Pathogenesis of an infectious mononucleosis-like disease induced by a murine gamma-herpesvirus: role for a viral superantigen?

The murine gamma-herpesvirus 68 has many similarities to EBV, and induces a syndrome comparable to infectious mononucleosis (IM). The frequency of activated CD8+ T cells (CD62L(lo)) in the peripheral blood increased greater than fourfold by 21 d after infection of C57BL/6J (H-2(b)) mice, and remained high for at least a further month. The spectrum of T cell receptor usage was greatly skewed, with as many as 75% of the CD8+ T cells in the blood expressing a Vbeta4+ phenotype. Interestingly, the Vbeta4 dominance was also seen, to varying extents, in H-2(k), H-2(d), H-2(u), and H-2(q) strains of mice. In addition, although CD4 depletion from day 11 had no effect on the Vbeta4 bias of the T cells, the Vbeta4+CD8+ expansion was absent in H-2IA(b)-deficient congenic mice. However, the numbers of cycling cells in the CD4 antibody-depleted mice and mice that are CD4 deficient as a consequence of the deletion of MHC class II, were generally lower. The findings suggest that the IM-like disease is driven both by cytokines provided by CD4+ T cells and by a viral superantigen presented by MHC class II glycoproteins to Vbeta4+CD8+ T cells.     

Estimating costs of programme services and products using information provided in standard financial statements

OBJECTIVE: To determine whether spectral analysis of unprocessed radiofrequency (RF) signal offers advantages over standard videodensitometric analysis in identifying the morphology of coronary atherosclerotic plaques. METHODS: 97 regions of interest (ROI) were imaged at 30 MHz from postmortem, pressure perfused (80 mm Hg) coronary arteries in saline baths. RF data were digitised at 250 MHz. Two different sizes of ROI were identified from scan converted images, and relative amplitudes of different frequency components were analysed from raw data. Normalised spectra was used to calculate spectral slope (dB/MHz), y-axis intercept (dB), mean power (dB), and maximum power (dB) over a given bandwidth (17-42 MHz). RF images were constructed and compared with comparative histology derived from microscopy and radiological techniques in three dimensions. RESULTS: Mean power was similar from dense fibrotic tissue and heavy calcium, but spectral slope was steeper in heavy calcium (-0.45 (0.1)) than in dense fibrotic tissue (-0.31 (0.1)), and maximum power was higher for heavy calcium (-7.7 (2.0)) than for dense fibrotic tissue (-10.2 (3.9)). Maximum power was significantly higher in heavy calcium (-7.7 (2.0) dB) and dense fibrotic tissue (-10.2 (3.9) dB) than in microcalcification (-13.9 (3.8) dB). Y-axis intercept was higher in microcalcification (-5.8 (1.1) dB) than in moderately fibrotic tissue (-11.9 (2.0) dB). Moderate and dense fibrotic tissue were discriminated with mean power: moderate -20.2 (1.1) dB, dense -14.7 (3.7) dB; and y-axis intercept: moderate -11.9 (2.0) dB, dense -5.5 (5.4) dB. Different densities of fibrosis, loose, moderate, and dense, were discriminated with both y-axis intercept, spectral slope, and mean power. Lipid could be differentiated from other types of plaque tissue on the basis of spectral slope, lipid -0.17 (0.08). Also y-axis intercept from lipid (-17.6 (3.9)) differed significantly from moderately fibrotic tissue, dense fibrotic tissue, microcalcification, and heavy calcium. No significant differences in any of the measured parameters were seen between the results obtained from small and large ROIs. CONCLUSION: Frequency based spectral analysis of unprocessed ultrasound signal may lead to accurate identification of atherosclerotic plaque morphology.     

Binding of Clostridium difficile toxin A to human milk secretory component

The objective of the present study was to evaluate the effect of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-alpha (IL-1a), on myoblast proliferation and fusion and on myocyte protein metabolism and stress protein expression. Proliferation was suppressed (p < 0.05) by both cytokines, alone and in combination, and at lower concentrations, the suppression was additive. Likewise, fusion was retarded (p < 0.05) by these cytokines alone and in combination. Myosin synthesis was not altered acutely or chronically by TNF-alpha alone or by the combination of this cytokine with IL-1alpha. Chronic exposure to TNF-alpha did not alter total cellular protein synthesis, but exposure to IL-1alpha and the cytokine combination resulted in an increase (14% to 19%, p < 0.05) in synthesis. Neither total cellular protein nor myosin degradation were influenced by either cytokine alone or by the combination. There was no detectable induction, acutely or chronically, of any of the stress proteins evaluated (HSC70, HSP70, or HSP60). These data suggest that cytokines may alter muscle growth and development prenatally and postnatally and that the changes in muscle protein metabolism during periods of immune challenge are not direct effects of TNF-alpha or IL-1alpha.     

Effect of smoking cessation counseling on recovery from alcoholism: findings from a randomized community intervention trial

AIMS: To assess the effects of a smoking cessation program for recovering alcoholics on use of alcohol, tobacco and illicit drugs after discharge from residential treatment. DESIGN AND SETTING: A randomized community intervention trial design was employed in which 12 residential drug treatment centers in Iowa, Kansas and Nebraska were matched and then randomly assigned to the intervention or control condition. PARTICIPANTS: Approximately 50 adult residents (inpatients) from each site were followed for 12 months after treatment discharge. INTERVENTION: Participating residents in the six intervention centers received a 4-part, individually tailored, smoking cessation program while those in the six control sites received usual care. FINDINGS: Both moderate and heavy drinking rates were reduced in the intervention group. Intervention site participants were significantly more likely than controls to report alcohol abstinence at both the 6-month (OR = 1.59, 95%CI: 1.09-2.35) and 12-month assessment (OR = 1.84, 95%CI: 1.28-2.92). Illicit drug use rates were comparable. Effect of the intervention on tobacco quit rates was not statistically significant. CONCLUSIONS: Counseling alcoholics in treatment to quit smoking does not jeopardize the alcohol recovery process. However, low-intensity tobacco interventions are unlikely to yield high tobacco quit rates.     

Surface structure of human mucin using X-ray photoelectron spectroscopy

The stimulating effect of antiparkinsonian drugs, talipexole and bromocriptine, on the striatal postsynaptic dopamine receptors were studied by measuring contralateral rotational behavior in rats. The nigro-striatal dopamine system of rats was degenerated by unilateral injection of 6-hydroxydopamine (6-OHDA, 8 micrograms/rat) into substantia nigra. By subcutaneous administration, talipexole at 0.16 mg/kg and bromocriptine at 10.24 mg/kg induced significantly increased rotational behavior to the contralateral direction to the lesioned side. The onset of the effect was 30 min for talipexole and 90 min for bromocriptine. By intragastric administration, talipexole at 0.4 mg/kg and bromocriptine at 20.48 mg/kg significantly increased the rotational behavior, and the onset of the effect was 60 min for talipexole and 180 min for bromocriptine. Rotational behavior induced by talipexole was suppressed by a D2 antagonist, sulpiride (40 mg/kg, s.c.), but not by a D1 antagonist, SCH23390 (1 mg/kg, s.c.). In contrast, rotational behavior induced by bromocriptine was suppressed by both sulpiride and SCH23390. These results indicated that when the nigrostriatal dopaminergic functions are disrupted, talipexole stimulates the striatal postsynaptic dopamine receptors at much lower doses than bromocriptine. Also it was indicated that the stimulating effect of talipexole is solely mediated by dopamine D2 receptors, whereas the effect of bromocriptine is mediated by both D1 and D2 receptors.     

Ectopic expression of metallothionein-III causes pancreatic acinar cell necrosis in transgenic mice

Mice express four distinct metallothioneins (MTs) that have similar metal-binding properties. MT-I and MT-II are expressed coordinately in most organs, whereas MT-III is expressed predominantly in a subset of neurons and MT-IV is expressed in certain stratified epithelia. The restricted expression of MT-III suggests that it may severe a specialized function. To test this hypothesis, transgenic mice were generated that express MT-III in the wider expression domain of MT-I. Similar transgenic lines expressing extra MT-I under the same regulation were generated as controls for the effect of over-expression of MT. Transgenic mice that express MT-III ectopically frequently die at 2-3 months of age. The pancreata of moribund mice were abnormally small and histological examination, at various ages, revealed a progressive degeneration of the acinar cells. At early stages multifocal acinar cell eosinophilia and swollen nuclei were seen and this pathology progressed to multifocal acinar cell necrosis and fibrosis. The terminal stages were characterized by a loss of the acinar compartment, leaving the islets embedded in a fibrotic remnant. Other organs of these mice were grossly and histologically normal. All organs examined from mice expressing excess MT-I were unremarkable even though expression of either MT-I or MT-III transgenes resulted in similar accumulations of zinc and copper in the pancreata. This study indicates that pancreatic acinar cells are unusually sensitive to chronic expression of MT-III. The mechanism by which MT-III disrupts pancreatic function is unclear, but the results provide further evidence that MT isoforms exhibit distinct properties and probably serve distinct biological functions.     

Analysis of data from group-randomized trials with repeat observations on the same groups

This study used Monte Carlo simulations to evaluate the performance of alternative models for the analysis of group-randomized trials having more than two time intervals for data collection. The major distinction among the models tested was the sampling variance of the intervention effect. In the mixed-model ANOVA, the sampling variance of the intervention effect is based on the variance among group x time-interval means. In the random coefficients model, the sampling variance of the intervention effect is based on the variance among the group-specific slopes. These models are equivalent when the design includes only two time intervals, but not when there are more than two time intervals. The results indicate that the mixed-model ANOVA yields unbiased estimates of sampling variation and nominal type I error rates when the group-specific time trends are homogenous. However, when the group-specific time trends are heterogeneous, the mixed-model ANOVA yields downwardly biased estimates of sampling variance and inflated type I error rates. In contrast, the random coefficients model yields unbiased estimates of sampling variance and the nominal type I error rate regardless of the pattern among the groups. We discuss implications for the analysis of group-randomized trials with more than two time intervals.