Interleukin 2 induction of lymphokine-activated killer (LAK) activity in the peripheral blood and bone marrow of acute leukemia patients. I. Feasibility of LAK generation in adult patients with active disease and in remission

The feasibility of in vitro interleukin 2 (IL-2) activation and expansion of mononuclear cells (MNCs) derived from adult patients with acute myelogenous leukemia (ANLL) was studied. Patients' natural killer (NK) and lymphokine-activated killer (LAK) cell activity was compared with that of normal donors in terms of: (a) cytolytic activity (four- hour 51Cr release assay) against an NK-sensitive target (K562), NK- resistant targets (Raji/Daudi), and fresh/cryopreserved autologous and allogeneic leukemic blasts; (b) proliferation and expansion in culture with 1,000 U/mL recombinant IL 2 (rIL 2); and (c) the cell surface phenotype of the cultured cells. In 21 of 24 patients with active disease (AP) MNCs derived from the peripheral blood (PBL) or bone marrow (BM) could be cultured and expanded in the presence of rIL 2. These cultures initially contained between 30% and 50% blasts, and during 2 to 4 weeks of culture destruction of blasts and enrichment of up to 60% in cells with the morphology of large granular lymphocytes (LGLs) was observed. Expansion in culture varied between two- and 100- fold. MNCs from all patients in remission (RP) could be activated by rIL 2 and expanded up to 30-fold after 1 to 3 weeks in culture. NK activity of fresh PBLs from AP was significantly lower than in normal controls, whereas NK activity of RP was within the normal range. High levels of postactivation NK and LAK activity on K562/Raji/Daudi and on fresh/cryopreserved leukemic blasts was generated in approximately 50% of cases of AP and in most RP. Cell surface phenotype studies showed that cultured cells derived from ANLL patients were significantly enriched (up to 40%) in NKH-1 (Leu 19) positive cells, with RP LAK cells also expressing a high proportion of CD16 positive cells (up to 40%). This study has shown that it is feasible to activate and significantly expand killer cells derived from active disease and remission ANLL patients during 1 to 3 weeks culture with IL 2 with good maintenance of cytolytic activity. Both initial NK activity and LAK generation was optimal in remission patients. Based on data from this study, a clinical protocol has been developed for treatment of early relapse ANLL patients with LAK cells cultured for 1 to 3 weeks and systemic IL 2.     

An inhibitory monoclonal antibody to factor X that blocks prothrombin activation but not prothrombinase enzyme assembly

A monoclonal antibody (designated alpha BFX-2b) prepared against bovine factor X inhibited factor X activity in human, bovine, porcine, rabbit, and canine plasma. In assays using purified prothrombinase components, factor Xa, factor Va, phospholipid vesicles, and calcium ion with the fluorescent active site thrombin inhibitor dansylarginyl-N-(3-ethyl-1,5- pentanediyl)amide, the antibody inhibited the conversion of prothrombin to thrombin. Antibody alpha BFX-2b also blocked prothrombinase cleavage of the macromolecular substrates prethrombin 1 and prethrombin 2 but did not inhibit factor Xa hydrolysis of the synthetic substrate benzoyl- Ile-Glu-Gly-Arg-p-nitroanilide. The antibody also prevented the inactivation of factor Xa by antithrombin III but did not prevent the inactivation by soybean trypsin inhibitor. Antibody alpha BFX-2b bound factor Xa with a stoichiometry of 1:1 and an apparent dissociation constant of 9.0 x 10(-11) mol/L as estimated from its inhibition of prothrombinase activity. Antibody alpha BFX-2b did not prevent binding of factor Xa to factor Va-phospholipid as measured by using fluorescence polarization or high-pressure liquid gel chromatography with the fluorescent Factor Xa analogue dansyl-glutamyl-glycyl-arginyl- Xa. Immunoblotting of factor X following electrophoresis on sodium dodecyl sulphate-polyacrylamide gels and transfer to nitrocellulose indicated that the antigenic determinant recognized by antibody alpha BFX-2b was found on the heavy chain of factors X and Xa. From these observations it can be concluded that antibody alpha BFX-2b recognizes a highly conserved epitope on the factor X heavy chain that is remote from the topographic sites required for prothrombinase complex assembly and substrate hydrolysis but may be located at or near a portion of the macromolecular substrate binding site.     

Cystic fibrosis: An update for clinicians. Part 2: Hepatobiliary and pancreatic manifestations

This paper, the second in the series, will build on the first and explore the importance of liver and pancreatic manifestations of cystic fibrosis (CF) and the effect on morbidity and mortality of this multifaceted genetic condition. It will also further develop the critical role of the gastroenterologist as part of the multidisciplinary group of clinicians and allied health staff in the effective management of patients with CF.     

L-精氨酸对糖尿病大鼠心肌缺血再灌注损伤的影响

目的:观察糖尿病大鼠心肌缺血再灌注时血管紧张素Ⅱ、胰岛素样生长因子1、醛固酮、细胞间黏附分子1和自由基代谢的变化及L-精氨酸对其的影响。方法:实验于2005-02/2006-06在江苏大学医学院机能学实验室完成。①实验分组:腹腔注射链脲佐菌素制作糖尿病大鼠模型,30只大鼠造模成功。按随机数字表法分为3组(n=10):心肌缺血再灌注组:开胸结扎冠脉,造成心肌缺血,60min后放松再灌注60min;L-精氨酸治疗组:于手术前4周灌胃L-精氨酸250mg/(kg·d),然后重复心肌缺血再灌注组操作;假手术组:完成操作后只穿线不结扎,观察2h作为对照。实验结束时心室取血6mL,摘取心脏,留取左心室心肌组织。②实验评估:检测大鼠血浆血管紧张素Ⅱ、醛固酮和血清胰岛素样生长因子1含量及心肌细胞间黏附分子1蛋白表达。检测大鼠血清、心肌组织超氧化物歧化酶、谷胱甘肽-过氧化物酶活性、丙二醛含量及心肌线粒体Na ,K -ATP酶、Mg2 -ATP酶、Ca2 -ATP酶活性。结果:30只大鼠全部进入结果分析。①与假手术组相比,心肌缺血再灌注组血浆血管紧张素Ⅱ、醛固酮含量明显升高(P<0.05～0.01),血清胰岛素样生长因子1含量降低(P<0.05);L-精氨酸治疗4周后血浆血管紧张素Ⅱ、醛固酮含量低于心肌缺血再灌注组(P<0.05～0.01),血清胰岛素样生长因子1含量高于心肌缺血再灌注组(P<0.05)。②与假手术组相比,心肌缺血再灌注组血清、心肌丙二醛含量明显升高(P<0.05),血清、心肌超氧化物歧化酶和谷胱甘肽-过氧化物酶活性明显降低(P<0.05￣0.01);用L-精氨酸治疗4周后血清、心肌丙二醛含量低于心肌缺血再灌注组(P<0.05￣0.01),血清、心肌超氧化物歧化酶和谷胱甘肽-过氧化物酶活性高于心肌缺血再灌注组(P<0.05～0.01)。③与假手术组相比,心肌缺血再灌注组心肌线粒体Na ,K -ATP酶、Mg2 -ATP酶、Ca2 -ATP酶活性明显降低(P<0.05),心肌细胞间黏附分子1蛋白表达明显升高(P<0.01);用L-精氨酸治疗4周后心肌线粒体Na ,K -ATP酶、Mg2 -ATP酶、Ca2 -ATP酶活性明显高于心肌缺血再灌注组(P<0.05),心肌细胞间黏附分子1蛋白表达低于心肌缺血再灌注组(P<0.05)。结论:血管紧张素Ⅱ、醛固酮和胰岛素样生长因子1可能共同参与了糖尿病心肌缺血再灌注的发生,细胞间黏附分子1蛋白表达与糖尿病心肌损伤关系密切。L-精氨酸通过减少细胞间黏附分子1蛋白表达,起心肌保护作用。糖尿病心肌缺血再灌注时存在自由基代谢异常,补充L-精氨酸后,可通过提高超氧化物歧化酶、谷胱甘肽-过氧化物酶和ATP酶活性,降低丙二醛水平,减轻自由基损伤,改善心肌组织功能。     

Systematic review of the predictors of health service use in pancreatic cancer

Introduction: Pancreatic cancer (PC) has a dismal prognosis, with identified disparities in survival outcomes based on demographic characteristics. These disparities may be ameliorated by equitable access to treatments and health services. This systematic review identifies patient and service-level characteristics associated with PC health service utilisation (HSU). Methods: Medline, Embase, CINAHL, PsycINFO and Scopus were systematically searched between 1^st January, 2010 and 17 May, 2021 for population-based, PC studies which conducted univariable and/or multivariable regression analyses to identify patient and/or service-level characteristics associated with use of a treatment or health service. Direction of effect sizes were reported in an aggregate manner. Results: Sixty-two eligible studies were identified. Most (48/62) explored the predictors of surgery (n=25) and chemotherapy (n=23), and in populations predominantly based in the United States of America (n=50). Decreased HSU was observed among people belonging to older age groups, non-Caucasian ethnicities, lower socioeconomic status (SES) and lower education status. Non-metropolitan location of residence predicted decreased use of certain treatments, and was associated with reduced hospitalisations. People with comorbidities were less likely to use treatments and services, including specialist consultations and palliative care but were more likely to be hospitalised. A more recent year of diagnosis/year of death was generally associated with increased HSU. Academically affiliated and high-volume centres predicted increased treatment use and hospital readmissions. Conclusion: Findings of this review may assist identification of vulnerable patient groups experiencing disparities in accessing and using treatments and therapies.     

Drinking patterns, dependency and life-time drinking history in alcohol-related liver disease

Aims   To examine the hypothesis that increases in UK liver deaths are a result of episodic or binge drinking as opposed to regular harmful drinking.
Design   A prospective survey of consecutive in-patients and out-patients.
Setting   The liver unit of a teaching hospital in the South of England.
Participants   A total of 234 consecutive in-patients and out-patients between October 2007 and March 2008.
Measurements   Face-to-face interviews, Alcohol Use Disorders Identification Test, 7-day drinking diary, Severity of Alcohol Dependence Questionnaire, Lifetime Drinking History and liver assessment.
Findings   Of the 234 subjects, 106 had alcohol as a major contributing factor (alcoholic liver disease: ALD), 80 of whom had evidence of cirrhosis or progressive fibrosis. Of these subjects, 57 (71%) drank on a daily basis; only 10 subjects (13%) drank on fewer than 4 days of the week—of these, five had stopped drinking recently and four had cut down. In ALD patients two life-time drinking patterns accounted for 82% of subjects, increasing from youth (51%), and a variable drinking pattern (31%). ALD patients had significantly more drinking days and units/drinking day than non-ALD patients from the age of 20 years onwards.
Conclusions   Increases in UK liver deaths are a result of daily or near-daily heavy drinking, not episodic or binge drinking, and this regular drinking pattern is often discernable at an early age.     

Risk factors of sudden infant death and of death by accidents. According to a national survey in the total postneonatal death]

BACKGROUND. The incidence of sudden infant death syndrome (SIDS) peaks at 2-4 month of age and during the colder months of the year. Other risk factors such as sex, birth weight, maternal age and multiple pregnancy also seem to be shared by the other causes of death after the neonatal period. POPULATION AND METHODS. A retrospective, exhaustive survey of all deaths of infants aged 28 days-one year was carried out between September 1986 to December 1987. The control group was a representative sample of the live births in France during 1989. The deaths were classified into 3 groups: group I, 1184 SIDS, group II 228 SIDS remaining unexplained after autopsy (out of 315 autopsied SIDS), and group III 83 accidental deaths. The factors studied were: sex, birth weight, maternal age, number of infants born from the pregnancy. The risk factors were measured by Odds Ratios and the variables related to mortality were introduced into a logistic model. RESULTS. Incidence of deaths peaked between the 2nd and the 4th month of age in groups I and II while deaths were evenly distributed throughout the first year in group III. Colder months, male gender, low birthweight, multiple birth and the young age of the mother all increased the risk of death in SIDS (groups I and II) but the same factors were also linked to accidental deaths. CONCLUSION. The results confirm those of earlier reports and raise the question why the risk factors for accidental deaths are similar to those for explained or unexplained SIDS, except for infant age.