Frequent ongoing T-cell receptor rearrangements in childhood B- precursor acute lymphoblastic leukemia: implications for monitoring minimal residual disease

Crosslineage T-cell receptor delta (TCR delta) rearrangements are widely used as tumor markers for the follow up of minimal residual disease in childhood B-precursor acute lymphoblastic leukemia (ALL) by polymerase chain reaction (PCR). The major drawback of this approach is the risk of false-negative results due to clonal evolution. We investigated the stability of V delta 2D delta 3 rearrangements in a group of 56 childhood B-precursor ALL patients by PCR and Southern blot analysis. At the PCR level, V delta 2D delta 3-to-J alpha rearranged subclones (one pathway for secondary TCR delta recombination) were demonstrated in 85.2% of V delta 2D delta 3-positive patients tested, which showed that small subclones are present in the large majority of patients despite apparently monoclonal TCR delta Southern blot patterns. Sequence analysis of V delta 2D delta 3J alpha rearrangements showed a biased J alpha gene usage, with HAPO5 and J alpha F in 26 of 32 and 6 of 32 clones, respectively. Comparison of V delta 2D delta 3 rearrangement status between diagnosis and first relapse showed differences in seven of eight patients studied. In contrast, from first relapse onward, no clonal changes were observed in six patients studied. To investigate the occurrence of crosslineage TCR delta rearrangements in normal B and T cells, fluorescence-activated cell sorter-sorted peripheral blood CD19+/CD3- and CD19-/CD3+ cell populations from three healthy donors were analyzed. V delta 2D delta 3 rearrangements were detected at low frequencies in both B and T cells, which suggests that V delta 2-to-D delta 3 joining also occurs during normal B-cell differentiation. A model for crosslineage TCR delta rearrangements in B-precursor ALL is deduced that explains the observed clonal changes between diagnosis and relapse and is compatible with multistep leukemogenesis of B-precursor ALL.     

'Doctors must not kill'

Four physicians respond to "It's over, Debbie," an anonymous resident physician's account of an incident when he or she injected a terminally ill cancer patient with a lethal dose of morphine (JAMA 1988 Jan 8; 259(2): 272). Gaylin and his colleagues condemn both the physician's violation of legal and ethical norms, and the conduct of JAMA's editor in publishing the article without editorial rebuke or comment. They warn that the issue of active euthanasia "touches medicine at its very moral center," and that, as pressure to legalize euthanasia in response to patient demand increases, the medical profession must repudiate direct and intentional killing of patients and discipline doctors who kill.     

Sequence comparison of human and yeast telomeres identifies structurally distinct subtelomeric domains

We have sequenced and compared DNA from the ends of three human chromosomes: 4p, 16p and 22q. In all cases the pro-terminal regions are subdivided by degenerate (TTAGGG)n repeats into distal and proximal sub- domains with entirely different patterns of homology to other chromosome ends. The distal regions contain numerous, short (<2 kb) segments of interrupted homology to many other human telomeric regions. The proximal regions show much longer (approximately 10-40 kb) uninterrupted homology to a few chromosome ends. A comparison of all yeast subtelomeric regions indicates that they too are subdivided by degenerate TTAGGG repeats into distal and proximal sub-domains with similarly different patterns of identity to other non-homologous chromosome ends. Sequence comparisons indicate that the distal and proximal sub-domains do not interact with each other and that they interact quite differently with the corresponding regions on other, non- homologous, chromosomes. These findings suggest that the degenerate TTAGGG repeats identify a previously unrecognized, evolutionarily conserved boundary between remarkably different subtelomeric domains.      

Three-dimensional optical tomographic brain imaging in small animals, part 2: unilateral carotid occlusion

This is the second part of a two-part study that explores the feasibility of 3-D, volumetric brain imaging in small animals by optical tomographic techniques. In part 1, we demonstrated the ability to visualize global hemodynamic changes in the rat head in response to elevated levels of CO(2) using a continuous-wave instrument and model-based iterative image reconstruction (MOBIIR) algorithm. Now we focus on lateralized, monohemispherically localized hemodynamic effects generated by unilateral common carotid artery (CCA) occlusion. This illustrates the capability of our optical tomographic system to localize and distinguish hemodynamic responses in different parts of the brain. Unilateral carotid occlusions are performed in ten rodents under two experimental conditions. In the first set of experiments the normal systemic blood pressure is lowered to 50 mmHg, and on unilateral carotid occlusion, we observe an ipsilateral monohemispheric global decrease in blood volume and oxygenation. This finding is consistent with the known physiologic response to cerebral ischemia. In a second set of experiments designed to observe the spatial-temporal dynamics of CCA occlusion at normotensive blood pressure, more complex phenomena are observed. We find three different types of responses, which can be categorized as compensation, overcompensation, and noncompensation.     

European vestibular experiments on the Spacelab-1 mission: 7. Ocular counterrolling measurements pre- and post-flight

Summary The static ocular counterrolling (OCR) of the four scientific crew members in the first Spacelab mission was measured during baseline-data-collection before and after the flight of SL-1. It was presumed that the modification of otolithic responses during spaceflight will be reflected in specific changes of the OCR-gain on the first days after recovery. The magnitude of OCR was determined analysing colour-transparencies of subjects right eyes that were produced in different positions of lateral body tilt. In general, one subject did not show any changes at all; three subjects exhibited a significant decrease of OCR-gain after exposure to weightlessness, whereby differences could be found between the responses for small and large angles of lateral body tilt. Moreover, asymmetrical effects of OCR-gain were found between body tilt to the left and tilt to the right side. Two subjects already demonstrated such an asymmetry before the flight with the higher gain on left-tilt (or right eye up), and three subjects exhibited left-right asymmetries after the spaceflight with the higher gain tilting to the right (or right eye down). A possible correlation between these vestibular asymmetries and space-sickness susceptibility is discussed.