with seasonal AR (SAR). Patients with anatomic nasal defects were excluded. Total symptom scores (including nasal itching, sneezing, rhinorrhea, and nasal obstruction), sensitizations, nasal eosinophils, and cytokines (including interleukin 4 [IL-4], IL-5, and interferon-gamma) were evaluated. Electronic rhinomanometry and decongestion testing were performed in all the patients. RESULTS: After administration of a topical nasal vasoconstrictor agent, mean nasal airflow significantly increased from 471 to 580 mL/s (P < .001). In 12 patients (3 with PAR, 3 with MAR, and 6 with SAR), no increase was shown. Changes from baseline were different in the PAR, MAR, and SAR populations (PAR vs MAR, P < .001; PAR vs SAR, P < .001; and MAR vs SAR, P = .25). Type of sensitization (MAR, PAR, or SAR), concentration of eosinophils, and levels of IL-4, IL-5, and interferon-gamma were associated with nasal airflow recovery of at least 120 mL/s. CONCLUSIONS: This study provides the first evidence of a different response to decongestion testing taking into consideration the type of AR.     

Proteinase-activated receptors 1 and 2 in rat olfactory system: layer-specific regulation of multiple signaling pathways in the main olfactory bulb and induction of neurite retraction in olfactory sensory neurons

Proteinase-activated receptors (PARs) are a family of four G protein-coupled receptors that are widely distributed in the CNS and involved in neural cell proliferation, differentiation and survival. The olfactory system undergoes continuous neurogenesis throughout life and may represent a critical target of PAR cellular actions. In the present study we investigated the functional activity of PAR1 and PAR2 in microdissected tissue preparations of olfactory nerve-glomerular layer (ON-GL), external plexiform layer (EPL) and granule cell layer (GRL) of the rat main olfactory bulb and in primary cultures of olfactory neuroepithelial cells. Activation of either PAR1 or PAR2 regulated multiple signaling pathways, including activation of pertussis-toxin sensitive Gi/o proteins, inhibition of cyclic AMP formation, stimulation of Gq/11-mediated phosphoinositide (PI) hydrolysis, phosphorylation of Ca2+/calmodulin-dependent protein kinase II and activation of the monomeric G protein Rho, predominantly in ON-GL, whereas only activation of Rho was detected in the deeper layers. Olfactory nerve lesion by nasal irrigation with ZnSO4 induced a marked decrease of PAR signaling in ON-GL. In primary cultures of olfactory neurons, double immunofluorescence analysis showed the localization of PAR1 and PAR2 in cells positive for olfactory-marker protein and neuron-specific enolase. Cell exposure to either nanomolar concentrations of thrombin and trypsin or PAR-activating peptides caused rapid neurite retraction. This study provides the first characterization of the laminar distribution of PAR1 and PAR2 signaling in rat olfactory bulb, demonstrates the presence of the receptors in olfactory sensory neurons and suggests a role of PARs in olfactory sensory neuron neuritogenesis.     

Levocetirizine is effective for symptom relief including nasal congestion in adolescent and adult (PAR) sensitized to house dust mites

BACKGROUND: Antihistamines are the most commonly prescribed class of medication for perennial allergic rhinitis (PAR). The primary objective of this study was to determine whether levocetirizine (Xyzal(R)), the active enantiomer of cetirizine, could achieve at least a 50% improvement in PAR symptoms compared to the placebo over the first week of treatment. METHODS: A total of 294 patients with PAR due to house dust mites were randomized in this 8-week double-blind, placebo-controlled, multicentre trial to receive either levocetirizine 5 mg/day or placebo. Mean Total Four-Symptom Scores (T4SS) (nasal pruritus, ocular pruritus, rhinorrhoea and sneezing) were compared between treatment groups over weeks 1, 4 and 6. All individual symptom scores, including nasal congestion, were also studied. RESULTS: Levocetirizine showed an 86% improvement in T4SS over the first week of treatment and a 47% improvement over the entire treatment period compared with placebo. Absolute changes from baseline were 3.64 and 2.47 for levocetirizine and placebo, respectively. Individual symptom scores showed statistically significant (P < or = 0.01) differences in favour of levocetirizine for all study time-points. Nasal congestion was unexpectedly significantly improved (P < 0.001). The incidence of reported adverse events was comparable between treatment and placebo group. CONCLUSIONS: Levocetirizine 5 mg/day is an effective and well-tolerated treatment of PAR. In addition, levocetirizine is effective for the relief of nasal congestion.     

The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response

Poly-ADP-ribosylation is a unique post-translational modification participating in many biological processes, such as DNA damage response. Here, we demonstrate that a set of Forkhead-associated (FHA) and BRCA1 C-terminal (BRCT) domains recognizes poly(ADP-ribose) (PAR) both in vitro and in vivo. Among these FHA and BRCT domains, the FHA domains of APTX and PNKP interact with iso-ADP-ribose, the linkage of PAR, whereas the BRCT domains of Ligase4, XRCC1, and NBS1 recognize ADP-ribose, the basic unit of PAR. The interactions between PAR and the FHA or BRCT domains mediate the relocation of these domain-containing proteins to DNA damage sites and facilitate the DNA damage response. Moreover, the interaction between PAR and the NBS1 BRCT domain is important for the early activation of ATM during DNA damage response and ATM-dependent cell cycle checkpoint activation. Taken together, our results demonstrate two novel PAR-binding modules that play important roles in DNA damage response.