ABL-specific tyrosine kinase inhibitor imatinib as salvage therapy in a child with Philadelphia chromosome-positive acute mixed lineage leukemia (AMLL).
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Acute Disease↗
Biomedical subjects
S Hecker
Publications and source records attributed to S Hecker.
Ventricular tachycardia with QRS configuration similar to that in sinus rhythm and a myocardial origin: differential diagnosis with bundle branch reentry.
INTRODUCTION: Tachycardia with a QRS configuration which resembles that in sinus rhythm is usually thought to be supraventricular. Ventricular tachycardia, with a similar QRS configuration to that in sinus rhythm on the 12-lead ECG, can occur. The mechanisms of this form of ventricular tachycardia have not been previously reported. METHODS AND RESULTS: The mechanism of ventricular tachycardia was defined during electrophysiological study in five patients. During sinus rhythm, all patients had a wide QRS complex (>0.12 s) on the 12-lead ECG. The morphology remained grossly unchanged during spontaneous, symptomatic tachycardia. Four of the five patients had coronary artery disease and left ventricular dysfunction. The remaining patient had idiopathic dilated cardiomyopathy. The relationship between the His bundle, deflection, the right bundle branch and the QRS complex was evaluated during tachycardia. Atrial and ventricular pacing, and ventricular activation mapping were performed during tachycardia to define the tachycardia mechanism. The tachycardia induced at electrophysiological testing, which was similar to the clinical tachycardia, was proven to be ventricular tachycardia in each patient. The morphology of ventricular tachycardia was right bundle branch block in two patients and left bundle branch block in three patients. The median tachycardia cycle length was 300 ms (range: 260-480 ms). His bundle activation occurred in a 1:1 relationship with ventricular activation during tachycardia in all patients at least intermittently. The tachycardias were thought initially to be bundle branch reentry tachycardia. With further intervention and continued observation, it became clear that His bundle activation was passive and was not required for the tachycardia to sustain. During tachycardia, His bundle activation appeared to precede the local ventricular activation. Instead, the His bundle was activated slowly from the previous ventricular beat causing a long ventricular-His (VH) interval. This was shown by: (1) activation patterns, (2) response to pacing, (3) intermittent VH dissociation, and (4) termination of ventricular tachycardia. CONCLUSION: A unique form of ventricular tachycardia is described. The QRS complex morphology on the 12-lead ECG during tachycardia was grossly similar to that during sinus rhythm. The His bundle activation was passive and occurred with a long activation time from the ventricle to the His bundle. Although it mimics usual bundle branch reentry, this form of ventricular tachycardia appears to be due to a different mechanism in which the His bundle is not obligatory for the continuation of the reentrant phenomenon.
Adult↗
Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy.
Whole-cell assays were implemented to search for efflux pump inhibitors (EPIs) of the three multidrug resistance efflux pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN) that contribute to fluoroquinolone resistance in clinical isolates of Pseudomonas aeruginosa. Secondary assays were developed to identify lead compounds with exquisite activities as inhibitors. A broad-spectrum EPI which is active against all three known Mex efflux pumps from P. aeruginosa and their close Escherichia coli efflux pump homolog (AcrAB-TolC) was discovered. When this compound, MC-207,110, was used, the intrinsic resistance of P. aeruginosa to fluoroquinolones was decreased significantly (eightfold for levofloxacin). Acquired resistance due to the overexpression of efflux pumps was also decreased (32- to 64-fold reduction in the MIC of levofloxacin). Similarly, 32- to 64-fold reductions in MICs in the presence of MC-207,110 were observed for strains with overexpressed efflux pumps and various target mutations that confer resistance to levofloxacin (e.g., gyrA and parC). We also compared the frequencies of emergence of levofloxacin-resistant variants in the wild-type strain at four times the MIC of levofloxacin (1 microg/ml) when it was used either alone or in combination with EPI. In the case of levofloxacin alone, the frequency was approximately 10(-7) CFU/ml. In contrast, with an EPI, the frequency was below the level of detection (<10(-11)). In summary, we have demonstrated that inhibition of efflux pumps (i) decreased the level of intrinsic resistance significantly, (ii) reversed acquired resistance, and (iii) resulted in a decreased frequency of emergence of P. aeruginosa strains that are highly resistant to fluoroquinolones.
Anti-Infective Agents↗
CD95 (APO-1/FAS)-mediated apoptosis in cytokine-activated hematopoietic cells.
Elimination of peripheral T cells is crucially regulated via apoptosis through CD95 (APO-1/Fas) receptor ligand interaction. Because homeostasis in hematopoietic cells may also involve the CD95 system, we analyzed CD95 expression and sensitivity to CD95-induced apoptosis in human bone marrow cells. During hematopoiesis CD95 is differentially expressed on distinct cell types and at different maturational stages with an increase in receptor density from early CD34+ stem cells to maturing progenitor cells. Incubation of bone marrow cells with anti-APO-1 (anti-CD95) induces apoptosis in maturing erythroblasts and neutrophil progenitors (10-19%) and to a lesser extent in stem cells and myeloblast/proerythroblasts (4-9%). On in vitro culture, CD95 expression is particularly upregulated on activated CD71+ myeloid progenitors. Hematopoietic cytokines (stem cell factor, interleukin-3, granulocyte macrophage colony-stimulating factor [GM-CSF], and granulocyte-colony-stimulating factor [G-CSF] contribute to upregulation of CD95 on bone marrow cells. CD95-induced apoptosis in activated progenitors was markedly enhanced by activating cytokines. Thus cytokines known to mediate proliferation, survival, and maturation, in hematopoiesis do not prevent, but rather facilitate negative growth regulation via the CD95 pathway in activated cells. Deregulation of the CD95 system may provide a molecular basis for the development of bone marrow failure or immune-mediated cytopenia. Defects in the CD95 pathway may contribute to the development of hematopoietic malignancy by abrogating CD95-mediated growth control of activated cells.
Apoptosis↗
Predictive value of statin, a G0-associated cell cycle protein, in childhood acute lymphoblastic leukemia.
Blast cells of 71 children with newly diagnosed acute lymphoblastic leukemia (ALL) were examined with a novel monoclonal antibody (MAb), S-44, immunoreactive to statin, a nuclear protein specifically expressed in non-proliferating cells. The statin labeling index (LI) varied greatly from case to case and ranged from 0.3% to 86%, with a mean value of 10%. The degree of statin LI correlated inversely with the expression of Ki-67. When patients were subdivided according to whether the statin LI was higher or lower than the mean value, patients with higher statin LI did not respond to chemotherapy and survived for a shorter period of time. Our results suggest that labeling of statin with the S-44 MAb is a useful prognostic marker of the cytotoxic effects of anti-cancer drugs in patients with ALL.
Adolescent↗
Two types of cholinergic projections to the rat amygdala.
The cholinergic innervation of the rat amygdala was studied immunohistochemically with antibodies against choline acetyltransferase and the low affinity p75 nerve growth factor receptor in normal rats and in rats lesioned with an immunotoxin, 192 IgG-saporin, directed against the p75 nerve growth factor receptor. The density of choline acetyltransferase-positive fibers was high in the nucleus of the lateral olfactory tract, the basolateral nucleus, and the amygdalohippocampal area; medium in the lateral nucleus, the cortical nucleus, the accessory basal nucleus, the periamygdaloid cortex, and the anterior amygdaloid area; and low in the medial and central nuclei. Nerve growth factor receptor-positive fibers were of medium density in the lateral nucleus, the accessory basal nucleus, the cortical nucleus, the anterior amygdaloid area, the periamygdaloid cortex, and the amygdalohippocampal area. The medial nucleus and the central nucleus displayed a low density of nerve growth factor receptor-positive fibers. The basolateral nucleus and the nucleus of the lateral olfactory tract also contained a low density of nerve growth factor receptor-positive fibers even though the two nuclei displayed the highest density of choline acetyltransferase-positive fibers in the amygdala. Injections of 192 IgG-saporin induced a complete loss of cholinergic nerve growth factor receptor-positive neurons in the basal forebrain but spared a subpopulation of nerve growth factor receptor-negative cholinergic neurons in the nucleus basalis-substantia innominata complex. Following 192 IgG-saporin injections, choline acetyltransferase-positive and acetylcholinesterase-positive fibers were essentially unchanged in the nucleus of the lateral olfactory tract and the basolateral nucleus and showed a partial reduction in the remaining nuclei of the amygdaloid complex. Cholinergic fibers emanating from cholinergic cell group 4 neurons reached the amygdala via the stria terminalis and the ventral amygdalofugal pathway. These observations indicate that two amygdaloid nuclei, the nucleus of the lateral olfactory tract and the basolateral nucleus, receive their cholinergic projections predominantly, if not exclusively, from nerve growth factor receptor-negative cholinergic neurons whereas all remaining amygdaloid regions receive fibers from nerve growth factor receptor-negative as well as nerve growth factor receptor-positive cholinergic neurons.
Amygdala↗
Workplace drug testing as social control.
In this article, the emergence of employee drug screening is examined in the context of the historical development of the principle and practice of workplace surveillance. The authors trace the evolution of disciplinary and control systems from the early Industrial Revolution through the Scientific Management movement and its recent offshoots. Industrial medicine and industrial psychology are presented as elements of the "scientification" of surveillance. Drug testing and other contemporary surveillance technologies are placed in this context, and their cultural, political-economic, and moral underpinnings are examined. The dilemma posed by the need to address the real problem of drug abuse in the context of a social control paradigm is explored.
Efficiency↗
Diagnostic evaluation of phosphoribosylpyrophosphate synthetase activities in hemolysates.
Superactivity of phosphoribosylpyrophosphate (PRPP) synthetase is one of several hereditary enzyme abnormalities associated with gout and excessive uric acid excretion. Although measurement of PRPP synthetase activities in erythrocyte lysates should provide a practical means to detect abnormalities of the enzyme, reported values for normal individuals have varied considerably. We describe a radioisotopic procedure for measurement of PRPP synthetase activities in dialyzed hemolysates under a variety of conditions permitting evaluation of enzyme catalytic function and responsiveness to inhibitors and activators. Utilizing this procedure, enzyme activities for normal individuals were higher than generally reported, a difference attributable in part to the following measures undertaken to assure accuracy in activity determinations: precise control of pH of reaction mixtures, provision of verified excesses of the auxiliary enzyme adenine phosphoribosyltransferase, and measurement of all of the radiolabeled products of the assay. Under each condition of measurement, enzyme activities in 44 normal individuals, 13 patients with gout and normal uric acid excretion, and 10 patients with gout and uric acid overproduction were indistinguishable. In four additional individuals with uric acid overproduction, however, excessive enzyme activities were identifiable at all inorganic phosphate concentrations, but responses to purine nucleotide inhibitors were normal. In hemolysates from a patient with an inhibitor-resistant PRPP synthetase, an altered pattern of inorganic phosphate activation and diminished nucleotide inhibitor response was demonstrated. Our studies confirm the ability of the assay procedure to detect kinetically distinct variant forms of PRPP synthetase. Application of this procedure should aid in evaluation of the prevalence of derangements of PRPP synthetase among patients with gout and uric acid overproduction.
Adenine Phosphoribosyltransferase↗
p53 expression and poor prognosis in childhood acute lymphoblastic leukemia.
Ninety-one children with untreated acute lymphoblastic leukemia (ALL) were analysed for expression of p53 using immunocytochemistry. p53 expression was found in 80% of the cases by Mab 421. Kaplan-Meier estimates show that patients with p53-positive leukemic cells had significantly shorter survival times under chemotherapy than those with p53-negative leukemic cells (p = 0.05, log-rank test). Statistical analysis revealed no correlation between p53 expression and patient's age, sex, immunotyping and initial peripheral blast cell count.
Antibodies, Monoclonal↗