Elevated Peptides in Lung Lavage Fluid Associated with Bronchiolitis Obliterans Syndrome

Objective

The objective of this discovery-level investigation was to use mass spectrometry to identify low mass compounds in bronchoalveolar lavage fluid from lung transplant recipients that associate with bronchiolitis obliterans syndrome.

Experimental Design

Bronchoalveolar lavage fluid samples from lung transplant recipients were evaluated for small molecules using ESI-TOF mass spectrometry and correlated to the development of bronchiolitis obliterans syndrome. Peptides associated with samples from persons with bronchiolitis obliterans syndrome and controls were identified separately by MS/MS analysis.

Results

The average bronchoalveolar lavage fluid MS spectrum profile of individuals that developed bronchiolitis obliterans syndrome differed greatly compared to controls. Controls demonstrated close inter-sample correlation (R = 0.97+/−0.02, average+/−SD) while bronchiolitis obliterans syndrome showed greater heterogeneity (R = 0.86+/−0.09, average+/−SD). We identified 89 features that were predictive of developing BOS grade 1 and 66 features predictive of developing BOS grade 2 or higher. Fractions from MS analysis were pooled and evaluated for peptide content. Nearly 10-fold more peptides were found in bronchiolitis obliterans syndrome relative to controls. C-terminal residues suggested trypsin-like specificity among controls compared to elastase-type enzymes among those with bronchiolitis obliterans syndrome.

Conclusions

Bronchoalveolar lavage fluid from individuals with bronchiolitis obliterans syndrome has an increase in low mass components detected by mass spectrometry. Many of these features were peptides that likely result from elevated neutrophil elastase activity.     

Association of Soluble HLA-G with Acute Rejection Episodes and Early Development of Bronchiolitis Obliterans in Lung Transplantation

Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of bronchiolitis obliterans syndrome (BOS). Soluble HLA-G, a mediator of adaptive immunity that modulates regulatory T cells and certain classes of effector T cells, may be a useful marker of survival free of BOS. We conducted a retrospective, single-center, pilot review of 38 lung transplant recipients who underwent collection of serum and bronchoalveolar lavage fluid 3, 6 and 12 months after transplantation, and compared soluble HLA-G concentrations in each to the presence of type A rejection and lymphocytic bronchiolitis in the first 12 months and to the presence of BOS at 24 months after transplantation. Lung soluble HLA-G concentrations were directly related to the presence of type A rejection but not to lymphocytic bronchiolitis. Our data demonstrate that soluble HLA-G concentrations in bronchoalveolar lavage but not in serum correlates with the number of acute rejection episodes in the first 12 months after lung transplantation, and thus may be a reactive marker of rejection.     

Development of Obliterative Bronchiolitis in a Murine Model of Orthotopic Lung Transplantation

Orthotopic lung transplantation in rats was first reported by Asimacopoulos and colleagues in 1971 ¹. Currently, this method is well accepted and standardized not only for the study of allo-rejection but also between syngeneic strains for examining mechanisms of ischemia-reperfusion injury after lung transplantation. Although the application of the rat and other large animal model ² contributed significantly to the elucidation of these studies, the scope of those investigations is limited by the scarcity of knockout and transgenic rats. Due to no effective therapies for obliterative bronchiolitis, the leading cause of death in lung transplant patients, there has been an intensive search for pre-clinical models that replicate obliterative bronchiolitis. The tracheal allograft model is the most widely used and may reproduce some of the histopathologic features of obliterative bronchiolitis ³. However, the lack of an intact vasculature with no connection to the recipient''s conducting airways, and incomplete pathologic features of obliterative bronchiolitis limit the utility of this model ⁴. Unlike transplantation of other solid organs, vascularized mouse lung transplants have only recently been reported by Okazaki and colleagues for the first time in 2007 ⁵. Applying the basic principles of the rat lung transplant, our lab initiated the obliterative bronchiolitis model using minor histoincompatible antigen murine orthotopic single-left lung transplants which allows the further study of obliterative bronchiolitis immunopathogenesis⁶.     

Intravenous Immunoglobulin for Hypogammaglobulinemia after Lung Transplantation: A Randomized Crossover Trial

Background

We aimed to determine the effects of treatment with intravenous immunoglobulin on bacterial infections in patients with hypogammaglobulinemia (HGG) after lung transplantation.

Methods

We performed a randomized, double-blind, placebo-controlled two-period crossover trial of immune globulin intravenous (IVIG), 10% Purified (Gamunex, Bayer, Elkhart, IN) monthly in eleven adults who had undergone lung transplantation more than three months previously. We randomized study participants to three doses of IVIG (or 0.1% albumin solution (placebo)) given four weeks apart followed by a twelve week washout and then three doses of placebo (or IVIG). The primary outcome was the number of bacterial infections within each treatment period.

Results

IVIG had no effect on the number of bacterial infections during the treatment period (3 during IVIG and 1 during placebo; odds ratio 3.5, 95% confidence interval 0.4 to 27.6, p = 0.24). There were no effects on other infections, use of antibiotics, or lung function. IVIG significantly increased trough IgG levels at all time points (least square means, 765.3 mg/dl during IVIG and 486.3 mg/dl during placebo, p<0.001). Four serious adverse events (resulting in hospitalization) occurred during the treatment periods (3 during active treatment and 1 during the placebo period, p = 0.37). Chills, flushing, and nausea occurred during one infusion of IVIG.

Conclusions

Treatment with IVIG did not reduce the short-term risk of bacterial infection in patients with HGG after lung transplantation. The clinical efficacy of immunoglobulin supplementation in HGG related to lung transplantation over the long term or with recurrent infections is unknown.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00115778","term_id":"NCT00115778"}}NCT00115778     

Application of ThinPrep Bronchial Brushing Cytology in the Early Diagnosis of Lung Cancer: A Retrospective Study

The majority of lung cancer patients are diagnosed at advanced stages of disease. This study evaluated the diagnostic value of ThinPrep (TP) bronchial brushing cytology in lung cancer. A total of 595 patients with suspicious lung cancer were enrolled in this study. The bronchial brushing samples were prepared by TP. The data were then compared to histology of lung tissue samples. Histologically, 479 of these 595 patients were diagnosed with lung cancer, including 223 cases of lung squamous cell carcinoma (SCC), 77 cases of lung adenocarcinoma (ADC), and 152 cases of small cell lung carcinoma (SCLC). The TP cytology revealed a total of 460 cases of lung cancer (including 232 SCCs, 91 ADCs, and 108 SCLCs). The TP cytological technique had 87.06% sensitivity and 62.93% specificity in the diagnosis of lung cancer. Specifically, TP cytology confirmed 195 of 223 SCCs, 47 of 77 ADCs, and 94 of 152 SCLCs. The TP cytology showed 87.44% sensitivity and 90.05% specificity for the diagnosis of SCC, with a Matthew''s correlation coefficient (MCC) of 0.820; while the sensitivity was reduced to 61.04% and the specificity was 90.93% for the diagnosis of ADC, with a MCC of 0.464. For the diagnosis of SCLC, the sensitivity was 61.84% and the specificity was 96.84%, with a MCC of 0.648. Thus, this study demonstrated the usefulness of TP bronchial brushing cytology in the early diagnosis of lung cancer, especially the early stage of lung SCC. A prospective clinical trial will verify these data before being translated into the clinic.     

Biochemical Diagnosis of Adrenal Insufficiency: the Added Value of Dehydroepiandrosterone Sulfate Measurements

ObjectiveTo review biochemical tests used in establishing the challenging diagnosis of adrenal insufficiency.MethodsWe reviewed the relevant literature, including our own data, on various biochemical tests used to determine adrenal function. The advantages and limitations of each approach are discussed.ResultsBaseline measurements of serum cortisol are helpful only when they are very low (≤ 5 μg/dL) or clearly elevated, whereas baseline plasma adrenocorticotropic hormone levels are helpful only when primary adrenal insufficiency is suspected. Measurements of baseline serum dehydroepiandrosterone sulfate (DHEA-S) levels are valuable in patients suspected of having adrenal insufficiency. Although serum DHEA-S levels are low in patients with primary or central adrenal insufficiency, a low level of this steroid is not sufficient by itself for establishing the diagnosis. A normal age- and sex-adjusted serum DHEA-S level, however, practically rules out the diagnosis of adrenal insufficiency. Many patients require dynamic biochemical studies, such as the 1-μg cosyntropin test, to assess adrenal function.ConclusionIn establishing the diagnosis of central adrenal insufficiency, we recommend measurements of baseline serum cortisol and DHEA-S levels. In addition to these, determination of plasma levels of aldosterone, adrenocorticotropic hormone, and renin activity is necessary when primary adrenal insufficiency is suspected. With a random serum cortisol level of ≥ 12 μg/dL in the ambulatory setting or a normal age- and sex-adjusted DHEA-S level (or both), the diagnosis of adrenal insufficiency is extremely unlikely. When serum DHEA-S levels are low or equivocal, however, dynamic testing will be necessary to determine hypothalamic-pituitary-adrenal axis function. (Endocr Pract. 2011;17:261-270)     

支气管哮喘急性发作期患者呼出气一氧化氮的诊断价值及与肺功能和血清ECP、IL-13的关系研究

摘要 目的：研究支气管哮喘（BA）急性发作期患者呼出气一氧化氮（FeNO）的诊断价值及与其肺功能和血清嗜酸性粒细胞阳离子蛋白（ECP）、白细胞介素-13（IL-13）的关系。方法：将我院从2018年1月～2020年1月收治的78例BA患者纳入研究,将其按照病情的不同分成急性发作组（急性发作期）42例与非急性发作组（缓解期）36例。比较两组FeNO、肺功能指标水平和血清ECP、IL-13水平,并作相关性分析。此外,以受试者工作特征（ROC）曲线分析FeNO对BA急性发作期的有关诊断效能。结果：急性发作组FeNO水平高于非急性发作组,而最大呼气流量占预计值的百分比（PEF%pred）、第1秒用力呼气末容积占预计值的百分比（FEV₁%pred）及用力肺活量占预计值的百分比（FVC%pred）水平均低于非急性发作组（均P＜0.05）。急性发作组血清ECP、IL-13水平均高于非急性发作组（均P＜0.05）。经Pearson相关分析发现：BA急性发作期患者FeNO与PEF%pred、FEV₁%pred、FVC%pred均呈负相关,而与血清ECP、IL-13水平均呈正相关（均P＜0.05）。经ROC曲线分析发现：FeNO诊断BA急性发作期的曲线下面积为0.818,敏感度与特异度分别为75.51%、94.05%。结论：BA急性发作期患者FeNO水平显著升高,且和肺功能、血清ECP、IL-13密切相关,检测FeNO对BA急性发作期患者具有较高的诊断价值。     

Elevated Levels of the Complement Activation Product C4d in Bronchial Fluids for the Diagnosis of Lung Cancer

Molecular markers in bronchial fluids may contribute to the diagnosis of lung cancer. We previously observed a significant increase of C4d-containing complement degradation fragments in bronchoalveolar lavage (BAL) supernatants from lung cancer patients in a cohort of 50 cases and 22 controls (CUN cohort). The present study was designed to determine the diagnostic performance of these complement fragments (hereinafter jointly referred as C4d) in bronchial fluids. C4d levels were determined in BAL supernatants from two independent cohorts: the CU cohort (25 cases and 26 controls) and the HUVR cohort (60 cases and 98 controls). A series of spontaneous sputum samples from 68 patients with lung cancer and 10 controls was also used (LCCCIO cohort). Total protein content, complement C4, complement C5a, and CYFRA 21-1 were also measured in all cohorts. C4d levels were significantly increased in BAL samples from lung cancer patients. The area under the ROC curve was 0.82 (95%CI = 0.71–0.94) and 0.67 (95%CI = 0.58–0.76) for the CU and HUVR cohorts, respectively. In addition, unlike the other markers, C4d levels in BAL samples were highly consistent across the CUN, CU and HUVR cohorts. Interestingly, C4d test markedly increased the sensitivity of bronchoscopy in the two cohorts in which cytological data were available (CUN and HUVR cohorts). Finally, in the LCCCIO cohort, C4d levels were higher in sputum supernatants from patients with lung cancer (area under the ROC curve: 0.7; 95%CI = 0.56–0.83). In conclusion, C4d is consistently elevated in bronchial fluids from lung cancer patients and may be used to improve the diagnosis of the disease.     

沙格雷酯治疗2型糖尿病伴下肢动脉硬化闭塞症患者的疗效评估

目的:探讨沙格雷酯治疗2型糖尿病伴下肢动脉硬化闭塞症(ASO)患者的临床疗效。方法:选择2014年4月~2015年5月我院2型糖尿病伴下肢ASO患者80例,给予口服沙格雷酯100 mg,3次/日,连续8周,监测治疗前后患肢的症状与体征、双下肢动脉峰值血流速度、血糖、血脂及血液流变学等指标的变化。结果:口服沙格雷酯8周后,患者疼痛感、冷感、间歇性踱行、麻木感及下肢溃疡等主观症状有效率均大于91%,临床总有效率为93.75%。治疗后患者左、右下肢动脉血管直径与治疗前比较,差异无统计学意义(P0.05),但左、右下肢动脉峰值血流速度比治疗前显著降低,差异有统计学意义(P0.05)。治疗后患者的甘油三酯、总胆固醇、低密度脂蛋白、全血高切黏度及全血低切黏度比治疗前降低,差异有统计学意义(P0.05)。结论:沙格雷酯可改善2型糖尿病伴下肢ASO患者的症状,降低双下肢动脉峰值血流速度,临床疗效确切,值得临床推广应用。     

肺癌患者肺动脉和支气管动脉CTA的临床研究

目的:对比分析肺癌患者和肺部非癌性病变肺动脉和主支气管动脉CTA特点。方法:回顾性统计分析82例行高度怀疑肺癌患者的肺部CTA,经病理证实肺癌54例,肺结核球28例,同时选择对照组22例。对比分析肺动脉(Pulmonary artery,PA)内径、主支气管动脉(Bronchial artery,BA)显影率和及其各级分支显影率。结果:肺癌组、肺结核球组和对照组左主支气管动脉显影率分别为83.3%、77.7%和72.7%。右主支气管动脉显影率87.0%、83.3%和68.1%。肺癌组左右主支气管动脉清晰显影率高于肺结核球组和对照组,差异有统计学意义(P0.05)。左右两侧肺癌组PA内径明显大于结核球和对照组,差异有统计学意义(P0.05)。左右侧肺癌组PA显影分级明显高于结核球和对照组,差异有统计学意义(P0.05)。左右双侧PA主干内径差异无统计学意义(P0.05)。结论:肺部癌性病灶动脉供血增加,肺动脉和支气管动脉CTA能够显示肺癌病灶供血情况,可用于临床辅助鉴别诊断影像学不能确诊的肺部病变。     

Expression of Calcineurin Activity after Lung Transplantation: A 2-Year Follow-Up

The objective of this pharmacodynamic study was to longitudinally assess the activity of calcineurin during the first 2 years after lung transplantation. From March 2004 to October 2008, 107 patients were prospectively enrolled and their follow-up was performed until 2009. Calcineurin activity was measured in peripheral blood mononuclear cells. We report that calcineurin activity was linked to both acute and chronic rejection. An optimal activity for calcineurin with two thresholds was defined, and we found that the risk of rejection was higher when the enzyme activity was above the upper threshold of 102 pmol/mg/min or below the lower threshold of 12 pmol/mg/min. In addition, we report that the occurrence of malignancies and viral infections was significantly higher in patients displaying very low levels of calcineurin activity. Taken together, these findings suggest that the measurement of calcineurin activity may provide useful information for the management of the prevention therapy of patients receiving lung transplantation.     

Diagnostic Value of Multiple Tumor Markers for Patients with Esophageal Carcinoma

BackgroundVarious studies assessing the diagnostic value of serum tumor markers in patients with esophageal cancer remain controversial. This study aims to comprehensively and quantitatively summarize the potential diagnostic value of 5 serum tumour markers in esophageal cancer.MethodsWe systematically searched PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM), through February 28, 2013, without language restriction. Studies were assessed for quality using QUADAS (quality assessment of studies of diagnostic accuracy). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were pooled separately and compared with overall accuracy measures using diagnostic odds ratios (DORs) and symmetric summary receiver operating characteristic (SROC) curves.ResultsOf 4391 studies initially identified, 44 eligible studies including five tumor markers met the inclusion criteria for the meta-analysis, while meta-analysis could not be conducted for 12 other tumor markers. Approximately 79.55% (35/44) of the included studies were of relatively high quality (QUADAS score≥7). The summary estimates of the positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) for diagnosing EC were as follows: CEA, 5.94/0.76/9.26; Cyfra21-1, 12.110.59/22.27; p53 antibody, 6.71/0.75/9.60; SCC-Ag, 7.66/0.68/12.41; and VEGF-C, 0.74/0.37/8.12. The estimated summary receiver operating characteristic curves showed that the performance of all five tumor markers was reasonable.ConclusionsThe current evidence suggests that CEA, Cyfra21-1, p53, SCC-Ag and VEGF-C have a potential diagnostic value for esophageal carcinoma.     

血清CRP, PCT 水平在脓毒血症患者中的早期诊断及预后评估价值

目的:探讨血清C反应蛋白(CRP)、降钙素原(PCT)水平在脓毒血症患者中的早期诊断及预后评估价值。方法:100例重症患者按照是否发生全身感染分为脓毒血症组67例、非脓毒血症组33例;脓毒血症组按照预后分为存活组42例、死亡组25例,同时选取健康者30例为正常对照组,进入重症监护室24小时后,抽取患者静脉血8ml,CRP采用免疫比浊法,PCT采用免疫层析法检测,分析CRP、PCT水平在脓毒血症患者早期诊断及预后价值。结果:CRP、PCT水平在组间差异具有统计学意义(P0.05),其中脓毒血症组和非脓毒血症组水平均高于对照组,脓毒血症组水平高于非脓毒血症组,差异具有统计学意义(P0.05);脓毒血症存活组患者CRP、PCT随着住院时间延长逐渐降低,差异具有统计学意义(P0.05),死亡组从第3天较第1天升高,第7、9天逐渐降低,但降低幅度不大,差异无统计学意义(P0.05);同一住院时间死亡组CRP、PCT水平均高于存活组,差异具有统计学意义(P0.05)。CRP、PCT联合并联检测对于早期发现脓毒血症具有较高的灵敏度。结论:PCT、CRP联合并联检测对于脓毒血症有更好的早期诊断价值,其表达水平可以较好地反映患者预后。     

评价抗SSA、抗SSB 和抗a- 胞衬蛋白抗体在诊断干燥 综合征中的价值

目的：评价SSA、SSB 和胞衬蛋白在诊断干燥综合征(SS)中的价值。方法：用酶联免疫吸附试验（ELISA）检测47 例确诊为SS 患者、20 例其它自身免疫病(类风湿关节炎7 例、SLE6 例、自身免疫性肌炎7 例)和20 例体检健康者血清抗SSA、SSB 和a- 胞衬 蛋白抗体,分析三种自身抗体阳性率。结果：抗SSA抗体、抗SSB 抗体和抗a-胞衬蛋白抗体敏感性分别为76.6%、38.3%、42.6%; 特异性分别为72.5%、95.0%、82.5%;三种抗体联合检测后敏感性为89.4%,特异性50.0%。结论：抗a- 胞衬蛋白抗体与抗SSA、 SSB 抗体联合检测时可提高阳性率,对症状不典型的SS 患者诊断有一定的补充意义。     

Diagnostic Value of Thyrotropin-Releasing-Hormone Stimulation in Patients With Pituitary Tumor

Plasma prolactin response to thyrotropin-releasing-hormone (TRH) stimulation was diminished in 30 patients with prolactinomas and 9 patients with acromegaly who had normal serum prolactin levels. There was no overlap of prolactin responses when compared with 32 control patients. Responses of ten patients with adrenocorticotropin (ACTH)-secreting pituitary tumors were similar to those of controls. Plasma growth hormone concentrations after TRH stimulation changed significantly in 28% of normal control and 20%, 25% and 50% of patients with prolactin-, growth hormone- and ACTH-secreting pituitary tumors, respectively. Our data suggest that the blunted TRH-induced rise in plasma prolactin levels in patients with prolactinomas and those with acromegaly may be related to humoral factor(s) affecting TRH receptor or postreceptor function. Growth hormone responses to TRH are nonspecific and should not be considered a marker for active acromegaly.     

Use of Anti-Granulocyte Scintigraphy with 99mTc-Labeled Monoclonal Antibodies for the Diagnosis of Periprosthetic Infection in Patients after Total Joint Arthroplasty: A Diagnostic Meta-Analysis

The accurate diagnosis of periprosthetic joint infections (PJI) is crucial for therapy and the prevention of complications. No diagnostic test of PJI is 100% accurate. The aim of this study was to assess the use of anti-granulocyte scintigraphy using 99 mTc-labeled monoclonal antibodies to diagnose PJI after total joint arthroplasty. A systematic search of all relevant studies published through January 2013 was conducted using the MEDLINE, EMBASE, OVID, and ScienceDirect databases. Observational studies that assessed the accuracy of the anti-granulocyte scintigraphy with monoclonal antibodies or antibody fragments labeled with technetium 99 m in diagnosis for PJI and provided data on specificity and sensitivity were identified. Standard methods recommended for meta-analysis of diagnostic accuracy were used. Nineteen studies were eligible for inclusion. The results demonstrated that the area under the summary receiver operator curve was 0.88, and the diagnostic accuracy (Q*) was 0.81. Additionally, the diagnostic odds ratio (DOR) was 18.76 with a corresponding 95% confidence interval of 10.45–33.68. The pooled sensitivity and specificity of the diagnostic method for the diagnosis of PJI were 83% and 79%, respectively, while the pooled positive likelihood ratio (PLR) was 3.56, and the negative likelihood ratio (NLR) was 0.26. Anti-granulocyte scintigraphy using 99 mTc-labeled monoclonal antibodies has a reasonable role in the diagnosis of PJI after total joint arthroplasty. Due to the limitations of the present meta-analysis, additional high-quality original studies are required to confirm the predictive value.     

支纤镜肺活检联合刷检与经皮肺穿刺活检对肺周围型病变诊断价值的研究

目的:探讨两种肺检查方法对肺部周围常见疾病的诊断价值.方法:回顾性分析胸片和CT检查发现肺周围型病变的43例患者,在经支气管肺活检联合刷检和/或CT引导经皮肺穿刺活检病理确诊阳性率.结果:43例患者共行33次支气管肺活检联合刷检,26例获取标本成功,阳性诊断率为78.79%.经皮肺穿刺活检17例,全部获取标本成功,1例患者因取材量少,病理结果无诊断意义,阳性诊断率为94.11%,两者结合诊断率97.67%.结论:经支气管肺活检联合刷检与经皮肺穿刺活检对肺周围型病变诊断都是安全、有效、准确、损伤小的诊断方法,两种方法联合使用可明显提高诊断率.     

葡萄糖-6-磷酸异构酶早期诊断类风湿关节炎的临床意义

目的：探讨血清葡萄糖6-磷酸异构酶（GPI）早期诊断类风湿关节炎（RA）的临床意义。方法：用ELISA法检测105例RA组、51例风湿病组、42例非风湿病组及40例健康对照组的血清GPI浓度,其中RA组分为早期组和中晚期组。同时收集RA患者类风湿因子（RF）、血沉（EsR）、免疫球蛋白、C-反应蛋白（CRP）、补体（C3、C4）、关节炎部位数等相关临床指标。结果：GPI对早期RA和中晚期RA诊断的敏感性分别为70．03％,和79．41％;特异性分别为89．89％和90．91％;二者敏感性、特异性比较均无显著差异;在RA患者中,GPI结果与RF、CRP、ESR、IgA、IgG、关节炎部位数均有相关性（P〈0．05）,与c3、C4、IgM无相关性;RF诊断RA的敏感性80．95％,特异性为78．19％,与GPI比较,二者敏感性无显著差异,特异性有差异（P〈0．05）,二者同时检测诊断RA的敏感性为69．52％,特异性达93．99％。结论：GPI诊断早期RA具有较好的敏感性和特异性,与RF联合检测对RA诊断具有很高的特异性,且可能成为判断RA病情活动的指标之一。