Hormone replacement therapy in healthy postmenopausal women. Effects on intraplatelet cyclic guanosine monophosphate, plasma endothelin-1 and neopterin

Abstract. Anwaar I, Rendell M, Gottsäter A, Lindgärde F, Hulthén UL, Mattiasson I (University of Lund, University Hospital, Malmö, Sweden). Hormone replacement therapy in healthy postmenopausal women. Effects on intraplatelet cyclic guanosine monophosphate, plasma endothelin‐1 and neopterin. J Intern Med 2000; 247: 463–470. Objectives. To evaluate beneficial effects of postmenopausal hormone replacement therapy (HRT) on endothelial function, measured as intraplatelet cyclic guanosine monophosphate (cGMP, mediator of nitric oxide), cyclic adenosine monophosphate (cAMP, mediator of prostacyclin) and plasma endothelin‐1 (ET‐1), and on monocyte activation, measured as plasma neopterin. Design. Part 1: double‐blind randomized trial for 3 months; part 2: open study for 9 months. Setting. The study was performed at the Department of Endocrinology, University Hospital, Malmö, Sweden. Subjects. Fifty‐one postmenopausal women participated in part 1 and 46 in part 2. Inclusion criteria included a history of amenorrhoea for at least 6 months before the study and body mass index ≥ 24 kg m^–2. Intervention. Randomization for either placebo (n = 24) or HRT (n = 27). HRT was given as 2 mg oestradiol valerate for the first 3 months with the addition of 10 mg medroxyprogesterone for 10 days every third month thereafter. Measurements. Performed at baseline and after 3 and 12 months of the study. Results. In the HRT group, intraplatelet cGMP increased from 0.56 (0.35–0.94) to 0.61 (0.42–3.40) and 0.65 (0.43–1.08) pmol (10⁹ platelets)^–1 after 3 and 12 months, respectively (P = 0.01), whereas plasma ET‐1 decreased from 3.2 (1.1–6.8) to 2.0 (0.8–5.1) and 1.8 (0.4–15.4) pg mL^–1 (P < 0.001). Intraplatelet cAMP and plasma neopterin were unchanged. When smokers (n = 15) and non‐smokers (n = 12) in the HRT group were analysed separately, significant effects were seen only amongst smokers. The control group showed unchanged levels of cGMP, cAMP, ET‐1 and neopterin. Conclusions. These data suggest beneficial effects of HRT on endothelial function which may account for anti‐atherogenic effects of HRT in postmenopausal women, especially in smokers. No effects of HRT were seen upon monocyte activation.     

单核细胞趋化蛋白-1与心力衰竭

炎症是心力衰竭的重要组成部分.然而其导致心力衰竭发生、发展的详细机制仍不清楚.单核细胞趋化蛋白.1是引起慢性炎症的主要趋化因子并且在心力衰竭的发病学中起着重要作用.抗单核细胞趋化蛋白-1将是治疗心力衰竭极有希望的措施.     

Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition

BACKGROUND AND AIMS: The extent and severity of mucosal injury in inflammatory bowel diseases are determined by the disequilibrium between 2 opposing processes: reparative and cytoprotective mechanisms vs. inflammation-induced injury. Probiotics may provide clinical benefit by ameliorating colitis; however, their mechanisms of action remain largely unknown. Our objective was to investigate microbial-epithelial interactions that could explain the beneficial therapeutic effects of probiotics. METHODS: The effect of VSL#3-conditioned media on the nuclear factor-kappaB pathway in young adult mouse colonic epithelial cells was assessed by using monocyte chemoattractant protein-1 enzyme-linked immunosorbent assays; IkappaBalpha, IkappaBbeta, and p105 immunoblot analysis; and nuclear factor-kappaB luciferase reporter gene and proteasome assays. Effects on heat shock proteins were determined by electrophoretic mobility shift assay and immunoblot for heat shock proteins 25 and 72 in young adult mouse colonic cells. Cytoprotection against oxidant injury was determined by chromium 51 release and filamentous and globular actin assays. RESULTS: VSL#3 produces soluble factors that inhibit the chymotrypsin-like activity of the proteasome in gut epithelial cells. Proteasome inhibition is an early event that begins almost immediately after exposure of the epithelial cells to the probiotic-conditioned media. In addition, these bacteria inhibit the proinflammatory nuclear factor-kappaB pathway through a mechanism different from the type III secretory mechanisms described for other nonpathogenic enteric flora. They also induce the expression of cytoprotective heat shock proteins in intestinal epithelial cells. CONCLUSIONS: The resulting inhibition of nuclear factor-kappaB and increased expression of heat shock proteins may account for the anti-inflammatory and cytoprotective effects reported for probiotics and may be a novel mechanism of microbial-epithelial interaction. These effects seem to be mediated through the common unifying mechanism of proteasome inhibition.     

Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity

BACKGROUND & AIMS: Inflammatory mediators released by nonparenchymal inflammatory cells in the liver have been implicated in the progression of acetaminophen (APAP) hepatotoxicity. Among hepatic nonparenchymal inflammatory cells, we examined the role of the abundant natural killer (NK) cells and NK cells with T-cell receptors (NKT cells) in APAP-induced liver injury. METHODS: C57BL/6 mice were administered a toxic dose of APAP intraperitoneally to cause liver injury with or without depletion of NK and NKT cells by anti-NK1.1 monoclonal antibody (MAb). Serum alanine transaminase (ALT) levels, liver histology, hepatic leukocyte accumulation, and cytokine/chemokine expression were assessed. RESULTS: Compared with APAP-treated control mice, depletion of both NK and NKT cells by anti-NK1.1 significantly protected mice from APAP-induced liver injury, as evidenced by decreased serum ALT level, improved survival of mice, decreased hepatic necrosis, inhibition of messenger RNA (mRNA) expression for interferon-gamma (IFN-gamma), Fas ligand (FasL), and chemokines including KC (Keratinocyte-derived chemokine); MIP-1 alpha (macrophage inflammatory protein-1 alpha); MCP-1 (monocyte chemoattractant protein-1); IP-10 (interferon-inducible protein); Mig (monokine induced by IFN-gamma) and decreased neutrophil accumulation in the liver. Hepatic NK and NKT cells were identified as the major source of IFN-gamma by intracellular cytokine staining. APAP induced much less liver injury in Fas-deficient (lpr) and FasL-deficient (gld) mice compared with that in wild-type mice. CONCLUSIONS: NK and NKT cells play a critical role in the progression of APAP-induced liver injury by secreting IFN-gamma, modulating chemokine production and accumulation of neutrophils, and up-regulating FasL expression in the liver, all of which may promote the inflammatory response of liver innate immune system, thus contributing to the severity and progression of liver injury downstream of the metabolism of APAP and depletion of reduced glutathione (GSH) in hepatocytes.     

Monocyte/macrophages and their role in HIV neuropathogenesis

Neurological sequelae of human immunodeficiency virus (HIV) infection have been and remain a significant problem. Monocytes and macrophages in humans and monkeys are susceptible to infection by HIV and simian immunodeficiency virus (SIV), and are considered to be a main mechanism by which the central nervous system (CNS) is infected. Within the infected CNS, perivascular macrophages and, in some cases, parenchymal microglia are infected as are multinucleated giant cells when present. While neurons are not themselves directly infected, neuronal damage occurs within the infected CNS. Despite the success of antiretroviral therapy (ART) in limiting virus in plasma to non-detectable levels, neurological deficits persist. This review discusses the continued neurological dysfunctions that persist in the era of ART, focusing on the roles of monocyte and macrophage as targets of continued viral infection and as agents of pathogenesis in what appears to be emergent macrophage-mediated disease resulting from long-term HIV infection of the host. Data discussed include the biology of monocyte/macrophage activation with HIV and SIV infection, traffic of cells into and out of the CNS with infection, macrophage-associated biomarkers of CNS and cardiac disease, the role of antiretroviral therapy on these cells and CNS disease, as well as the need for effective adjunctive therapies targeting monocytes and macrophages.     

Activation of Monocyte-Derived Cells in the Bone Marrow of Myelodysplastic Syndrome

Abstract

Object: To study the relationship between monocyte/histiocyte activation and myelodysplastic syndrome (MDS).

Methods: Analyzing ultrastructure and myeloperoxidase reaction of nucleated cells in bone marrow from 59 cases of MDS by transmission electron microscopy. Four groups of MDS were subdivided on the basis of their content of activated inflammatory cells – morbid hematopoiesis with minimal inflammatory cell activation (MH-MICA); MDS with monocytic system activation (MSA); MDS with lymphocyte activation (LCA); and MDS with granulocyte activation (GCA).

Results: About 20, 22, 7, and 10 cases were classified as MH-MICA (34%), MSA (37%), LCA (12%), and GCA sub-types (17%), respectively. About 3, 5, 0, and 3 cases from MH-MICA, MSA, LCA, and GCA, respectively, underwent leukemic transformation within 2 years.

Conclusion: The findings suggest that activation of inflammatory cells in bone marrow is an important feature of MDS, and that monocytes/histocytes are perhaps the most prominent cellular participants in the pathogenesis of MDS.     

乙型肝炎患者外周血单核细胞CD14^＋CD16^＋亚群及HLA-DR的检测及其意义

目的：通过检测乙型肝炎患者外周血单核细胞各亚群分布情况以及HLA—DR表达水平,探讨慢性乙型肝炎患者外周血中CD14^＋CD16^＋单核细胞及HLA-DR的表达特点,以及与疾病进程之间的关系。方法：利用流式细胞仪（FCM）检测50例慢性乙型肝炎患者,其中21例免疫耐受（IT）患者、29例免疫活化（IA）患者,及31例正常人外周血CD14、CD16、HLA—DR的表达。同时调查肝功能、乙肝五项和血清HBVDNA等相应临床资料。结果：免疫活化组（IA）的CD14^＋CD16^＋亚群比率明显高于正常对照组和免疫耐受组（IT）（P〈0．01）;单核细胞CD14^＋CD16^＋亚群HLA．DR表达明显高于CD14^＋CD16^＋亚群（P〈0．01）;乙型肝炎患者CD14^＋CD16^＋单核细胞比率与ALT呈正相关（r=0．876,P〈0．01）,与HBVDNA载量成负相关（r=-0．267,P〈0．01）。结论：CD14^＋CD16^＋单核细胞可能在乙型肝炎患者外周血中参与调节针对HBV的免疫反应,CD14^＋CD16^＋单核细胞与HBV复制和肝脏炎症之间存在相关性,因此检测单核细胞CD14^＋CD16^＋亚群及HLA-DR水平对于了解乙型肝炎患者疾病进程具有重要的临床应用价值。     

外周血血细胞参数在急性主动脉夹层与急性心肌梗死鉴别中的价值

目的　探讨外周血血细胞参数在急性主动脉夹层（ acute aortic dissection, AAD）与急性心肌梗死（ acute myocardial infarction ,AMI）鉴别诊断中的价值。方法　回顾性分析 2019年 1~9月就诊于徐州医科大学附属医院急诊科并于入院后完善相关检查确诊为 AAD的患者 30例,AMI患者 30例,及同期健康体检者 20例外周血血细胞参数水平变化,利用 ROC曲线评估相关参数的诊断鉴别价值。结果　与 AMI组相比较, AAD组单核细胞（ monocyte,MON）和血小板平均体积 /血小板比值（ MPP）水平较高,血小板（ platelet,PLT）、血小板平均体积（ mean platelet volume, MPV）水平较低,差异均有统计学意义（ t=-2.363~3.890, 均 P<0.05）;与健康对照组相比, AAD组白细胞（ white blood cell,WBC）、中性粒细胞（ neutrophils,NEU）、MON,中性粒细胞 /淋巴细胞比值（ NLR）、血小板分布宽度（ Platelet distribution width,PDW）和 MPP均升高,淋巴细胞（ lymphocyte,LYM）、PLT和 MPV均降低,差异有统计学意义（t=-5.283~5.565,均 P<0.05）。MON,PLT,MPV和 MPP对 AAD和 AMI鉴别诊断的 ROC曲线下面积（ Area under curve, AUC）分别为 0.662,0.753,0.652和 0.664,联合 MON和 MPP的 AUC为 0.749,联合 MON,PLT和 MPV的 AUC为 0.872,四项联合检测的 AUC为 0.874;与单项指标检测相比四项联合检测 AUC最大,敏感度为 80.00%,特异度为 86.67%。结论　应用 MON+PLT+MPV+MPP四项联合检测鉴别诊断 AAD与 AMI优于单项指标检测,有望在临床推广应用。     

含海洋药物的经方及其在妇科疾病治疗中的现代应用概况

通过分析《伤寒杂病论》中涉及的海洋药物及含海洋药物经方在现代妇科疾病辨治中的运用,并参照历代文献的相关阐述,探讨海洋药物药理作用的物质基础及临床应用的理论依据,分析海洋药物研究与发展的趋势,以帮助开拓用药思路,推动相关海洋药物治疗妇科疾病的现代化研究进程。     

Dose‐Intensified Granulocyte‐Monocyte Apheresis in Therapy Refractory Ulcerative Colitis

Granulocyte‐monocyte apheresis (GMA) is an emerging therapeutic option in active course of ulcerative colitis (UC). Appropriate GMA dose, including total number, frequency, and duration of the individual GMA session, is a matter of debate. It was the aim of the present study to evaluate the efficacy of a dose‐intensified GMA regimen in patients with moderately to severely active UC. A prospective open‐label, single‐center study was performed in 10 patients with active UC (Rachmilewitz Clinical Activity Index [CAI] ≥ 8 points; Rachmilewitz Endoscopic Index ≥ 7 points). Patients had failed to improve after treatment with steroids and/or immunomodulators. GMA was performed twice weekly for 2 h to a maximum of 10 sessions. In each GMA session, the adsorber was changed after 1 h of treatment time. Four patients achieved remission with a CAI ≤ 4 points. Three patients had a response with an improvement of CAI of ≥3 points. Three patients showed no benefit from GMA. The quality of life score determined by the inflammatory bowel disease questionnaire‐Deutschland increased by 26 points in median. First and second filters had similar efficiency in granulocyte and monocyte adsorption. No major adverse effects were observed. Dose‐intensified GMA as reported in this study provided an encouraging short‐term response rate of 70% in patients with moderately to severely active UC not responding to standard steroid or immunomodulator therapy. Although all patients relapsed not later than 16 weeks, GMA might be useful to reduce steroid and immunomodulator usage, or to delay surgery in this patient group.