Comparison of the chronic toxicity of piroxantrone, losoxantrone and doxorubicin in spontaneously hypertensive rats

We have determined the time course, the spatial spread in brain tissue, and the intracellular distribution of biotin- and fluorescein-labeled phosphorothioate oligodeoxynucleotides (ODNs) following single injections into the rat striatum or the lateral ventricle. These time and space parameters were correlated with the ability of c-fos phosphorothioate antisense ODNs to suppress the induction of Fos protein by cocaine. A rapid and dose-dependent tissue penetration of labeled ODNs was observed following either intrastriatal or intraventricular injections of a constant sample volume. Inspection of tissue sections by confocal microscopy uncovered a distinct change in the intracellular disposition of labeled ODNs during the 24 h post-injection period. At 1, 6 and 12 h, the vast majority of the fluorescent signal was confined to the interstitial spaces throughout the zone penetrated by ODNs. Neuronal nuclei displayed faint labeling along the outer portion of the nucleus at 1 and 6 h post-injection. At these time-points, ODNs were not detected in the cytoplasm. By 16 h, ODNs were barely detectable in the extracellular space and absent from neuronal nuclei. Instead, ODNs were seen in large cytoplasmic granules of neurons throughout the tissue zone penetrated by the ODNs. Experiments with intrastriatal injections of antisense ODNs to c-fos mRNA revealed Fos suppression between 3 and 12 h, but not at 16 and 24 h. This combined analysis has revealed that (1) restricted tissue penetration by ODNs limits their antisense effects on protein expression, and (2) depletion of extracellular ODNs and sequestration of c-fos antisense ODNs into large intracellular granules coincides with the loss of their biological activity.     

Mechanistic model predicts a U-shaped relation of radon exposure to lung cancer risk reflected in combined occupational and US residential data

A mechanistically based cytodynamic two-stage (CD2) cancer model was shown recently to predict both ecologic US county data and underground-miner data on lung-cancer mortality (LCM) vs radon concentration, indicating biological plausibility of the apparent negative dose-response relation exhibited by the ecologic data. To further investigate this hypothesis, the CD2 model was fitted to combine age-specific LCM data vs estimated radon-exposure in white females of age 40+ years in 2821 US counties during 1950-1954 using new estimates of county-specific mean residential radon exposure, and in five cohorts of underground nonsmoking miners. The negative association of radon levels and corresponding county-level LCM rates apparent in women dying in 1950-1954 (11% of whom never smoked) was also apparent in women of age 60+ years (5% of whom never smoked). The CD2 fit obtained to the combined residential and occupational data was found to predict the combined data using biologically plausible parameter values, and also to predict inverse dose-rate effects exhibited in nonsmoking miner data to which the CD2 model was not fit. These results are consistent with the hypothesis that residential radon exposure has a nonlinear U-shaped relation to LCM risk, and that current linear extrapolation models substantially overestimate such risk.     

Obesity and insulin resistance in human growth hormone transgenic rats

A line of transgenic rats (heterozygotes) carrying a chimeric gene comprising a regulatory portion of murine whey acidic protein and a structural portion of human GH (hGH) genes developed severe obesity with age. To characterize physiological mechanisms that lead to fat accumulation, an array of parameters related to obesity were studied. Blood hGH levels were continuously low, endogenous rat GH secretion was suppressed, and the pulsatility in peripheral GH levels was absent. Plasma glucose, insulin, triglyceride, and FFA levels in the male transgenic rats significantly exceeded those in nontransgenic littermates at 12 and 17 weeks, but not at 7 weeks, of age. All symptoms except hyperlipidemia were restored to normal by treatment with an antidiabetic agent, thiazolidinedione (troglitazone), for 1 week from 17 weeks of age. As phenotypic expression of obesity was already evident before aberration of physiological parameters, it was assumed that animals had a condition in which obesity or hyperlipidemia caused hyperinsulinemia. Gene expression and enzymatic activity of lipoprotein lipase in the adipose tissue in the transgenic rats were not different from those in normal rats. In contrast, the gene expression level of glycerol-3-phosphodehydrogenase was markedly elevated, suggesting that glycerol synthesis was much enhanced in the adipocytes of the transgenic rats. In an i.p. glucose tolerance test, the transgenic rats were not hyperglycemic at 7 weeks of age; however, the animal became hyperglycemic at 15-17 weeks of age. Finally, treatment with recombinant hGH for 1 week to produce pulsatile secretion reduced the size of epididymal and kidney fat pads and restored normal weight gain. These observations suggest that continuously low peripheral GH levels with the lack of pulsatile secretion resulted in obesity and noninsulin-dependent diabetes mellitus.     

Relation between intracarotid amobarbital memory asymmetry scores and hippocampal sclerosis in patients undergoing anterior temporal lobe resections

The intracarotid amobarbital procedure (IAP) is used to evaluate memory function preoperatively in candidates for anterior temporal lobe resections (ATL). We examined IAP memory asymmetry scores in 30 patients undergoing ATL (17 R, 13 L), as a function of the presence (HS+) or absence (HS-) of hippocampal sclerosis. Ictal onset zones were determined by extraoperative recording with subdural strip electrodes in all but 3 patients in whom magnetic resonance imaging (MRI) scan showed HS. MRI scans were otherwise normal. All patients were left hemisphere dominant for language except 1, in whom language was represented bilaterally. IAP memory testing involved presentation of eight subjects during anesthesia of each hemisphere, followed by recognition testing after patients recovered from amobarbital effects. A score of 1 was given for each correctly recognized object, and 0.5 was deducted for each false-positive identification. There were 16 foils. A total asymmetry score was calculated, which was positive if there was agreement between the direction of the symmetry and side of operation and negative if reversed. The mean asymmetry score for HS- (n = 8) was 0.9; that for HS+ (n = 22) was 4.1 (p < 0.01). IAP memory performance provided lateralizing information (asymmetry score > or = + or -2) in 73% of cases; among these, the lateralization was correct in 91%. Our data indicate that IAP memory asymmetry predicts both laterality of ictal onset and the presence of HS.     

Biodegradation of phenols by a eukaryotic alga

A series of dental outpatients in Brazil was anonymously screened for HIV antibodies in whole unstimulated saliva with an immunoglobulin G antibody-capture enzyme-linked immunosorbent assay. Salivary HIV antibodies were detected in 40 patients in the control group who were known to be HIV-seropositive but were not detected in any of a series of 40 known HIV-seronegative patients in the control group, confirming the very high sensitivity and specificity of the immunoglobulin G antibody-capture enzyme-linked immunosorbent assay. Only one patient from 84 consecutive dental outpatients of unknown HIV serostatus who were examined anonymously for HIV by immunoglobulin G antibody-capture enzyme linked immunosorbent assay showed HIV positivity (1.2% of the population).     

In Vitro antimicrobial susceptibilities of Streptococcus pneumoniae isolated from two teaching hospitals in Taiwan, 1989-1995

The susceptibility of 46 pneumococcal isolates collected during October 1989 to May 1995 from National Taiwan University Hospital and Taipei Municipal Yang Ming Hospital was studied. Among these isolates, the resistant rate of penicillin G was 21.7%; the penicillin G-resistant strains were more frequently resistant than the penicillin-sensitive strains to other beta-lactam antimicrobial drugs. The minimum bactericidal concentrations (MBCs) of penicillin G for all isolates were equal to, or one dilution higher than, minimum inhibitory concentrations (MICs). Three strains were false positive for penicillin resistance among isolates of Streptococcus pneumoniae screened with oxacillin. On the other hand, resistance to penicillin G was often independent of resistance to erythromycin. Vancomycin was the most active agent tested.     

Thromboembolism in chronic atrial flutter: is the risk underestimated?

OBJECTIVES: We sought to evaluate the risk of thromboembolic events in the presence of chronic atrial flutter and to determine the impact of anticoagulation therapy, if any, on this risk. BACKGROUND: Thromboembolic events are thought to be rare after cardioversion of atrial flutter. METHODS: This study was a retrospective analysis of 110 consecutive patients referred to the electrophysiology laboratory for cardioversion of chronic atrial flutter from 1986 to 1996. Atrial flutter was present for at least 6 months. Of the 110 patients reviewed, 100 had adequate information available regarding the effectiveness of anticoagulation (mean age 64 years, range 27 to 86; 75 men, 25 women; mean left ventricular ejection fraction 42%). RESULTS: Thirteen patients (13%) had a thromboembolic event. Of these, seven were attributable to causes other than atrial flutter. In the remaining six patients (6%), thromboembolic events occurred during a rhythm of atrial flutter or after cardioversion to sinus rhythm. Other causes of thromboembolism were excluded. Effective anticoagulation was associated with a decreased risk of thromboembolism (p = 0.026). CONCLUSIONS: Patients with chronic atrial flutter are at an increased risk of thromboembolic events. Effective anticoagulation may decrease this risk.     

The effect of alterations to action potential duration on beta-adrenoceptor-mediated aftercontractions in human and guinea-pig ventricular myocytes

Aftercontractions induced by beta-adrenoceptor stimulation in human and guinea-pig cardiomyocytes may be related to changes in action potential duration (APD). We investigated the effects of altering APD during the occurrence of isoproterenol-induced aftercontractions, using the KATP channel openers cromakalim and lemakalim or the action potential voltage clamp technique, in guinea-pig and human ventricular cardiomyocytes. Contractile responses were measured at 32 degrees C using a video-based edge-detection system. In guinea-pig myocytes, action potentials, Indo-1 fluorescence and contraction were measured at 22 degrees C. Isoproterenol (< or = 12 nM) had variable effects on APD but induced aftercontractions, the majority (14/19 cells) of which occurred during the action potential. Short action potentials were produced using K+ channel openers. These compounds reduced or completely abolished the isoproterenol-induced aftercontractions. Increasing isoproterenol in the presence of K+ channel opener restored the main contraction to a level similar to or above those with isoproterenol alone, but without the reappearance of aftercontractions. When cells were stimulated to contract under action potential voltage clamp, isoproterenol-induced aftercontractions were abolished by voltage clamping with action potentials of short duration. It was possible to induce aftercontractions in some cells without application of isoproterenol if voltage clamp-imposed action potentials of very long duration were used. These aftercontractions were also abolished by shortening action potential duration. We conclude that K+ channel openers or the imposition of action potentials of short duration can dissociate positively inotropic beta-adrenoceptor stimulation from aftercontraction formation and that action potentials of long duration can be pro-arrhythmic.