乙型肝炎病毒基因的整合机制及对宿主的影响

乙型肝炎病毒是导致慢性肝炎、肝纤维化、肝细胞癌的主要病因,目前认为乙型肝炎病毒基因整合在其致病机制中具有重要作用,本文试就该领域内目前研究成果做一综述．     

Molecular characteristics of two esophageal carcinosarcomas: a hint for theclonality of carcinomatic and sarcomatic tumor components

AIM To study the clonality of the esophageal carcinosarcoma by using molecular approaches.METHODS Two esophageal carcinosarcomas were included in the study. Tumor area from dysplasticlesion, squamout cell carcinoma, basaloid cell carcinoma and spindle cell elements were microdissectedseparately. Each element was analyzed with 14 microsatellite markers and direct sequenced for p53 gene andras gene mutation.RESULTS Both tumors displayed a typical histologic feature of carcinosarcoma. Both cases showed thedivergent differentiation by immunohistochemistry study. In case 1 the identical LOH at p53 and hMLH1 lociwas detected. The heterogenous LOH was detected only in carcinosarcoma at RB1 and BRCA1 loci, whilethe LOH at ACTC locus was seen only in sarcoma. The same mutation of the splice site of exon 6-intron 6displayed in the two tumor elements. In case 2, a coordinate LOH at RB locus was demonstrated in threetypes of tumor elements: sqamous carcinoma, basaloid carcinoma and spindle cell element. A heterogenousLOH was seen only in spindle cells at TAP1 locus. No mutation in exon 5-8 of p53 gene has been found incase 2. No mutation of K-ras gene was found.CONCLUSION Although the different differentiation, the two elements of esophageal carcinosarcoma mayhave a single clonality. The p53 gene mutation occurred before the two differentiation directions switched.The distinct molecular genotype can be determined through molecular biological analysis. The microsatelliteprofiling can serve as an approach to find out which genetic alteration occurs before or after thedifferentiation is determines.     

急性缺血性卒中影像学检查的建议——美国心脏协会的科学声明（上）

卒中是一种常见、严重的疾病,仅美国每年的新发病例就高达795000例,并已成为全世界人类死亡和残疾的主要病因。10年前,重组型组织纤溶酶原激活剂（recombinant tissue plasminogen activator,rt—PA）被批准用于治疗急性缺血性卒中。rt—PA应用指南建议,应在卒中发病后3h内静脉给予rt—PA,给药前应行头部CT检查,排除颅内出血。     

急性缺血性卒中影像学检查的建议——美国心脏协会的科学声明（中）

2．3核磁共振血管成像（MRA） 2．3．1背景和方法：在头部MRI检查中常结合MRA,用于急性卒中患者病情评估以指导治疗决策的制定^[19]。日前,有几种不同的MRA技术用于脑血管成像,包括二维时间飞跃（timeof-flight,TOF）序列、三维TOF序列、     

A phase I study of sequential versus concurrent interleukin-3 and granulocyte-macrophage colony-stimulating factor in advanced breast cancer patients treated with FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy

Cumulative thrombocytopenia is a dose-limiting toxicity of dose- intensive chemotherapy for advanced breast cancer. In this phase I study, we have studied the hematologic toxicity associated with sequential interleukin-3 (IL-3) and granulocyte-macrophage colony- stimulating factor (GM-CSF; molgramostim) administration after multiple cycles of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy compared with that after concurrent cytokine administration or to each cytokine administered alone. Ninety- three patients with advanced breast cancer were treated with five cycles of FLAC chemotherapy and either IL-3 alone, GM-CSF alone, sequential IL-3 and GM-CSF administered by schedule A (5 days of IL-3 followed by 10 days of GM-CSF) or schedule B (9 days of IL-3 followed by 6 days of GM-CSF), or concurrent administration of IL-3 and GM-CSF for 15 days. Cohorts of patients were treated with one of four dose levels of IL-3 (1,2.5, 5, and 10 micrograms/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 micrograms/kg/day. Sequential IL-3 and GM- CSF (schedule B) was associated with higher platelet nadirs, shorter durations of platelet counts less than 50,000/microL, and the need for fewer platelet transfusions over five cycles of FLAC chemotherapy compared with concurrent cytokines, sequential IL-3 and GM-CSF schedule A, and GM-CSF alone. Concurrent IL-3 and GM-CSF was associated with unexpected platelet toxicity. The duration of granulocytopenia after FLAC chemotherapy was significantly worse with IL-3 alone compared with each of the GM-CSF-containing cytokine regimens. Although no cycle 1 maximum tolerated dose for IL-3 was defined in this study, 5 micrograms/kg was well tolerated over multiple cycles of therapy and is recommended for future studies. The data from this phase I study suggest that sequential IL-3 and GM-CSF with IL-3 administered for 9 days before beginning GM-CSF may be superior to shorter durations of IL- 3 administered sequentially with GM-CSF, to concurrent IL-3 and GM-CSF, and to either colony-stimulating factor alone in ameliorating the cumulative hematologic toxicity associated with multiple cycles of FLAC chemotherapy. Additional studies of sequential IL-3 and GM-CSF are warranted.     

Tumor necrosis factor-α and interleukin-6 in cirrhotic patients with spontaneous bacterial peritonitis

AIM: To evaluate the role of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cirrhotic patients who have hepatic and renal impairment with spontaneous bacterial peritonitis (SBP).METHODS: We prospectively studied 120 cirrhotic patients with SBP and 80 cirrhotic patients with sterile ascitic fluid. They included 144 males and 56 females with ages ranging between 34 and 62 years. The diagnosis of cirrhosis was established by clinical and laboratory criteria that did not require histological confirmation. The severity of underlying liver disease was evaluated using Pugh’s modification of Child’s criteria (Child-Pugh scores). Ascitic fluid was sent to the laboratory for cell count, culture, sensitivity testing, and measurement of chemical elements (i.e., albumin, glucose). Specimens were inoculated into aerobic and anaerobic blood culture bottles. Serum and ascitic fluid were also collected in sterile tubes at study entry (before the initiation of antibiotic treatment) and 48 h later. Assays for TNF-α and IL-6 in the serum and ascitic fluid were performed with an immunoenzymometric assay using manufacture’s instructions.RESULTS: Cytokine levels in serum and ascitic fluid were significantly higher in the patients with SBP. (plasma TNF-α: 135.35 ng/mL ± 11.21 ng/mL vs 92.86 ng/mL ± 17.56 ng/mL, P < 0.001; plasma IL-6: 32.30 pg/mL ± 7.07 pg/mL vs 12.11 pg/mL ± 6.53 pg/mL, P < 0.001; ascitic fluid TNF-α: 647.54 ± 107.11 ng/mL vs 238.43 ng/mL ± 65.42 ng/mL, P < 0.001); ascitic fluid IL-6: 132.84 ng/mL ± 34.13 vs 40.41 ± 12.85 pg/mL, P < 0.001). About 48 (40%) cirrhotic patients with SBP developed renal and hepatic impairment and showed significantly higher plasma and ascitic fluid cytokine levels at diagnosis of infection. [(plasma TNF-α: 176.58 ± 17.84 vs 135.35 ± 11.21 ng/mL) (P < 0.001) and (IL-6: 57.83 ± 7.85 vs 32.30 ± 7.07 pg/mL) (P < 0.001); ascitic fluid TNF-α: 958.39 ± 135.72 vs 647.54 ± 107.11 ng/mL, (P < 0.001), ascitic fluid IL-6: 654.74 ± 97.43 vs 132.84 ± 34.13 pg/mL, (P < 0.001)]. Twenty nine patients (60.4%) with SBP and renal impairment died whereas, only four patients (5.55%) with SBP but without renal impairment died from gastrointestinal hemorrhage (P < 0.0005).CONCLUSION: It appears that TNF-α production may enhance liver cell injury and lead to renal impairment. This correlated well with the poor prognosis and significantly increased mortality associated with SBP in cirrhotic patients.     

Tumour necrosis factor-related apoptosis-inducing ligand is a novel therapeutic target in pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension is a fatal disease characterised by progressive narrowing of pulmonary arterioles, driven by aberrant cellular proliferation. Identification of key pathways in disease pathogenesis is required for the development of new-targeted therapies. We have previously reported tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic pulmonary arterial hypertension and animal models. Since TRAIL induces endothelial cell apoptosis and smooth muscle cell proliferation, we hypothesised that TRAIL is an important driver of disease in pulmonary arterial hypertension.MethodsWe characterised the expression of TRAIL in human and rodent pulmonary arterial hypertension and determined the effects of TRAIL on pulmonary artery smooth muscle cells (PASMCs) in vitro. Using genetic deletion, pharmacological overexpression, antibody blockade, and bone marrow transplant (BMT) chimera experiments we determined the direct pathogenic role of TRAIL in three independent rodent models of pulmonary arterial hypertension. We then tested the efficacy of inhibiting TRAIL in halting or regressing established disease in two preclinical models. Terminal phenotyping included cardiac catheterisation, echocardiography, and pulmonary vascular immunohistochemistry.FindingsTRAIL mRNA and protein expression was upregulated in PASMCs from patients with pulmonary arterial hypertension. In vitro, TRAIL was a mitogen for PASMCs. TRAIL-deficient mice were protected from both hypoxia-induced and diet-induced pulmonary arterial hypertension. Antibody blockade prevented rats from developing toxin-induced disease. In BMT chimeras, only mice with expression of TRAIL restricted to tissue developed pulmonary arterial hypertension. In rodents with established pulmonary arterial hypertension, an anti-TRAIL antibody reversed pulmonary vascular remodelling, through reducing proliferation and inducing apoptosis, improved pulmonary haemodynamics, and significantly improved survival.InterpretationOur studies are the first to determine the importance of TRAIL in the pathogenesis of pulmonary arterial hypertension and demonstrate its potential for translation into a novel therapeutic targetFundingBritish Heart Foundation.     

Dynamic holographic imaging of the beating human heart

Background--Currently, the reporting and archiving of echocardiographic data suffer from the difficulty of representing heart motion on printable 2-dimensional (2D) media. Methods and Results--We studied the capability of holography to integrate motion into 2D echocardiographic prints. Images of normal human hearts and of a variety of mitral valve function abnormalities (mitral valve prolapse, systolic anterior motion of the mitral leaflets, and obstruction of the mitral valve by a myxoma) were acquired digitally on standard echocardiographic machines. Images were processed into a data format suitable for holographic printing. Angularly multiplexed holograms were then printed on a prototype holographic "laser" printer, with integration of time in vertical parallax, so that heart motion became visible when the hologram was tilted up and down. The resulting holograms displayed the anatomy with the same resolution as the original acquisition and allowed detailed study of valve motion with side-by-side comparison of normal and abnormal findings. Comparison of standard echocardiographic measurements in original echo frames and corresponding hologram views showed an excellent correlation of both methods (P<0.0001, r2=0.979, mean bias=2.76 mm). In this feasibility study, both 2D and 3D holographic images were produced. The equipment needed to view these holograms consists of only a simple point-light source. Conclusions--Holographic representation of myocardial and valve motion from echocardiographic data is feasible and allows the printing on a 2D medium of the complete heart cycle. Combined with the recent development of online holographic printing, this novel technique has the potential to improve reporting, visualization, and archiving of echocardiographic imaging.