冠心病患者炎症反应与血小板活化功能的关系

目的：探讨白介素－6,C－反应蛋白及α－颗粒膜蛋白与心绞痛的关系。方法：不稳定型心绞痛组25例（Ⅰ组）,分为急性（ⅠA组）和病情稳定（ⅠB两个阶段,稳定型心绞痛组（Ⅱ组）35例,正常对照组（Ⅲ组）30例。检测各组血清白介素－6浓度,C－反应蛋白水平,α－颗粒膜蛋白浓度。结果白介素－6,C－反应蛋白,α－颗粒膜蛋白水平ⅠA组均高于ⅠB组、Ⅱ组、Ⅲ组（P值均＜0．05）。ⅠB组、Ⅱ组3个指标比Ⅲ组高（P值均＜0．05）。ⅠB组、Ⅱ组比较差异无显著性（P＞0．05）,白介素－6,C－反应蛋白,α－颗粒膜蛋白浓度间彼此呈直线相关（P值均＜0．01）。结论①炎性细胞因子白介素－6及其诱生的急性相蛋白C－反应蛋白在心绞痛发病中起重要作用。②炎症反应影响心绞发生发展可能机制之一是通过激活血小板实现的。     

雌激素对氧化型低密度脂蛋白诱导的血管内皮细胞凋亡的影响

目的：观察雌激素（１７β－雌二醇）对氧化型低密度脂蛋白（ｏｘＬＤＬ）诱导人脐静脉内皮细胞（ＨＵＶＥＣ）凋亡的影响。方法 以ＨＵＶＥＣ为对象,观察不同浓度的１７β－雌二醇（１,１０和１００μｍｏｌ／Ｌ）对ｏｘＬＤＬ（４μｇ／Ｌ）诱导的凋亡的影响。结果 不同剂量的１７β－雌二醇对使用ｏｘＬＤＬ诱导的ＨＵＶＥＣ凋亡减少７０％￣９３％,其抑制呈明显的正向量效应关系,１７β－雌二醇１μｍｏｌ／Ｌ组细胞凋亡占     

Interleukin-12: A bridge between innate resistance and adaptive immunity with a role in infection and acquired immunodeficiency

Interleukin-12 (IL-12) is a disulfide-linked heterodimeric cytokine originally identified as a product of EBV-transformed B cell lines. Monocyte/macrophages are the physiologically most relevant producers of IL-12, in response to both Gram-positive and -negative bacteria, bacterial products, and intracellular parasites. Although IL-12 has an enhancing effect on the survival and growth of early hematopoietic progenitor cells, most of the IL-12 biological activity has been described on T and NK cells, on which it induces production of lymphokines, primarily IFN-, enhances cytotoxic activity, and, in cooperation with other stimuli, increases proliferation. IL-12 is an inducer of development of T helper type 1 (Th-1) cells and the equilibrium between IL-12 and IL-4 is probably important for the balancein vivo between Th-1 and Th-2 responses. IL-12 has an important role in the host resistance to infection, in particular to intracellular pathogens, by activating macrophages through induction of IFN- from NK and T cells and by enhancing cell-mediated immune responses, dependent on Th-1 cell development. Peripheral blood mononuclear cells from HIV-seropositive individuals are impaired in their ability to produce IL-12 in response to bacterial stimulation, and IL-12 restoresin vitro some of the depressed immunological functions, suggesting that a defect in IL-12 production may have a pathogenic role in the immunodeficiency of HIV-infected individuals. Natural IL-12 appears to provide a regulatory link between innate resistance and the development of the antigen-specific adaptive immune response and the recombinant protein has therapeutic potential because of its activity against tumors and infections and its effectiveness as an adjuvant enhancing cell-mediated immunity in vaccination.     

Biological response modifiers and infectious diseases: actual and potential therapeutic agents

Biological response modifiers (BRMs) are agents which can modify the immune response to cancer or invasion of the organism by infectious agents. An explosive appearance of new BRMs has resulted from the development of recombinant gene technology and the availability of monoclonal antibodies. Colony-stimulating factors first became available for the prevention of neutropenia but may also have a role in the treatment of infections. Interleukin-1 is being tested as a modular of hematopoiesis and may be useful as a helper factor for T- and B-cell function. Immunoglobulins are being used against viral and bacterial infections while interferons can prevent viral upper respiratory infections and suppress or irradicate some viral hepatitides. Other BRMs which show promise include chemical agents and traditional herbal medicines.     

Interleukin-1β-converting enzyme and related proteases as potential targets in inflammation and apoptosis

Summary Interleukin-1-converting enzyme (ICE, EC 3.4.22.36) is the cysteine protease responsible for the production of interleukin-1 in monocytes. Since its discovery in 1989, this enzyme has been the subject of enthusiastic investigation because of the suspected role of this cytokine in the pathogenesis of inflammatory diseases such as rheumatoid arthritis. These studies have culminated in the purification and cloning of the enzyme, development of potent inhibitors, determination of its structure by X-ray crystallography and the development of knockout mice, which have confirmed an important role for this protease in inflammation. Late in 1993, the protease became the subject of further interest because of its homology to CED-3, the product of a gene required for programmed cell death in the nematodeC. elegans. It is now clear that ICE is the first identified member of a new cysteine protease family that includes CED-3 and at least four other human homologues. Although the extent to which ICE itself plays a role in mammalian apoptosis remains controversial, it is clear that at least one of these homologues, CPP32, is an important player. The recognition that members of this family play key biological roles in both inflammation and apoptosis, two extremely attractive targets for therapeutic intervention, has led to intense interest in these proteases.     

Clinical application of18F-FUdR in glioma patients — PET study of nucleic acid metabolism

Summary Positron emission tomography was used to investigate the metabolism of nucleic acids by¹⁸F-fluoro-2-deoxyuridine (¹⁸F-FUdR) in 22 patients with gliomas. Sixteen cases of high grade glioma clearly demonstrated a region of high activity with a differential absorption rate (DAR) of 0.64 ± 0.34. Six cases of low grade glioma failed to reveal a positive image of the tumor and the DAR in tumor was 0.21 ± 0.042 (p < 0.01). This PET-¹⁸F-FUdR study succeeded in differentiating high and low grade gliomas from the view point of nucleic acid metabolism.     

Isolation perfusion in extracorporeal circulation with interleukin-2 and lymphokine-activated killer cells in the treatment of in-transit metastases from limb cutaneous melanoma

Background: Therapies of advanced melanoma patients with interleukin-2 (IL-2) and cytotoxic lymphocytes have produced interesting results, but a larger diffusion of these treatments is limited by the severe side effects due to IL-2 systemic infusion. A strictly regional administration of IL-2 and cells by an isolation perfusion (IP) in extracorporeal circulation (ECC) for the treatment of regional melanoma metastases could improve tolerability and efficacy of this specific modality of immunotherapy. Methods: Ten patients were submitted to adoptive immunotherapy with IL-2 and lymphokine-activated killer (LAK) cells by IP in ECC. The schedule of treatment included the first course of a 5-day systemic administration of IL-2 (Proleukin, EuroCetus 9–12 × 10⁶ IU/M²/day continuous infusion); autologous LAK cells were obtained via leukapheresis and after in vitro activation were given (range 8–28 × 10⁹) along with IL-2 (120-2,400 IU/ml of perfusion priming) to the affected limb by IP; IL-2 (9–12×10⁶ IU/m²/day) was also administered by systemic continuous infusion for 5 days starting on the day after IP. Results: All patients concluded the treatment without any major local or systemic toxicities. Clinical responses included one complete and six partial remissions; three patients had stable disease. All patients are alive. Follow-up after IP ranged from 12 to 35 months (median: 22). The analysis of circulating lymphocytes revealed the rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. Conclusions: IP with IL-2 and LAK cells is a new approach for the treatment of in-transit metastases due to cutaneous melanoma. The treatment appears to be feasible and reliable. Further biological and immunological studies should permit amelioration of the present modality of treatment.     

Diuretic-related hypokalaemia: the role of diuretics,potassium supplements,glucocorticoids and β2-adrenoceptor agonists

All 5,047 consecutive inpatients admitted to the Internal Medicine Division of a teaching hospital (Zieglerspital, Berne) between 1982 and 1985 were registered in accordance with the CHDM (Comprehensive Hospital Drug Monitoring) questionnaire of adverse drug reactions (ADRs). Of them, 2,439 were treated with at least one potassium losing diuretic. The hospital records of the patients were reviewed with particular regard to serum potassium levels, and on the basis of this evaluation, the patients were assigned to four different diuretic treatment groups, and the incidence of hypokalaemia related to diuretic treatment was estimated. The overall rate of occurrence of hypokalaemia was 21.1% at a serum potassium level <3.5 mmol·1^–1, and 3.8% <3.0 mmol·1^–1. Hypokalaemia of less than 3.5 mml·1^–1 developed 24.9% (217/870) of patients treated with potassium losing diuretics alone; in 19.7% (101/513) treated with potassium losing diuretics in conjunction with potassium substitution, in 15.1% (66/438) treated with a combination of diuretics (potassium losing with potassium sparing), and in 20.0% (12/60) treated with combined diuretics and potassium substitution. Only the differences between the first and the two subsequent groups were statistically significant. The overall incidence of hypokalaemia below 3.0+mmol·1^–1 was significantly lower in the patients on combined diuretics without potassium substitution than in the patients on potassium losing diuretics with potassium substitution.Oral or parenteral administration of glucocorticoids (prednisone 5 to 2,000 mg/d) was a significant risk factor for hypokalaemic events. ₂-Adrenoceptor agonists had not effect. The patient's age, sex, renal function and numbers of drugs received were evaluated in a multivariate analysis, in order to take into account their influence on the risk of developing hypokalaemia. The number of drugs above 12 (and, less importantly, female sex) was the main risk factor for this ADR.The comparison between hypokalaemia and hyperkalaemia in this group of inpatients showed the significance of reduced renal function in the occurrence of hyperkalaemia.     

Adoptive Immunotherapy With Tumor-Infiltrating Lymphocytes and Subcutaneous Recombinant Interleukin-2 Plus Interferon Alfa-2a for Melanoma Patients With Nonresectable Distant Disease: A Phase I/II Pilot Trial

Background: On the basis of our previous experience, we designed this study to determine the activity and toxicity of outpatient treatment with autologous tumor-infiltrating lymphocytes (TIL) together with intermediate-dose recombinant interleukin-2 (rIL-2) and low-dose recombinant interferon alfa-2a (rIFN-2a), for patients with metastatic melanoma.Methods: Between April 1992 and October 1994, we processed 38 melanoma samples derived from 36 patients with metastases. Proliferative cultures of expanded lymphocytes (TIL) were infused only once into patients with metastatic melanoma. rIL-2 was administered subcutaneously for 1 month, starting on the day of TIL infusion, at an escalating dose of 6–18 × 10⁶ IU/m²/day for the first week and at the maximum-tolerated dose for the subsequent 3 weeks and then, after a 15-day interval, for 1 week/month for 3 months. rIFN-2a was administered subcutaneously at 3 × 10⁶ IU three times each week until progression.Results: Of 38 melanoma samples, 19 (50%) resulted in proliferative cultures and were infused. The median number of expanded lymphocytes was 18 × 10⁹ (range, 1–43 × 10⁹), and the median period of culture was 52 days (range, 45–60). rIL-2 was administered at doses ranging between 6 and 18 × 10⁶ IU/m²/day. Toxicity was mild or moderate, and no life-threatening side effects were encountered. Two of 19 treated patients experienced complete responses of their metastatic sites (soft tissue), 10 had stable disease, and 7 showed progressive disease. The response rate was 11% (95% confidence interval, 2–35%).Conclusions: Outpatient treatment with TIL plus rIL-2 and rIFN-2a is feasible, although, within the context of the small sample size, the activity of the combination was no different from the reported activity of any of the components used alone.     

Inflammatory mechanisms in Alzheimer's disease

In recent years many studies have indicated an involvement of inflammatory mechanisms in Alzheimer's disease (AD). Acute-phase proteins such as 1-antichymotrypsin and c-reactive protein, elements of the complement system, and activated microglial and astroglial cells are consistently found in brains of AD patients. Most importantly, also cytokines such as interleukin-6 (IL-6) have been detected in the cortices of AD patients, indicating a local activation of components of the unspecific inflammatory system. Up to now it has remained unclear whether inflammatory mechanisms represent a primary event or only an unspecific reaction to brain tissue damage. Therefore, we investigated whether IL-6 immunoreactivity could be found in plaques prior to the onset of neuritic changes, or whether the presence of this cytokine is restricted to later stages of plaque pathology. we confirmed our previous observation that IL-6 is detectable in a significant proportion of plaques in the brains of demented patients. In AD patients IL-6 was found in diffuse plaques in a significant higher ratio as would have been expected from a random distribution of IL-6 among all plaque types. This observation suggests that IL-6 may precede neuritic changes, and that immunological mechanism may be involved both in the transformation from diffuse to neuritic plaques in AD and in the development of dementia.