Additive value of low-dose dobutamine to technetium-99m sestamibi-gated single-photon emission computed tomography for prediction of wall motion improvement in patients undergoing coronary artery bypass graft

BACKGROUND: The two most useful methods for myocardial viability assessment are perfusion imaging and dobutamine echocardiography. HYPOTHESIS: The present study investigated the additive value of a new method, dobutamine technetium 99m (99mTc)-sestamibi-gated single-photon emission computed tomography (SPECT), which combines these two modalities, to the prediction of wall motion improvement after revascularization. METHODS: Fifty-five consecutive patients with ischemic cardiomyopathy, who were referred for viability evaluation, underwent resting and dobutamine (dose, 5-10 microkg/kg/min) gated SPECT with 99mTc-sestamibi. Of these patients, 36 underwent coronary artery bypass graft (CABG) within 1 month of the study and 32 had repeat resting gated SPECT within 1 year. Global and regional wall motion, wall thickness, and perfusion were simultaneously analyzed at rest and after dobutamine using the 20-segment model; the sestamibi uptake and wall motion response to dobutamine of each segment were rated quantitatively. Based on these findings, the segments were categorized as normal, viable, or nonviable. The predictive values for wall motion improvement were assessed by perfusion, using cutoffs of 50 and 60% of sestamibi uptake, and thereafter by the addition of dobutamine response in the segments that were rated nonviable. RESULTS: Of the 1,080 myocardial segments studied, 906 (84%) had abnormal wall motion and were analyzed for viability. Concordance between perfusion and wall motion response to dobutamine was 60% with the 50% cutoff of sestamibi uptake, and increased to 65% with the 60% sestamibi cutoff (p < 0.04). The respective predictive values of wall motion improvement using the 50 and 60% cutoff points were as follows: sensitivity 93 and 70%, respectively, (p < 0.01); specificity 59 and 86% (p < 0.001), respectively; accuracy 77% for both. The addition of the wall motion response to dobutamine to the assessment of the nonviable segments by perfusion (60% cutoff) increased the sensitivity from 70 to 85% (p = 0.001) and the negative predictive value from 70 to 81% (p = 0.009); the positive predictive value remained high (86 vs. 82%). No additive value of wall motion response to dobutamine was demonstrated for nonviable segments by perfusion with a 50% cutoff. CONCLUSION: Dobutamine sestamibi-gated SPECT is a feasible method for the analysis of myocardial perfusion, function, and contractile reserve of individual myocardial segments in patients with ischemic cardiomyopathy. Viability assessment based on a threshold of 60% uptake of sestamibi, with the addition of the wall motion response to dobutamine in the nonviable segments, seems to yield better predictive values for wall motion improvement after CABG.     

Patches of synchronized activity in the cerebellar cortex evoked by mossy-fiber stimulation: Questioning the role of parallel fibers

The discrepancy between the structural longitudinal organization of the parallel-fiber system in the cerebellar cortex and the functional mosaic-like organization of the cortex has provoked controversial theories about the flow of information in the cerebellum. We address this issue by characterizing the spatiotemporal organization of neuronal activity in the cerebellar cortex by using optical imaging of voltage-sensitive dyes in isolated guinea-pig cerebellum. Parallel-fiber stimulation evoked a narrow beam of activity, which propagated along the parallel fibers. Stimulation of the mossy fibers elicited a circular, nonpropagating patch of synchronized activity. These results strongly support the hypothesis that a beam of parallel fibers, activated by a focal group of granule cells, fails to activate the Purkinje cells along most of its length. It is thus the ascending axon of the granule cell, and not its parallel branches, that activates and defines the basic functional modules of the cerebellar cortex.     

Glycopeptides from Surface Membranes of Neuroblastoma Cells

Sequential removal of surface glycopeptides was achieved by subjection of mouse neuroblastoma cells to a two-step trypsin treatment under different conditions. The glycopetides released by each trypsinization step were digested by Pronase and examined on columns of Sephadex G-50. Different chromatographic patterns were found for the two digests. Thus, several groups of glycopeptides can be distinguished by the trypsinization procedure. One group is readily removed and appears to be at a more accessible location on the cell surface. Among the four neuroblastoma clones examined, the glycopeptide patterns from axon-forming cells differed from those of axon-minus cells.     

ACE Overexpression in Myelomonocytic Cells: Effect on a Mouse Model of Alzheimer’s Disease

The angiotensin AT2-receptor mediates tissue protective actions. Its regenerative potential has been tested in multiple disease models including models of myocardial infarction. These studies used different experimental approaches in order to detect AT2-receptor-related effects such as AT2-receptor deficiency or overexpression, treatment with an AT1-receptor blocker leading to indirect stimulation of the unopposed AT2-receptor, or studies using AT2-receptor agonists. It is a common finding in these studies that the AT2-receptor improves cardiac function in the early phase post-MI, and that this effect is preserved over periods of up to four months. Depending on the experimental protocol, the AT2R also attenuates post-MI left ventricular remodeling or protects the heart from early left ventricular thinning and rupture. In combination with AT1-receptor blockade or deficiency, post-MI cardiac hypertrophy is reduced. This article reviews studies on the role of the AT2-receptor in myocardial infarction with an emphasis on the most recent data obtained in studies using AT2-receptor agonists.     

Cell lineage analysis of acute leukemia relapse uncovers the role of replication-rate heterogeneity and microsatellite instability

Human cancers display substantial intratumoral genetic heterogeneity, which facilitates tumor survival under changing microenvironmental conditions. Tumor substructure and its effect on disease progression and relapse are incompletely understood. In the present study, a high-throughput method that uses neutral somatic mutations accumulated in individual cells to reconstruct cell lineage trees was applied to hundreds of cells of human acute leukemia harvested from multiple patients at diagnosis and at relapse. The reconstructed cell lineage trees of patients with acute myeloid leukemia showed that leukemia cells at relapse were shallow (divide rarely) compared with cells at diagnosis and were closely related to their stem cell subpopulation, implying that in these instances relapse might have originated from rarely dividing stem cells. In contrast, among patients with acute lymphoid leukemia, no differences in cell depth were observed between diagnosis and relapse. In one case of chronic myeloid leukemia, at blast crisis, most of the cells at relapse were mismatch-repair deficient. In almost all leukemia cases, > 1 lineage was observed at relapse, indicating that diverse mechanisms can promote relapse in the same patient. In conclusion, diverse relapse mechanisms can be observed by systematic reconstruction of cell lineage trees of patients with leukemia.     

A single pentylenetetrazole-induced clonic-tonic seizure episode is accompanied by a slowly developing cognitive decline in rats

According to different studies, between 5% and 10% of people suffer a single isolated seizure episode at some time in their life. However, little is known about the effects of a single seizure episode on cognitive function, and clinical investigations of this issue are not easy to perform. In this situation, animal models may be a reasonable choice. The aim of our study was to follow the time course of delayed effects of generalized clonic-tonic convulsions on learning and memory functions in rats. A clonic-tonic seizure episode was induced by a single i.p. injection of pentylenetetrazole (70 mg/kg). Different behavioral tests were performed between days 10 and 100 after the convulsant administration. A single seizure episode resulted in a gradual decline in short-term memory function as assessed by novel object recognition and social recognition tests. The seizure episode induced a quick increase in hippocampal cell proliferation; however, the excessive newly generated cells seemed to be eliminated by the time of obvious cognitive impairment. These observations are indicative of a slowly developing and long-lasting influence of a single seizure episode on cognitive function. A rather long time period between the seizure episode and the manifestations of cognitive decline provides a window for a possible therapeutic intervention, and an elaboration of such “post-conditioning” treatments may be a promising opportunity to prevent subsequent mental impairments in patients.