Activation of cytotoxic lymphocytes by interferon-alpha: role of oxygen radical-producing mononuclear phagocytes

A significant part of the therapeutic benefit of interferon-alpha (IFN-alpha) therapy in malignant diseases and in chronic viral infections is assumed to result from activation of lymphocytes with natural killer (NK) and T cell phenotype. In tumor tissue and in chronically infected tissue, the function and viability of these lymphocytes are frequently impaired. Mononuclear phagocyte (MP)-derived reactive oxygen species (ROS) have been proposed to contribute to the lymphocyte suppression in these tissues. Here, we report that three types of human cytotoxic lymphocytes of relevance to immunoactivation by IFN-alpha, CD3epsilon+/8+/56- T cells, CD3epsilon-/56+ NK cells, and CD3epsilon+/56+ NK/T cells became anergic to IFN-alpha induction of the cell-surface activation marker CD69 after exposure to autologous MPs in vitro. In addition to their incapacity to express CD69, cytotoxic lymphocytes acquired features characteristic of apoptosis after incubation with MPs. The lymphocyte apoptosis and nonresponsiveness to IFN-alpha were prevented by two inhibitors of reduced nicotinamide adenine dinucleotide phosphate oxidase-dependent formation of ROS in MPs, histamine dihydrochloride and diphenylene ionodonium, as well as by catalase, a scavenger of ROS. We conclude that MP-derived ROS may negatively affect IFN-alpha-induced immunostimulation and propose that ROS inhibitors or scavengers may be useful to improve lymphocyte activation during treatment with IFN-alpha.     

Alleviating oxidative stress in cancer immunotherapy: a role for histamine?

Interleukin-2 is a remarkable activator of lymphocytes with anti-neoplastic properties such as T-cells or natural killer cells, but tumor regression only rarely occurs in interleukin-2-treated cancer patients. In this review, we focus on interactions between monocytes/macrophages and T-cells/natural killer-cells, and in particular the role of such interactions for the outcome of cancer immunotherapy with interleukin-2. We propose that interleukin-2 therapy should be supplemented with compounds that alleviate toxicity inflicted by monocyte/macrophagederived reactive oxygen metabolites within and around tumors. The hypothesis is founded on data demonstrating that (i) functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen metabolites, generated by neighboring monocytes/macrophages, (ii) interleukin-2 only weakly activates T-cells or natural killer cells in an environment of oxidative stress, and (iii) inhibitors of the formation of reactive oxygen metabolites or scavengers of reactive oxygen metabolites, synergize with interleukin-2 to activate these lymphocyte subsets. We also review the preclinical background to the use of histamine dihydrochloride, an inhibitor of reactive oxygen metabolite formation in monocytes/macrophages, as a supplement to cancer immunotherapy with interleukin-2.     

Histamine protects T cells and natural killer cells against oxidative stress.

Oxidative stress inflicted by monocytes/macrophages (MO) is recognized as an important immunosuppressive mechanism in human neoplastic disease. We report that two types of lymphocytes of relevance for protection against malignant cells, T cells and natural killer (NK) cells, became anergic to the T cell and NK cell activator interleukin-2 (IL-2) after exposure to MO-derived reactive oxygen metabolites and subsequently acquired features characteristic of apoptosis. The MO-induced anergy and apoptosis in T cells and NK cells were reversed by histamine, an inhibitor of reactive oxygen metabolite synthesis in MO. We propose that strategies to circumvent oxidative inhibition of lymphocytes may be of benefit in immunotherapy of neoplastic disease.     

Early planning of care and rehabilitation after amputation for vascular disease by means of Katz Index of Activities of Daily Living

The aim of the study was to investigate whether the Swedish version of the Katz Index of ADL (Activities of Daily Living), on days 5-7 after amputation for vascular disease, had predictive value regarding length of hospital stay, discharge to the patient's own home or death within 1 month. Patients who had recently undergone primary unilateral trans-tibial amputation, living in their own homes before the amputation, were included. Fifty-two patients with a median age of 78 years (60-92) were assessed with the Katz Index of ADL. Results revealed that of the 10 (20%) patients discharged to their own homes within 1 month, only 2 belonged to grades A-C, that is, were independent in the majority of functions in personal ADL. Within 6 months 62% were discharged to their own homes. Eighty-four percent of the patients in grades D-G, i.e. most dependent on others, were still at the hospital or dead 1 month post-operatively. All the patients who belonged to grades A-F survived the first month post-operatively. The Katz Index of ADL had predictive value regarding early outcome in terms of length of hospital stay, discharge to the patient's own home or death within 1 month, and positive predictive value regarding survival the first month post-operatively.     

Pharmacokinetics of moclobemide in male, virgin female, pregnant and nursing rats.

The disposition of moclobemide, a reversible inhibitor of monoamine oxidase isoenzyme A was studied in male, virgin female, pregnant and nursing rats. The average clearance in control rats (male and female) was 36 mL min-1 kg-1, the initial volume of distribution 1.4 L kg-1, the volume of distribution at steady state 2.3 L kg-1 and the terminal half-life 59 min. The blood-to-plasma concentration ratio of moclobemide was 0.84 giving rise to an average blood clearance of 30 mL min-1 kg-1. The clearance values in rats were higher than in man but as a fraction of hepatic blood flow were similar (36 vs 45%). The volume of distribution at steady state was approximately twice as high as in man while the half-life was similar. Pregnant and nursing rats showed no statistically significant differences in their disposition parameters for moclobemide compared with virgin female rats. Nursing rats had statistically significantly lower concentrations of the moclobemide N-oxide metabolite than did pregnant and control rats. Generally lower concentrations of the lactam metabolite were also found in this group although the differences did not reach statistical significance. Moclobemide as well as the N-oxide and lactam metabolites were found in the amniotic fluid suggesting that moclobemide is capable of crossing the placental barrier.     

High patient satisfaction after arthroscopic subacromial decompression for shoulder impingement: a prospective study of 50 patients

BACKGROUND: Arthroscopic subacromial decompression (ASD) for shoulder impingement has gained popularity. We evaluated the result of this common procedure prospectively, from a patient perspective. METHOD: We used the Disability of the Arm, Shoulder and Hand questionnaire (DASH) and the Visual Analogue Scale (VAS) to evaluate 50 patients with a mean age of 49 (27-72) years. All patients had undergone 6 months of failed nonoperative treatment prior to surgery. Exclusion criteria were total rotator cuff rupture, shoulder instability, clinically verified acromioclavicular joint osteoarthritis, calcifying tendonitis or neurological symptoms. All the decompressions were done by experienced shoulder arthroscopists. RESULTS: A significant improvement in both the median DASH score and the VAS had occurred 6 months after surgery. INTERPRETATION: ASD for impingement in properly selected patients performed by experienced surgeons gives a high degree of patient satisfaction 6 months after surgery.     

Hepatitis-associated antigen and antibody in Swedish blood donors. Relation to liver disease

Abstract. Screening of sera from 11,100 blood donors with an immunodiffusion method showed the presence of hepatitis-associated antigen (HAA) in 0.18% of the donors, and anti-HAA antibodies likewise in 0.18% of the donors. The antigen was found more often in men, while antibodies were demonstrated at a higher frequency in women. HAA was not found in any of the oldest donors (48–60 years), but anti-HAA antibodies were demonstrated in 0.31% of the oldest donors. The noted differences, however, were not statistically significant. 25 donors with HAA and 15 with antibodies were followed 4–12 months. Most of the HAA-positive donors (92%) had demonstrable antigen during the entire follow-up period, and some of these chronic antigen carriers (17%) had histopathological or biochemical signs of chronic liver disease. Presence of anti-HAA antibodies in serum was not associated with biochemical or histopathological abnormalities.