L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition

Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.     

60Co γ照射加深低温保存对大鼠同种带瓣主肺动脉免疫原性的作用

目的 本实验应用60Co γ射线照射加液氮深低温保存大鼠同种带瓣主肺动脉(valvedpulmonary homograft conduits,VPHC),并建立大鼠VPHC颈总动脉移植模型,观察不同照射剂量对同种带瓣主肺动脉免疫原性的作用,寻找合适照射剂量,为进一步基础研究及临床应用提供理论依据.方法 1月龄封闭群Wistar大鼠50只作为供体鼠,雌雄不拘,随机分为单纯深低温保存组(实验对照组)、300 Gy照射组、600 Gy照射组、900 Gy照射组和1200 Gy照射组;成年雄性SD大鼠50只作为受体鼠,随机分为5组;另取10只SD大鼠行颈总动脉切断吻合术,作为空白对照组.应用流式细胞术对VPHC移植术后1周、2周、3周受体鼠外周血行CD4+T细胞及CD8+T细胞检测.结果 照射组VPHC移植术后1周、2周、3周CD4+T细胞、CD8+T细胞百分率及CD4+/CD8+与空白对照组相比差异有统计学意义(P<0.05),与实验对照组相比差异有统计学意义(P<0.05).结论 应用60Co γ对VPHC进行照射在保持VPHC活性的同时明显降低了其免疫原性.     

C反应蛋白和肺功能测定在哮喘患者中的临床意义

目的研究哮喘患者不同时期血清C反应蛋白(CRP)和肺功能测定的临床意义。方法 85例哮喘患者(哮喘组)和23例健康对照者(对照组)为研究对象,测定哮喘组急性发作期、慢性持续期、缓解期及对照组的血清CRP、血常规、肺功能及动脉血气。结果哮喘组急性发作期血清CRP、外周血白细胞计数(WBC)及动脉血二氧化碳分压(p(CO2))均明显高于慢性持续期、缓解期和对照组(P均<0.01);哮喘组急性发作期FEV1%、FEV1/FVC%及动脉血氧分压(p(O2))均明显低于慢性持续期、缓解期和对照组(P均<0.01);哮喘组慢性持续期、缓解期CRP水平均高于对照组(P均<0.05)。病情3,4级哮喘患者慢性持续期FEV1%、FEV1/FVC%较第1,2级明显下降(P<0.05或0.01)。结论血清CRP可作为判断哮喘患者病情的一个炎性反应指标,有助于哮喘的诊断与疗效观察。     

PBEF在体外循环术后肺血管内皮通透性中的机制研究

目的:探讨PBEF在体外循环术后肺血管内皮通透性增加中的机制,为提出更好的体外循环期间肺保护措施提供依据。方法:建立动物模型并进行分组,A组仅行病毒转染;B组仅行30min深低温停循环;C组行病毒转染后,再行30min深低温停循环。应用Western blot检测各组大鼠肺组织。结果:C组的PBEF、磷酸化P38MAPK、磷酸化ERK、磷酸化MLC、磷酸化VE-cadherin、磷酸化FAK表达明显高于A、B组和对照组。结论:PBEF通过P38MAPK、ERK等途径改变内皮细胞和平滑肌细胞中MLC的磷酸化状态,VE-cadherin和FAK也参与了肺血管内皮通透性增加的过程。     

慢性肺原性心脏病中医病因病机探析

中医认为,慢性肺原性心脏病的发病以久病肺虚为主要内因,由于反复感邪而使病情进行性加重,病位在肺,继则影响脾、肾、心。其主要病理基础是痰浊与瘀血交阻为患,痰浊、血瘀既是病理产物又是导致正气不足,外邪与之胶结的致病因素。病机特点为"本虚标实"贯穿疾病的始终。     

Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services

Objectives  Hereditary haemorrhagic telangiectasia (HHT) affects 1 in 5–8000 individuals. Pregnancy outcomes are rarely reported. The major reason is that most women do not have their HHT diagnosed prior to pregnancy. Using a large well-characterised series, we studied all pregnancies known to have occurred in HHT-affected women, whether or not their diagnosis was known at the time of pregnancy. Our aim was to estimate rates and types of major complications of HHT in pregnancy, to guide management decisions.
Design  Cohort study, with prospective, retrospective and familial components.
Setting/Population  Tertiary referral centre population.
Methods  All 262 pregnancies in the 111 women with HHT and pulmonary arteriovenous malformations (PAVMs) reviewed between 1999 and 2005 were studied. Eighty-two women (74%) did not have a diagnosis of HHT/PAVM at the time of pregnancy. 222 pregnancies in their 86 HHT-affected relatives were also studied.
Main outcome measures  PAVM bleed, stroke and maternal death.
Results  Thirteen women experienced life-threatening events during pregnancy: 1.0% (95% CI 0.1–1.9) of pregnancies resulted in a major PAVM bleed; 1.2% (0.3–2.2%) in stroke (not all were HHT related); and 1.0% (0.13–1.9%) in maternal death. All deaths occurred in women previously considered well. In women experiencing a life-threatening event, prior awareness of HHT or PAVM diagnosis was associated with improved survival ( P  = 0.041, Fisher's exact test).
Conclusions  Most HHT pregnancies proceed normally. Rare major complications, and improved survival outcome following prior recognition, means that pregnancy in a woman with HHT should be considered high risk. Recommendations for pregnancy management are provided.     

A case of pulmonary type of ovarian small cell carcinoma

Small cell carcinoma is a rare form of ovarian cancer with a poor prognosis. It is divided into two types, the hypercalcemic and the pulmonary type, of which the latter is extremely rare. A 49-year-old woman presented with an acute abdomen and was suspected to have torsion of a left ovarian tumor, which was followed up with an emergency operation. Postoperative pathological examination gave a diagnosis of the pulmonary type of ovarian small cell carcinoma. Six courses of paclitaxel and carboplatin therapy were given as adjuvant chemotherapy. The patient has survived for 36 months without recurrence. Here we present an extremely rare patient with the pulmonary type of ovarian small cell carcinoma.     

性别对肥胖哮喘患儿吸入糖皮质激素后肺功能的影响

目的研究性别对肥胖哮喘患儿吸入糖皮质激素（ICS）治疗前后肺功能的影响。方法190例哮喘患儿根据性别分为男性 组（102例,正常体质量组/肥胖组57/45）、女性组（88例正常体质量组/肥胖组46/42）,检测所有患儿治疗前及规范化ICS治疗1 年后肺功能,包括第1秒时间肺活量（FEV1）、用力肺活量（FVC）、用力呼气50%流量（MEF50）、用力呼气25%流量（MEF25）。结 果治疗前各组肺功能男女性比较无统计学差异（均P>0.05）。ICS治疗1年后,正常体质量男女性组FVC%、FEV1%较治疗前 均明显升高（P<0.05）;肥胖男性组FVC%、FEV1%较治疗前明显升高（P<0.05）,而肥胖女性组仅FVC%较治疗前升高（P< 0.05）。结论ICS治疗能够改善哮喘大气道通气功能,性别对哮喘ICS治疗大气道通气功能的改善依赖于体质量指数,表现为 性别对正常体质量哮喘患儿ICS治疗影响作用较小,而女性肥胖哮喘患儿肺功能改善程度明显低于男性肥胖哮喘患儿。     

Neural network-based computer-aided diagnosis in distinguishing malignant from benign solitary pulmonary nodules by computed tomography

Background Computer-aided diagnosis (CAD) of lung cancer is the subject of many current researches. Statistical methods and artificial neural networks have been applied to more quantitatively characterize solitary pulmonary nodules (SPNs). In this study, we developed a CAD scheme based on an artificial neural network to distinguish malignant from benign SPNs on thin-section computed tomography (CT) images, and investigated how the CAD scheme can help radiologists with different levels of experience make diagnostic decisions.Methods Two hundred thin-section CT images of SPNs with proven diagnoses (135 small peripheral lung cancers and 65 benign nodules) were analyzed. Three clinical features and nine CT signs of each case were studied by radiologists, and the indices of qualitative diagnosis were quantified. One hundred and forty nodules were selected randomly to form training samples, on which the neural network model was built. The remaining 60 nodules, forming test samples, were presented to 9 radiologists with 3–20 years of clinical experience, accompanied by standard reference images. The radiologists were asked to determine whether a nodule was malignant or benign first without and then with CAD output. Diagnostic performance was evaluated by receiver operating characteristic (ROC) analysis.Results CAD outputs on test samples had higher agreement with pathological diagnoses (Kappa=0.841, P&lt;0.001). Compared with diagnostic results without CAD output, the average area under the ROC curve with CAD output was 0.96 (P&lt;0.001) for junior radiologists, 0.94 (P=0.014) for secondary radiologists and 0.96 (P=0.221) for senior radiologists, respectively. The differences in diagnostic performance with CAD output among the three levels of radiologists were not statistically significant (P=0.584, 0.920 and 0.707, respectively). Conclusions This CAD scheme based on an artificial neural network could improve diagnostic performance and assist radiologists in distinguishing malignant from benign SPNs on thin-section CT images.     

雾化吸入布地奈德与复方异丙托溴铵治疗慢性阻塞性肺疾病的临床分析

目的：研究在慢性阻塞性肺疾病的临床治疗中雾化吸入布地奈德与复方异丙托溴铵的治疗效果。方法整群选取2014年7月—2015年7月在该院接受治疗的慢性阻塞性肺疾病患者70人,将这些病患随机分成两组,治疗组与对照组,每组病患35人,为对照组中的病患提供常规治疗,治疗组中的病患在对照组的基础上雾化吸入布地奈德与复方异丙托溴铵,统计学方法对比分析两组患者的治疗效果。结果治疗7d后,治疗组中病患的治疗总有效率为94.3%,对照组中病患的治疗总有效率为74.3%,治疗组高于对照组,差异有统计学意义(P<0.05),进一步分析显示治疗组脉搏血氧饱和度较对照组明显改善,脉氧改善起效时间明显短于对照组[(4.7±1.2) h vs(8.5±2.1) h]、持续稳定时间明显长于对照组[(23.5±2.8) h vs (16.7±3.2) h],差异均具有统计学意义(P<0.05)。结论在临床治疗慢性阻塞性肺疾病时,雾化吸入布地奈德与复方异丙托溴铵治疗效果良好,可在临床治疗中推广使用。