Lack of involvement of reactive oxygen in the cytotoxicity of mitoxantrone,CI941 and ametantrone in MCF-7 cells: comparison with doxorubicin

Summary The MCF-7 cell S9 fraction and whole MCF-7 cells can mediate one-electron-redox cycling of doxorubicin, giving rise to concomitant oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH), formation of a drug semiquinone free radical, consumption of molecular oxygen and formation of superoxide anions and hydroxyl radicals. Doxorubicin redox cycling was consistent with DNA strand breakage and cell kill in MCF-7 cells. In contrast, no evidence for redox cycling was found for mitoxantrone (MIT), CI941 or ametantrone (AMET) in MCF-7 cells. Despite the absence of redox cycling, the CI941, MIT, and AMET concentrations resulting in 50% mortality (LC₅₀; 1.5×10^–10, 5.2×10^–9 and 1.2×10^–6 m, respectively) of MCF-7 cells were lower than that of DOX (3.0×10^–6 m). Furthermore, the higher cytotoxicity of MIT and CI941 as compared with AMET or DOX was associated with greater efficiency in inducing DNA strand breakage in MCF-7 cells as determined by alkaline elution. Sine MIT and CI941 proved to be the most potent DNA-damaging and cytotoxic agents in this study, the ability of DOX to undergo redox cycling does not appear to confer increased cytotoxic potential on this agent. The present study revealed several important aspects with regards to the structural modification of anthraquinone antitumour agents. Firstly, the C1 and C4 postitioning of the hydroxyethylamino side chains on MIT, CI941 and AMET is associated with a lack of flavin reductase-mediated activation of these agents. Secondly, the possession of a C5 or C8 aromatic hydroxyl group appears to be intimately involved in the enhanced DNA strand breakage and cytotoxic potency of MIT and CI941, since AMET does not possess these groups. These findings indicate that future development of quinone antitumour agents should concentrate on compounds that do not undergo redox cycling but do possess aromatic hydroxyl groups, since the latter appear to be responsible for the enhanced cytotoxicity of MIT and CI941.Abbreviations DOX doxorubicin - MIT mitoxantrone - AMET ametantrone - SOD superoxide dismutase - DMPO 5,5-dimethyl-1-pyrroline-N-oxide - ESR electron spin resonance - SSF strand scission factor This work was funded by the Cancer Research Campaign (UK)     

Carbamazepine in the treatment of phantom limb pain

The successful use of carbamazepine in treating a case of severe phantom limb pain prompted me to review this condition and its experiential treatment with carbamazepine, as well as the drug's possible mechanism of action on phantom limb pain. Experience to date indicates the need for controlled double-blind crossover studies to test the therapeutic validity of carbamazepine.     

Sociodemographic factors and obesity in preadolescent black and white girls: NHLBI's Growth and Health Study.

The association of sociodemographic and family composition data with obesity was studied in 1213 black and 1166 white girls, ages 9 and 10, enrolled in the National Heart, Lung, and Blood Institute''s Growth and Health Study. Obesity was defined as body mass index at or greater than age- and sex-specific 85th percentile as outlined in the Second National Health and Nutrition Examination Survey. The prevalence of obesity was higher for pubertal girls than for prepubertal girls and for girls with older mothers/female guardians. As odds ratio of 1.14 was observed for each 5-year increase in maternal age. Obesity was less common for girls with more siblings; the odds for obesity decreased by 14% for each additional sibling in the household. In blacks, the prevalence of obesity was not related to parental employment or to parental education. In whites, the odds of obesity were higher for girls with no employed parent/guardian in the household and for girls with parents or guardians with lower levels of educational attainment. Examining the associations between sociodemographic factors and risk of childhood obesity provides important clues for understanding racial differences in obesity, a major risk factor for coronary heart disease.     

Observation unit management of pediatric emergencies

Observation units for children in an Emergency Department setting can serve to improve the quality of medical care provided as well as reduce overall costs; however, they must be properly organized with careful consideration for the needs of children. Policies must be written specifying who is in charge as well as who can be accepted into these units and for how long. Procedures regarding documentation and sign-out must be formulated. These units must be well staffed and fully equipped, and they should be pleasant places for the children to stay; otherwise, what might begin as assets can quickly become disorganized and potentially dangerous liabilities.     

Detection of Trichomonas vaginalis in pregnant women with the InPouch TV culture system.

Trichomonas vaginalis causes a common genitourinary infection which is frequently asymptomatic. At present, pregnant women are not usually screened for the infection unless they are symptomatic. In the present study, we screened and obtained samples for culture from all pregnant women attending a prenatal clinic with the InPouch TV culture system and compared results with those of standard culture in Diamond's medium and slide wet mount examination. The InPouch TV culture system was as reliable as Diamond's medium in detecting T. vaginalis and may be useful and effective in a pregnancy clinic setting.     

The relationship of life adversity, social support, and coping to hospitalization with major depression.

We evaluated the relationship between life events, social support, coping, and depression in 27 male inpatients meeting the requirements for Research Diagnostic Criteria major depressive disorder and in 35 age- and sex-matched nonpatients. Overall, the hospitalized depressed patients reported significantly more events and difficulties than did the controls, but this difference in statistical significance disappeared after excluding from analysis "non-independent" happenings which could have been brought on by depression. More hospitalized depressed patients (23 of 27, or 85%) than controls (8 of 35, or 22.9%) experienced markedly threatening events and difficulties ("marked adversities") in the 6 months before their interview. The depressed group also reported having significantly fewer social supports, being less satisfied with the emotional component of this support, and using more emotion-focused coping than the controls. A discriminant analysis predicted depressive status from a combination of marked adversities, reduced number of social supports, and greater use of emotion-focused coping. The results indicate that the relationship of life events to depression is complex. The excess number of events might be partly a product of dysfunctional behavior that "produces" depression-related events which might, in turn, exacerbate depression; simultaneously, patients are more likely to experience highly adverse events which might precipitate the depression in the first place. Reduced social supports and the use of emotion-focused coping appear to also be associated with hospitalization for major depression.     

Assessment of bedside umbilical vein balloon septostomy using two-dimensional echocardiographic guidance in transposition of great arteries

The effectiveness of "bedside" balloon atrial septostomy via the umbilical vein using 2-dimensional echocardiography was compared to the traditional femoral vein approach using fluoroscopy in a series of neonates with transposition of great arteries from March, 1984 to April, 1987. There were 7 neonates who had balloon septostomy performed at the "bedside" (Group I) compared to 13 who had the procedure performed in the catheterization laboratory (Group II). Group II consisted of 7 newborns who had elective femoral vein catheterization under fluoroscopy (Group IIA) and 6 who failed "bedside" umbilical vein balloon septostomy and subsequently had the femoral vein approach under fluoroscopy (Group IIB). Results showed that adequacy of balloon septostomy was not related to the approach used, with 4 of 7 in Group I and 9 of 13 in Group II with an adequate atrial tear and clinical response. The Delay time to septostomy (i.e. time elapsed from initial assessment to commencement of balloon septostomy) and Procedure time (i.e. time taken to complete the balloon septostomy) was significantly shorter for Group I (mean time = 0.7 hours and 0.26 hours respectively) compared with Group IIA (mean time = 2.6 hours and 1.8 hours) and Group IIB (mean time = 2.4 hours and 1.4 hours). Of note, there was no significant increase in Delay time between Group IIA and IIB.(ABSTRACT TRUNCATED AT 250 WORDS)