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.     

Subxiphoid pericardiotomy versus echocardiography: a prospective evaluation of the diagnosis of occult penetrating cardiac injury

Diagnostic subxiphoid pericardiotomy (SP) is presently advocated for the diagnosis of occult cardiac injuries in patients with stable vital signs with juxta-cardiac-penetrating chest wounds. This approach, however, results in a reported 80% negative pericardial exploration rate. To investigate the reliability of bedside two-dimension echocardiography (2-D echo) in predicting cardiac injury as compared to SP, a prospective study was undertaken of patients with stable vital signs who were admitted with penetrating chest wounds that were located within the space bounded by the manubrium, nipples, and subcostal line. Initial evaluation of the patients with bedside 2-D echo was found to have a 96% accuracy, 97% specificity, and 90% sensitivity in predicting cardiac injury. The only false-negative findings were in a patient who consented to SP 18 hours after bedside 2-D echo was performed. The reliability of bedside 2-D echo compared to SP was not significantly different according to the kappa measure of reliability. These data suggest that bedside 2-D echo is an expeditious and reliable method to diagnose occult cardiac injuries during the initial assessment of a patient with stable vital signs who had penetrating chest trauma. This approach may allow for the selective use of SP on patients with positive bedside 2-D echo and could eliminate unnecessary surgical procedures.     

Growth hormone stimulates skeletal muscle protein synthesis and antagonizes insulin's antiproteolytic action in humans.

We examined the effects of a combined, local intra-arterial infusion of growth hormone (GH) and insulin on forearm glucose and protein metabolism in seven normal adults. GH was infused into the brachial artery for 6 h with a dose that, in a previous study, stimulated muscle protein synthesis (phenylalanine Rd) without affecting systemic GH, insulin, or insulinlike growth factor I concentrations. For the last 3 h of the GH infusion, insulin was coinfused with a dose that, in the absence of infused GH, suppressed forearm muscle proteolysis by 30-40% without affecting systemic insulin levels. Measurements of forearm glucose, amino acid balance, and [3H]phenylalanine and [14C]leucine kinetics were made at 3 and 6 h of the infusion. Glucose uptake by forearm tissues in response to GH and insulin did not change significantly between 3 and 6 h. By 6 h, the combined infusion of GH and insulin promoted a significantly more positive net balance of phenylalanine, leucine, isoleucine, and valine (all P less than 0.05). The change in net phenylalanine balance was due to a significant increase in phenylalanine Rd (51%, P less than 0.05) with no observable change in phenylalanine Ra. For leucine, a stimulation of leucine Rd (50%, P less than 0.05) also accounted for the change in leucine net balance, with no suppression of leucine Ra. The stimulation of Rd, in the absence of an observed effect on Ra, suggests that GH blunts the action of insulin to suppress proteolysis in addition to blunting insulin's action on Rd.     

A National Institutes of Health Workshop Report. Cellular and molecular mechanisms for suppression and reversion of tumorigenicity. A Chemical Pathology Study Section workshop

A workshop organized by the Chemical Pathology Study Section was convened to discuss recent findings on the suppression and/or reversal of neoplastic transformation. The existence of specific genes involved in suppressing tumorigenicity has been clearly demonstrated by molecular and cytogenetic analyses of tumor and normal cells from individuals predisposed to develop specific malignancies and by studies of hybrids between normal and neoplastic cells. The malignancy of tumor cells can be suppressed in hybrids with normal cells despite the continued expression of activated oncogenes. Reversal of the malignant state can also be affected by placing tumor cells in certain embryonic environments, such as the mouse blastocyst, or in response to differentiation inducing factors. The numerous examples of suppression and reversal of malignancy indicate that this is an important area for future study which may lead to new methods to control cancer.     

Mental object rotation in Parkinson's disease.

Deficits in visual-spatial ability can be associated with Parkinson's disease (PD), and there are several possible reasons for these deficits. Dysfunction in frontal-striatal and/or frontal-parietal systems, associated with dopamine deficiency, might disrupt cognitive processes either supporting (e.g., working memory) or subserving visual-spatial computations. The goal of this study was to assess visual-spatial orientation ability in individuals with PD using the Mental Rotations Test (MRT), along with other measures of cognitive function. Non-demented men with PD were significantly less accurate on this test than matched control men. In contrast, women with PD performed similarly to matched control women, but both groups of women did not perform much better than chance. Further, mental rotation accuracy in men correlated with their executive skills involving mental processing and psychomotor speed. In women with PD, however, mental rotation accuracy correlated negatively with verbal memory, indicating that higher mental rotation performance was associated with lower ability in verbal memory. These results indicate that PD is associated with visual-spatial orientation deficits in men. Women with PD and control women both performed poorly on the MRT, possibly reflecting a floor effect. Although men and women with PD appear to engage different cognitive processes in this task, the reason for the sex difference remains to be elucidated.     

Patients' recollections of therapeutic paralysis in the intensive care unit.

BACKGROUND: Neuromuscular blocking agents used for therapeutic purposes, such as facilitating mechanical ventilation and relieving life-threatening agitation, paralyze patients but leave them fully conscious. Aggressive sedation or analgesia is necessary to reduce awareness, relieve fear, produce comfort, decrease anxiety, induce unconsciousness, and minimize possible complications such as posttraumatic stress syndrome. Little information is available on the extent to which patients experience awareness during therapeutic paralysis. OBJECTIVES: To determine and describe the remembered experiences of critical care patients who were given neuromuscular blocking agents and sedatives and/or analgesics to facilitate mechanical ventilation, improve hemodynamic stability, and improve oxygenation. METHODS: A phenomenological approach with in-depth interviews with 11 patients was used. Data were analyzed by using the constant comparative approach. RESULTS: A total of 4 themes and 3 subthemes were identified. The first theme was back and forth between reality and the unreal, between life and death; the subtheme was having weird dreams. The second theme was loss of control; the 2 subthemes were (1) fighting or being tied down and (2) being scared. The third theme was almost dying, and the fourth theme was feeling cared for. CONCLUSIONS: Patients can remember having both negative and positive experiences during neuromuscular blockade. Steps to improve the experiences of patients receiving neuromuscular blockers include improving assessment parameters, developing and using sedation/analgesia guidelines, and investing in quality improvement programs to provide assessment of awareness during therapeutic paralysis and follow-up and referral as necessary. Ways to decrease the use of neuromuscular blockers would also be useful.     

The assessment of mood and affect in developmentally disabled children and adolescents: the Emotional Disorders Rating Scale

There is an unmet need for a reliable method of evaluating disorders of mood and affect in developmentally disabled children and adolescents. Such a measure is required for both accurate diagnosis and treatment monitoring in this population. An extensive review of existing assessment techniques confirms that: (a) current techniques for the evaluation of emotional disorders in cognitively normal individuals are inappropriate for most children with developmental disabilities; and (b) current instruments designed for the assessment of developmentally disabled children pay inadequate attention to affective symptoms. In this paper, the preliminary version of a new instrument, the "Emotional Disorders Rating Scale for Developmental Disabilities" (EDRS-DD), designed to evaluate mood and affect in children and adolescents with developmental disabilities, is presented. A pilot study indicates that interrater agreement is good.