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.     

Picotamide inhibition of excess in vitro thromboxane B2 release by colorectal mucosa in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease is associated with increased mucosal release of eicosanoids. Among these, thromboxane A2 has been proposed as a possible inflammatory mediator; its suppression may be a useful therapeutic option. METHODS: Using a tissue incubation technique, we compared release of immunoreactive thromboxane B2 by colonic biopsies from patients with ulcerative colitis, Crohn's disease and controls, and assessed the inhibitory effect of picotamide, a thromboxane synthesis inhibitor-receptor antagonist, which has been widely used in Italy for management of ischaemic heart and cerebrovascular disease. RESULTS: Increased amounts of thromboxane B2 were released from biopsies from patients with active ulcerative colitis (median 238 pg/20 min/mg wet weight (interquartile range 147- 325), n = 12) and active Crohn's disease (252 (174-450), 6) compared with those from patients with quiescent ulcerative colitis (95 (61- 140), 12) or Crohn's disease (105 (57-201), 13), or controls (136 (64- 206), 8). Incubation with picotamide at concentrations between 100 microM and 1 mM reduced thromboxane B2 release (IC50 890 microM). CONCLUSION: Since increased thromboxane A2 production may have pathogenetic importance, thromboxane synthesis inhibitor-receptor antagonists such as picotamide merit therapeutic trial in the management of inflammatory bowel disease.     

Myoclonic movements as a side-effect of treatment with therapeutic doses of clomipramine

Myoclonic movements have been observed in depressed patients receiving therapeutic doses of clomipramine. Such movements, which appear in states of deep muscular relaxation such as sleep, do not appear to have any repercussion in the outcome of the depression and are reversible following withdrawal of the drug. In this study the plasma levels of clomipramine and desmethylclomipramine were determined and their possible relationship with myoclonus studied. No statistically significant relationships were found.     

Isoflurane in pulmonary hypertension and failure of the right ventricle

We evaluated the effects of the use of 1.2% isoflurane (group A) in a group of patients (n = 13) referred for mitral valve surgery, with pulmonary hypertension and right ventricular failure. We evaluated the hemodynamic status in baseline conditions, after isoflurane ++ administration and in relative hyper- and hypovolemia. We compared the results with those in 17 patients (group B) in identical clinical state who did not receive isoflurane during anesthesia. The evaluated parameters were: mixed venous Hb saturation (SvO2), heart rate (HR), pulmonary capillary pressure (PCP), central venous pressure (CVP), mean blood pressure (mBP), mean pulmonary arterial pressure (mPAP), cardiac index (CI), arteriolar pulmonary resistances (APR), peripheral vascular resistances (SVR), stroke index (SI), left ventricular work (LVW), right ventricular work (RVW), and O2 consumption (VO2). In group A, after isoflurane ++ administration, CI was 107.05% and 80% of baseline values in relative hypervolemia and hypovolemia, respectively. In group B (control), CI was 121.48% and 88.28% of basal values in relative hypervolemia and hypovolemia, respectively. In group A, SVR were 73.59% and 76.72% in hypervolemia and hypovolemia, respectively, while in group B they were 86.21% and 106.80%. In group A, APR were 90.85% and 89.96% in hypervolemia and hypovolemia, while they were 80.72% and 102.34% in group B. We found that isoflurane results in a greater peripheral than pulmonary vasodilation with a greater impairment in right ventricular function.