Selective abstraction of 2H from C-5'' of thymidylate in an oligodeoxynucleotide by the radical center at C-6 of the diradical species of neocarzinostatin: chemical evidence for the structure of the activated drug-DNA complex.

Use has been made of the mechanism of DNA deoxyribose damage by the ene-diyne-containing chromophore of the antitumor antibiotic neocarzinostatin to provide chemical evidence for the structure of the activated drug-DNA complex. Radical centers at C-2 and C-6 of the diradical form of the glutathione-activated chromophore abstract hydrogen atoms from C-1' of the C residue and C-5' of the T residue in AGC.GCT to generate a bistranded lesion consisting of an abasic site at C and a strand break at T. This laboratory has proposed a molecular model for the drug-DNA interaction in which the naphthoate moiety of the chromophore intercalates between A.T and G.C, placing the diradical core in the minor groove, so that the radical centers at C-6 and C-2 are close to C-5' of T and C-1' of C, respectively. To determine which radical center abstracts one of the hydrogen atoms from C-5', the self-complementary oligodeoxynucleotide GCAGCGCTGC was synthesized with 2H at both 5' positions of the T residue and treated with glutathione-activated chromophore. Sequencing-gel electrophoresis showed that drug attack was limited to the T and C residues and that abstraction of 2H from C-5' exhibited a small isotope selection effect of 1.25. 1H NMR spectroscopic examination of the reacted chromophore, isolated by HPLC, indicated that 2H was selectively abstracted by C-6, providing experimental corroboration of the model and further elucidating the chemical mechanism. Since direct strand breakage at the T residue exceeds (44% more) abasic site formation at the C residue, other models of drug-DNA interaction leading to only single-strand breaks are also considered.     

Preventive care: do we practice what we preach?

We used insurance claims from enrollees in the Rand Health Insurance Experiment to determine the amount of selected components of preventive care received by a representative sample of the non-aged population in the United States and to determine whether insurance coverage was an important determinant of that amount. Only 45 percent of infants received timely immunization for DPT and polio; 93 per cent received some well child care by 18 months of age. In the three-year experimental period, only 4 per cent of adults had a tetanus shot, 66 per cent of women aged 17-44 and 57 per cent aged 45-65 received a Pap smear, and 2 per cent of women aged 45-65 had a mammogram. Cost sharing was associated with even less preventive care: 60 per cent of children on the free plan and 49 per cent on cost sharing plans received preventive care of any type. For adults, women on the free plan received more preventive care of several kinds, and those aged 45-65 received more Pap smears than those on cost-sharing plans. Even with free care, most enrollees did not receive adequate preventive care. Thus, free care alone, while significant, is not a sufficient incentive to providing recommended levels of preventive care. The average per person insurance charge for increasing the amount of preventive care to a level consistent with that recommended would be $22 for a complete set of immunizations by age 18 months, $9 for a Pap smear every three years, and $97 for a Pap test and mammogram every three years.     

Vestibular-nerve inputs to the vestibulo-ocular reflex: a functional-ablation study in the squirrel monkey

Advantage was taken of differences in the electrical excitability of vestibular-nerve fibers to characterize the afferent input to the canal-related vestibulo-ocular reflex. Large anodal (inhibitory) currents, when delivered to both ears, result in a selective, reversible ablation of irregular afferents. Their background discharge and responses to head rotations are temporarily abolished. The same currents have less effect on the background discharge and no effect on the rotational sensitivity of regular afferents. Eye movements were evoked by head rotations in alert monkeys. The ablating currents did not alter the ocular responses to sinusoidal head rotations in yaw or pitch planes. Responses to rapid changes in head velocity were similarly unaffected. It is concluded that irregular afferents do not make a net contribution to the reflex. Slow-phase eye movements evoked by unilateral galvanic currents are consistent with this conclusion. The results are incorporated into a systems model of the reflex. There are three conclusions from the model: (1) the signal to motoneurons consists of the sum of three components related, respectively, to head velocity, eye position, and filtered eye velocity; (2) regular afferents provide the best match to the dynamic requirements of the reflex; and (3) the central pathways responsible for all three signal components receive regular inputs.     

Link between the ability to detect and manage emotional disorders: a study of general practitioner trainees.

Independent ratings were made of videotaped consultations involving six general practice vocational trainees, of whom three were poor identifiers and three were able identifiers of emotional illness. Taped consultations were selected so that each trainee was rated interviewing five patients with low general health questionnaire scores, and five patients with high scores. It was found that able identifiers of emotional illness were more likely than poor identifiers to offer patients information, advice and treatment relevant to their illness, and that they did so in a manner likely to maximize patient satisfaction and cooperation. This was true for both distressed and non-distressed patients. It is argued that both the ability to identify emotional disturbances and the ability to manage emotional illness are characteristics of a generally superior interview style. This may reflect a common variable: the possession of good communication skills.     

Preliminary analysis of a randomized comparison of 5-fluorouracil versus 5-fluorouracil and high-dose continuous-infusion folinic acid in disseminated colorectal cancer

In this study, 50 patients were randomly assigned to treatment with 5-fluorouracil (FUra) or FUra plus high-dose continuous-infusion folinic acid. Five of 27 evaluable patients in the FUra group versus 10 of 21 patients in the FUra plus folinic acid arm of the study had objective partial remissions, P = 0.02. Time to progression was 3.9 months for FUra and 8.0 months for FUra and folinic acid, P = 0.006; however, median survivals (11.9 versus 14.5 months) were not different in this crossover study. Toxicity in both treatment arms was mild, although patients receiving FUra plus folinic acid experienced significantly more stomatitis than patients treated with FUra alone. This study suggests that high-dose, continuous-infusion folinic acid, which produces a steady-state level of biologically active folates of 10 microM, significantly increases the therapeutic activity of FUra.     

Left atrial myxoma: diagnosis by digital subtraction intravenous angiography

Digital subtraction intravenous angiography (DSIVA) represents an important technical advance in angiographic diagnosis. Herein we present three patients with left atrial myxoma assessed by DSIVA. We review the role of DSIVA in evaluation of patients with suspected cardiac tumors and the importance of careful atrial-phase scrutiny in examinations obtained for other purposes (ie, pulmonary angiography and assessment of ventricular function).