Superoxide inhibition following different stimuli of respiratory burst and metabolism of aminosalicylates in neutrophils

Reactive oxygen species such as superoxide radicals have been proposed to play an important role in the pathogenesis of inflammatory bowel disease. Some of the antiinflammatory actions of aminosalicylates have been ascribed to their capability to scavenge superoxide radicals directly or to inhibit its production in stimulated neutrophils. However, as a controversy still exists with regard to the precise mechanisms of inhibition and the metabolism within inflammatory cells, we compared scavenger properties of 5-aminosalicylic acid, 4-aminosalicylic acid,N-acetyl aminosalicylic acid, olsalazine, and benzalazine in systems with defined superoxide radical generation such as the dimethyl sulfoxide-NaOH and the potassium superoxide system. We also studied possible inhibition of the superoxide production following different stimuli of the respiratory burst in neutrophils and investigated the uptake and potential metabolism (N-acetylation) of 5-aminosalicylic acid in lipopolysaccharide-primed and resting neutrophils. We found that 5-aminosalicylic acid and 4-aminosalicylic acid had defined scavenger properties in the dimethyl sulfoxide-NaOH or potassium superoxide systems, respectively, whereas compounds with a modified aminophenolic structure had no effects. At the cellular level, 5-aminosalicylic acid inhibited phorbol myristate acetate (100 ng/ml)-activated superoxide generation to 82.3±9.3%, the formylmethionyl leucyl peptide (10^–5 M) to 61.0±6.8%, and the NaF (20 mM) -stimulated production to 32.3±3.2% (X±sd,P<0.01). the=" actions=" of=" the=" other=" drugs=" were=" less=" pronounced.=" almost=" identical=" retention=" times=">R _t=11.2 min) of³H-labeled phorbol myristate acetate in the presence and absence of 5-aminosalicylic acid revealed noin vitro interactions. 5-Aminosalicylic acid permeates cells in a dose- and time-dependent manner; there was, however, no acetylation of 5-aminosalicylic acid regardless whether the cells had been stimulated or not with lipopolysaccharide. From our results we suggest that (1) the extra- (scavenger) and intracellular inhibition of superoxide radicals by 5-aminosalicylic acid may be an important mechanism of action, (2) an intact aminophenolic structure may be necessary for such actions, and (3) the inability of inflammatory neutrophils to acetylate and, therefore, inactivate 5-aminosalicylic acid could be an important determinant for its local actions.This work was supported by a grant from Kabi-Pharmacia GmbH, Erlangen, Germany.     

Effects of Blood Donation on the Physical Fitness and Hemorheology of Healthy Elderly Donors

Background: International regulations for blood donation recommend a maximum donor age of 65 years. As the average population age is steadily rising in western societies, a considerable group of volunteers is lost to the donor base. Study Design and Methods: In a prospective study we investigated the effect of a 450-ml whole blood donation on the physical fitness and hemorheology of regular elderly allogeneic blood donors (n = 24, aged 63–69 years, mean = 65). Results were compared with a younger group of regular donors (n = 23, aged 55–62 years, mean = 58) and a group of elderly subjects (n = 7, aged 63–66 years, mean = 65), who did not donate blood for this study. Assessing the physical fitness, we determined the submaximal physical working capacity at a heart rate of 130 min^?1 (PWC 130) and the maximal working capacity (MWC) by treadmill exercise testing the day before (day ?1) and after donation (day + 1). The impact of the blood loss on hemorheology was examined by analyzing the plasma viscosity before, during and after donation. Results: We found an increase of mean values of PWC 130 and MWC on day +1 in all study groups, but increases were only significant in the younger group (PWC 130 p = 0.03; MWC p = 0.04). Values did not differ significantly between the three groups. Plasma viscosity decreased significantly directly after donation in both groups of donors. Conclusion: A single blood donation did not alter the physical fitness of otherwise healthy elderly people. The older blood donors and the younger controls showed a similar compensation mechanism to blood loss. We found no general reason for disqualifying blood donors aged 65 years from donating.     

Active surveillance in favorable intermediate-risk prostate cancer patients: Predictors of deferred intervention and treatment choice

IntroductionActive surveillance (AS) is increasingly used for favorable intermediate-risk (FIR) prostate cancer (PCa). Our objective was to determine oncological and sociodemographic predictors of deferred definitive therapy and decision for radical prostatectomy (RP) vs. radiotherapy (RT).MethodsThe Surveillance, Epidemiology, and End Results (SEER) Prostate with Watchful Waiting database was used to identify all FIR PCa diagnosed between 2010 and 2015 opting for AS for at least one year following diagnosis. We sought to determine predictors of treatment and treatment type using multivariable logistic regression.ResultsA total of 20 334 patients were identified. An annual decrease in incident FIR patients managed initially with AS between 2010 (4061) and 2015 (2947) was noted (p for trend <0.001); 17 895 (88.0%) patients underwent deferred RP and/or RT. Patients with higher baseline cancer volume and clinical stage were significantly more likely to discontinue AS. Patients of higher socioeconomic status were more likely to undergo deferred therapy, with increased odds for RT over RP. African American patients had lower odds of undergoing definitive intervention (odds ratio 0.83, p=0.030) and were significantly more likely to opt for XRT. Oncological characteristics leading to FIR classification influenced treatment choice at the time of deferred intervention: RT was treatment of choice in 86.3% and 86.0% of Gleason group 2 and prostate-specific antigen 10–20 FIR patients, respectively; 96.1% of treated cT2b-c FIR patients opted for RP.ConclusionsMost FIR PCa patients initially managed with AS eventually undergo deferred definitive therapy, with choice of treatment significantly influenced by patients’ baseline oncological and sociodemographic characteristics.     

Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2

Human T-cell lymphotropic virus I (HTLV-I)-induced adult T-cell leukemia (ATL) cells constitutively express interleukin-2 (IL-2) receptors identified by the anti-Tac monoclonal antibody (MoAb), whereas normal resting cells do not. This observation provided the scientific basis for a trial of intravenous anti-Tac in the treatment of nine patients with ATL. The patients did not suffer untoward reactions and did not have a reduction in the normal formed elements of the blood, and only one of the nine produced antibodies to the anti-Tac MoAb. Three patients had transient mixed, partial, or complete remissions lasting from 1 to more than 8 months after anti-Tac therapy, as assessed by routine hematologic tests, immunofluorescence analysis of circulating cells, and molecular genetic analysis of HTLV-I provirus integration and of the T-cell receptor gene rearrangement. The precise mechanism of the antitumor effects is unclear; however, the use of a MoAb that prevents the interaction of IL-2 with its receptor on ATL cells provides a rational approach for the treatment of this malignancy.