Plasma cytokine levels and monocyte activation in patients with obstructive jaundice

Some monocytic cytokines are important immune regulators. We have investigated cytokine production by monocytes and the blood levels of IL-1β, IL-6, TNFα, and TGFβ, in patients with obstructive jaundice. The supernatant from LPS stimulated monocytes from jaundiced patients released significantly increased quantities of TNFα by both bioassay and radioimmunoassay (RIA) (12.4 ± 2.5 fmol/mL and 32.6 ± 8.3 fmol/mL, respectively, for jaundice, compared with 1.6 ± 0.3 fmol/mL and 2.4 ± 0.5 fmol/mL respectively for controls, and also of IL-6 (54.8 ± 5.0 fmol/mL in jaundice compared with 35.6 ± 5.0 fmol/mL for controls). The production of IL-1β and TGFβ by stimulated monocytes was unchanged. Jaundiced patients had significantly higher plasma TGFβ, but TNFα and IL-1β were below the limits of detection. The highest monocyte TNFα and IL-6 levels were seen in malignant disease patients, especially those with a poor immediate prognosis. We conclude that the production of some cytokines by monocytes is up-regulated in patients with obstructive jaundice.     

Stenting and interventional radiology for obstructive jaundice in patients with unresectable biliary tract carcinomas

Together with biliary drainage, which is an appropriate procedure for unresectable biliary cancer, biliary stent placement is used to improve symptoms associated with jaundice. Owing to investigations comparing percutaneous transhepatic biliary drainage (PTBD), surgical drainage, and endoscopic drainage, many types of stents are now available that can be placed endoscopically. The stents used are classified roughly as plastic stents and metal stents. Compared with plastic stents, metal stents are of large diameter, and have long-term patency (although they are expensive). For this reason, the use of metal stents is preferred for patients who are expected to survive for more than 6 months, whereas for patients who are likely to survive for less than 6 months, the use of plastic stents is not considered to be improper. Obstruction in a metal stent is caused by a tumor that grows within the stent through the mesh interstices. To overcome such problems, a covered metal stent was developed, and these stents are now used in patients with malignant distal biliary obstruction. However, this type of stent has been reported to have several shortcomings, such as being associated with the development of acute cholecystitis and stent migration. In spite of these shortcomings, evidence is expected to demonstrate its superiority over other types of stent.     

Bilirubin levels predict malignancy in patients with obstructive jaundice

Background

Differentiating between benign and malignant causes of obstructive jaundice can be challenging, even with the advanced imaging and endoscopic techniques currently available. In patients with obstructive jaundice, the predictive accuracy of bilirubin levels at presentation was examined in order to determine whether such data could be used to differentiate between malignant and benign disease.

Methods

A total of 1026 patients with obstructive jaundice were identified. Patients were divided into benign and malignant groups. The benign patients were subgrouped into those with choledocholithiasis and those with inflammatory strictures of the biliary tree. Bilirubin levels at presentation and other demographic data were obtained from case records.

Results

Area under the curve (AUC) values for bilirubin as a predictor of malignancy were highly significant for all benign presentations and for those with benign biliary strictures (AUC: 0.8 for both groups; P < 0.001). A bilirubin level > 100 µmol/l was determined to provide the optimum sensitivity and specificity for malignancy in all patients and in those without choledocholithiasis (71.9% and 86.9%, 71.9% and 88.0%, respectively). The application of a bilirubin level > 250 µmol/l achieved specificities of 97.1% and 98.0% in each subgroup of patients, respectively.

Conclusions

In patients with obstructive jaundice, bilirubin levels in isolation represent an important tool for discriminating between benign and malignant underlying causes.     

胆汁内外引流术对梗阻性黄疸大鼠肝脏Kupffer细胞CD14表达的影响

目的探讨胆汁内外引流术对梗阻性黄疸大鼠肝脏Kupffer细胞CD14表达的影响。方法将60只成年SD雄性大鼠随机分为4组,梗阻性黄疸组(OJ组)、胆汁内引流术组(ID组)、胆汁外引流术组(ED组)及假手术组(SH组)并分别建立模型;采用免疫组织化学染色及半定量分析的方法测定各组大鼠肝脏Kupffer细胞CD14的表达情况。结果 OJ组大鼠肝脏Kupffer细胞CD14表达明显强于SH组(P0.01),ID组与OJ组比较表达明显降低(P0.01),ED组与OJ组比较无显著性差异(P=0.5907)。结论梗阻性黄疸时胆汁内引流术在改善Kupffer细胞CD14表达方面优于胆汁外引流术,提示胆汁内引流术优于外引流术的机制可能与肝脏Kupffer细胞CD14表达过程有关。     

Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia

Summary. Serum concentrations of tumour necrosis factor alpha (TNF-α), interleukin-1 receptor antagonist (IL-1ra), interferon gamma (IFN-γ), interleukin-6 (IL-6) and interleukin-10 (IL-10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram-negative (Gr⁻) bacteraemias after 2 h (TNF-α, IL-lra and IFN-γ), 4h (IL-6) and 6 h (IL-10), respectively. At time 0 the median TNF-α value was higher in the Gr⁻ group (80 pg/ml; range 54-516 pg/ml) as compared to both gram-positive bacteraemias (Gr⁺, 14pg/ ml; range 7-60 pg/ml; P < 0 05) and blood culture negative episodes (BCN, 8pg/ml; range 0-87pg/ml; P<0 05).
Furthermore, the peak values of TNF-α, IL-lra, IL-6 and IL-10 during the 24 h study period were significantly and/or numerically higher in the ^Gr- group in comparison to the Gr⁺ and BCN groups, respectively. It may be concluded that neutropenic patients have increased levels of both pro- and anti-inflammatory cytokines at start of fever, with the highest values recorded during the first hours in ^Gr- bacteraemias. Prospective studies will show whether monitoring of serum cytokines may be used as an early diagnostic tool before results of blood cultures are available, which may have important therapeutic implications.     

Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokines and monitoring of erythropoiesis

Abstract: Recombinant erythropoietin (r-EPO) was administered to 37 patients with advanced, transfusion-dependent and chemo-resistant multiple myeloma (MM), at the fixed dose of 10,000/U s.c, 3 times a week, for 2 months. Thirteen patients (35.1%) achieved a significant response in terms of complete abolition of red cell transfusions. Factors significantly predictive of response were: a) inappropriate production of endogenous EPO, as expressed by a reduced observed/predicted ratio; b) presence of a consistant number of circulating erythroid precursors BFU–E; c) low serum levels of tumor necrosis factor (TNF) and interleukin-1 (IL-1), cytokines with inhibitory activity on erythropoiesis; d) a single line of previously received chemotherapy. Renal failure, bone marrow plasma cell infiltration, serum levels of IL-6 and other main clinical and laboratory parameters did not affect significantly the response to r-EPO. High fluorescence reticulocytes (HFR) and soluble transferrin receptor (sTfR) values were useful to detect an early stimulation of erythropoiesis in responders, while a high percentage of circulating hypochromic erythrocytes (HE), as assessed by an automated counter, identified those patients developing functional iron deficiency during r-EPO treatment. We conclude that about one-third of severely anemic patients with advanced MM, unresponsive to chemotherapy, may benefit by r-EPO therapy. The clinical management of these patients can be accomplished using non-invasive parameters, such as sTfR, HFR and HE.     

Persistent systemic inflammatory response after stent insertion in patients with malignant bile duct obstruction

Background—Surgery in patients with malignantbile duct obstruction is associated with high postoperative morbidityand mortality. Tumour necrosis factor α (TNF-α) plays a key role inthe pathogenesis of these complications.
Aims—To determine the effect of biliary drainageon plasma concentrations of TNF-α, its soluble circulating receptors(sTNFr), and other proinflammatory cytokines.
Methods—Plasma concentrations of TNF-α,sTNFr-P75, interleukin 6 (IL-6), and IL-1α were measured in 25 patients with malignant bile duct obstruction before and afterendoscopic stent insertion.
Results—Mean serum bilirubin was 157 µmol/lbefore stent insertion and 35.2 µmol/l one week post stent insertion.There was complete relief of jaundice in 77% of patients by fourweeks. Plasma concentrations of TNF-α and IL-1α were below thedetection limit of the assays in all samples. Median plasma sTNFr-P75in the cancer patients was 960 ng/l (range 400-6600) before stent insertion and remained unchanged at one and four weeks after stenting. Plasma sTNFr-P75 in cancer patients was significantly higher(p<0.01) than in healthy controls (250 (200-650) ng/l).Before stent insertion, plasma IL-6 concentrations were detectable(above 5 ng/l) in 17(68%) patients. After relief of biliaryobstruction IL-6 levels fell from a prestent median of 13.2 to lessthan 5 ng/l at one week after stent insertion. Plasma concentrations ofIL-6 were undetectable in 76% of patients at this time.
Conclusion—Activation of the TNF/sTNFr complex isunchanged after biliary drainage in patients with malignant bile ductobstruction. This may explain why preoperative drainage does notinfluence the high morbidity and mortality associated with surgery inthese patients.

Keywords:jaundice; tumour necrosis factor α; biliarydrainage; pancreatic cancer

     

急性梗阻性化脓性胆管炎患者胆汁及血清中肿瘤坏死因子α、白细胞介素-6水平分析

目的通过研究急性梗阻性化脓性胆管炎（AOSC）患者胆汁及血清中肿瘤坏死因子（TNF）α和白细胞介素（IL）-6的含量,探讨二者在此病中的表达水平及临床意义。方法经内镜逆行胰胆管造影（ERCP）检查确诊AOSC30例,采用双抗体夹心酶联免疫吸附测定（ELISA）试剂盒检测胆汁和血清中TNFα、IL-6的含量,同时与40例非AOSC病例对照。并于术后第4d经鼻胆管引流测定30例AOSC患者胆汁中TNFα、IL-6的含量。结果AOSC组术中胆汁中TNFα、IL-6含量分别为（179．25±26．50）、（207．00±42．05）pg／ml,血清中TNFα、IL-6含量为（189．14±28．89）、（420．18±89．04）pg／ml。对照组胆汁中TNFα、IL-6含量为（4．02±2．17）、（7．48±3．89）pg／ml,血清中TNFα、IL-6含量为（8．16±2．29）、（14．92±4．73）pg／ml。AOSC组胆汁和血清TNFα、IL-6含量高于对照组（P〈0．01）,AOSC组患者术后第4d与术中胆汁TNFα、IL-6比较明显下降（P〈0．01）。结论AOSC组患者胆汁和血清中TNFα、IL-6含量高于对照组,TNFα、IL-6可能参与了AOSC的病理生理过程且可作为诊断AOSC的参考指标。     

无创正压通气对急性加重期 COPD 患者痰液及血液炎性因子水平的影响

目的：观察无创正压通气（ NPPV）对慢性阻塞性肺疾病急性加重期（ AECOPD ）患者痰液及血液中炎性因子水平的影响,探讨NPPV治疗和机制。方法将30例AECOPD患者随机分为NPPV组和对照组各15例,两组均予常规AECOPD治疗药物,在此基础上NPPV组辅助NPPV治疗。分别于治疗前和治疗72 h后评价两组医学研究会呼吸困难量表（ MRC）评分、动脉血气指标,收集痰及空腹静脉血标本测定IL-6、IL-8、肿瘤坏死因子（ TNF）-α含量。结果两组治疗后呼吸困难均缓解、动脉血气指标均改善,尤以NPPV组为著（P均＜0．05）;两组治疗后痰液及血液中IL-6、IL-8、TNF-α水平均较治疗前下降,尤以NPPV组为著（ P均＜0．05）。结论 NPPV治疗后AE-COPD患者痰液及血液中炎性因子水平下调,此可能为NPPV治疗AECOPD的机制之一。     

Perioperative hepatic functional risk assessed with technetium-99m diethylenetriamine pentaacetic acid-galactosyl human serum albumin liver scintigraphy in patients undergoing pancreaticoduodenectomy complicated by obstructive jaundice

Summary Conclusion: Liver scintigraphy with technetium-99m diethylenetriamine pentaacetic acid-galactosyl human serum albumin (Tc-GSA) can be used to predict outcome of biliary drainage and hepatic function after pancreaticoduodenectomy in patients with pancreatic, biliary, and ampullary carcinomas complicated by obstructive jaundice. Background: Preoperative obstructive jaundice has been reported as a crucial risk factor for serious postoperative complications in patients undergoing pancreaticoduodenectomy. The aim of the present study was to investigate whether Tc-GSA liver scintigraphy can assess hepatic functional risk in patients with pancreatic, biliary, and ampullary carcinomas complicated by obstructive jaundice. Methods: Liver scintigraphy was performed before biliary drainage in 18 patients with obstructive jaundice. The maximum removal rate of Tc-GSA (GSA-R_max; standard normal value ≥0.60) was calculated. These patients underwent pancreaticoduodenectomy with wide lymphadenectomy. The efficacy of preoperative biliary drainage was assessed with the decrease in serum bilirubin concentration in the first week after biliary drainage. Postoperative liver function was assessed with the increase in serum bilirubin concentration, which was the difference between the immediate preoperative and maximal postoperative bilirubin concentrations. Results: Serum bilirubin decreased more in the first week after biliary drainage in patients with GSA-R_max≥0.60 (7.64±1.09 mg/Dl/wk) than in patients with GSA-R_max<0.60 (3.56±1.25 mg/DL/wk, p=0.042). Postoperative bilirubin increased less in patients with GSA-R_max≥0.60 (0.81±0.30 mg/dL) than in patients with GSA-R_max<0.60 (4.00±0.69 mg/DL, p=0.0012). Multivariate analysis showed that GSA-R_max significantly predicted the postoperative bilirubin increase (p=0.020).     

原发性胆汁性肝硬化患者肝组织转化生长因子β-1表达水平变化

目的 探讨原发性胆汁性肝硬化（PBC）患者肝组织转化生长因子-β1（TGF-β1）表达的变化。 方法 52例PBC患者接受超声引导下肝穿刺活检,选择病理科留取的正常肝组织20份作为对照,另选择20例健康人采集静脉血。采用免疫组化法检测肝组织TGFβ-1表达,采用ELISA法检测血清肿瘤坏死因子α（TNF-α）和白介素6（IL-6）水平。 结果 正常肝组织不表达或仅有少量TGF-β1表达,而PBC患者肝实质细胞胞浆内呈TGF-β1高表达;PBC患者血清TNF-α和IL-6水平分别为（28.71±13.54） pg/ml和（21.3±9.4） pg/ml,显著高于健康人【分别为（21.3±15.4） pg/ml和（2.1±1.6） pg/ml,P<0.01】;7例PBC肝组织肝纤维化S0期患者肝组织TGF-β1表达及血清TNF-α和IL-6水平分别为（0.5±0.2）10-2、（7.1±4.1） pg/ml和（5.1±1.0） pg/ml,显著低于12例S1期【（4.2±1.3） 10-2、（18.6±6.2） pg/ml、（11.5±3.6） pg/ml,P<0.01】、18例S2期【（6.9±1.2） 10-2、（27.3±9.9） pg/ml、（19.4±4.1） pg/ml,P<0.01】、9例S3期【（13.3±15.1） 10-2、（39.7±15.18） pg/ml、（27.3±8.1） pg/ml,P<0.01】和6例S4期【（21.2±17.1） 10-2、（53.4±17.3） pg/ml、（47.8±11.0） pg/ml,P<0.01】;15例Child-Pugh A级患者肝组织TGF-β1表达及血清TNF-α和IL-6水平分别为（1.9±1.6） 10-2、（12.2±3.1） pg/ml和（7.3±2.5） pg/ml,显著低于25例Child-Pugh B级【（15.9±13.6） 10-2、（32.9±8.6） pg/ml、（21.8±6.3） pg/ml,P<0.01】或12例C级患者【（22.6±18.5） 10-2、（49.1±19.3） pg/ml、（45.5±12.7） pg/ml,P<0.01】。 结论 PBC患者肝组织TGFβ-1表达及血清TNF-α和IL-6水平显著升高,可能与肝组织纤维化增生和/或肝功能受损有关。     

急性心肌梗死患者血清人软骨糖蛋白39、可溶性肿瘤坏死因子受体1水平与心功能及预后的相关性

目的分析急性心肌梗死(AMI)患者血清人软骨糖蛋白39(YKL-40)、可溶性肿瘤坏死因子受体1(sTNFR1)水平与心功能及预后之间的关系。方法选取2016年3月—2018年10月在河北北方学院附属第一医院就诊的77例AMI患者为研究对象(AMI组),选取同期在该院健康体检的77例为对照组。对AMI患者出院后随访,记录患者预后情况,随访时间为24个月。超声心动图测定两组心功能参数左心室射血分数(LVEF)、左心室舒张末期内径(LVEDD)、左心室后壁厚度(LVPWT);酶联免疫吸附法测定血清YKL-40、sTNFR1水平;Pearson法分析血清YKL-40、sTNFR1水平与AMI患者心功能参数的相关性;分析血清YKL-40、sTNFR1水平与AMI患者预后不良的关系;COX回归分析影响AMI患者预后不良的危险因素。结果与对照组比较,AMI组血清YKL-40、sTNFR1水平和LVEDD、LVPWT显著升高,LVEF显著降低(P<0.05)。随着AMI患者心功能分级的升高,血清YKL-40、sTNFR1水平逐渐升高(P<0.05)。AMI患者血清YKL-40、sTNFR1水平与LVEF呈负相关,与LVEDD、LVPWT呈正相关(P<0.05)。AMI患者YKL-40高水平组、sTNFR1高水平组的预后不良发生率均高于低水平组(P<0.05)。多因素COX分析表明,心肌梗死类型、梗死部位与血清YKL-40、sTNFR1水平是影响AMI患者预后不良的危险因素(P<0.05)。结论AMI患者血清YKL-40、sTNFR1水平与心功能和预后不良的发生相关,可能是评估AMI患者预后的潜在生物标志物。     

PD-1/PD-L1及相关炎症因子在细粒棘球蚴感染致肝损伤中的免疫调节作用北大核心CSCD

目的探讨程序性死亡受体-1(programmed cell death receptor 1,PD-1)、程序性死亡受体配体1(programmed cell death-Ligand-1,PD-L1)及相关炎症因子在棘球蚴感染免疫损伤中的免疫调控机制。方法将BALB/c小鼠分为2个组:对照组(40只)、模型组(40只)。采用原头蚴腹腔注射制备细粒棘球蚴感染模型,腹腔接种后2 d、8 d、1个月、3个月、6个月时每组取8只小鼠行内眦静脉取血,采用流式细胞术微球阵列法试剂盒(Cytometric Bead Array,CBA)检测小鼠外周血中白细胞介素6(interleukin-6,IL-6)、白细胞介素17A(interleukin-17A,IL-17A)和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)的含量。取肝脏进行苏木精-伊红(hematoxylin-eosin staining,HE)染色,采用免疫组织化学染色法检测小鼠肝组织中PD-1、PD-L1的表达。结果对照组腹部未见异常。模型组小鼠腹部出现明显膨隆,腹腔中有包囊。对照组小鼠肝组织结构正常,模型组小鼠6个月时肝脏有大片肝细胞坏死变性,可见大量炎性细胞浸润。对照组小鼠肝组织PD-1、PD-L1表达均呈阴性,模型组小鼠3个月时肝脏开始出现明显PD-1表达的阳性细胞,主要位于肝损伤区域,6个月时小鼠PD-1的表达主要集中于肝坏死区域周围,可见明显增多的阳性细胞存在。模型组2 d和8 d时均可见PD-L1表达的大量阳性细胞,1个月肝脏PD-L1呈低表达,3个月开始表达又升高。模型组小鼠TNF-α在感染2 d时高于对照组(t=15.587,P<0.05),后开始下降,从3个月开始时TNF-α升高,至6个月时达高峰,模型组小鼠血清中IL-17A在感染8 d时高于对照组(t=0.067,P<0.05),后一直呈上升趋势,至6个月时达高峰,IL-6在感染2 d开始即高于对照组,6个月时达高峰。结论IL-6、TNF-α、IL-17A参与了细粒棘球蚴感染导致的炎症反应。细粒棘球感染模型小鼠肝脏出现高表达的PD-1/PD-L1,随着时间延长,PD-1表达逐渐增强,尤其是细粒棘球蚴感染早期,PD-L1高表达,PD-1、PD-L1在感染前期、中期就开始发挥负调节作用,可进一步促进棘球蚴组织在体内迅速生长,参与肝脏的损伤作用。在细粒棘球蚴感染早、中期,阻断PD-1/PD-L1信号通路,将有助于抗棘球蚴感染。     

A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease

BACKGROUND & AIMS: Interleukin-6 (IL-6) regulates immune response and inflammation. We carried out a pilot placebo-controlled study to investigate the efficacy, pharmacokinetics, and safety of MRA, a humanized monoclonal antibody to IL-6 receptor, in patients with active Crohn's disease. METHODS: Thirty-six patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] > or =150) were randomly assigned to receive biweekly intravenous infusion of either placebo, MRA, or MRA/placebo alternately for 12 weeks at a dose of 8 mg/kg. The study's primary end point was a clinical response rate that was defined as a reduction of CDAI > or =70. RESULTS: At the final evaluation, 80% of the patients (8 of 10) given biweekly MRA had a clinical response as compared with 31% of the placebo-treated patients (4 of 13; P = 0.019). Twenty percent of the patients (2 of 10) on this regimen went into remission (CDAI <150), as compared with 0% of the placebo-treated patients (0 of 13). The clinical response rate of the every-4-week regimen was 42% (5 of 12). The serum concentrations of MRA were detected at 2 weeks after every infusion, at which time acute phase responses were completely suppressed; however, they were not suppressed at 4 weeks. Endoscopic and histologic examination showed no difference between MRA and placebo groups. The incidence of adverse events was similar in all the groups. CONCLUSIONS: This is the first clinical trial of humanized anti-IL-6 receptor monoclonal antibody in Crohn's disease. A biweekly 8 mg/kg infusion of MRA was well tolerated, normalized the acute-phase responses, and suggests a clinical effect in active Crohn's disease.     

Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes

Inflammation and endothelial dysfunction are increasingly being recognized as key etiological factors in the development of atherosclerosis and subsequent cardiovascular disease. These pro-atherogenic factors are strongly correlated and are often found to co-segregate in patients with type 2 diabetes. The impact of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4, on inflammation and markers of endothelial function remains to be fully characterized.