Effects of Myocardial Water Exchange on T1 Enhancement during Bolus Administration of MR Contrast Agents

Interpretation of first-pass myocardial perfusion studies employing bolus administration of T₁ magnetic resonance (MR) contrast agents requires an understanding of the relationship between contrast concentration and image pixel intensity. The potential effects of myocardial water exchange rates among the intravascular, interstitial, and cellular compartments on this relationship are controversial. We directly studied these issues in isolated, nonbeating canine interventricular septa. Myocardial T₁ was measured three times/s during bolus transit of intravascular (albumin-Gd-DTPA and poly-lysine-Gd-DTPA) and extracellular (gadoteridol) contrast agents. For polylsine-Gd-DTPA, the peak changes in myocardial 1/T₁ (ΔR1) scaled nonlinearly with perfusate contrast concentration whereas a linear relationship would be expected for fast water exchange among the vascular, interstitial, and cellular compartments. For all agents, the peak ΔR1 were much smaller than the values expected on the basis of fast myocardial water exchange. The data demonstrate that in isolated myocardial tissue, myocardial T₁ enhancement during bolus administration of contrast can be strongly affected by myocardial water exchange for both intravascular and extracellular MR contrast agents.     

Buthionine sulfoximine-mediated depletion of glutathione in intracranial human glioma-derived xenografts

D-54 MG, a human glioma-derived continuous cell line growing as subcutaneous or intracranial xenografts in athymic mice, was found to be sensitive to the effects of D,L-buthionine-(SR)-sulfoximine, a selective inhibitor of gamma-glutamylcysteine synthetase. Intraperitoneal administration of one dose of buthionine sulfoximine (BSO, 5 mmol/kg) resulted in depletion of total intracellular glutathione to 57 and 47% of control 12 hr, and 73 and 23% of control 24 hr, after BSO in subcutaneous and intracranial xenografts respectively. Concurrent measurement of total glutathione in the contralateral (non-tumor-containing) cerebral hemisphere in mice bearing intracranial D-54 xenografts demonstrated insignificant depletion of glutathione. Multiple doses of BSO, at 12-hr intervals, resulted in further depletion to 27% (s.c.) and 16.5% (i.c.) of control 12 hr following the final dose of BSO. Quantitative analysis of BSO delivery to xenograft and contralateral brain tissue revealed transfer constants, K1, of 15.8-24.1 x 10(-3) and 2.4 x 10(-3) ml.g-1.min-1 for xenograft and "normal" brain respectively. This highly selective depletion of glutathione in neoplastic tissue versus surrounding non-neoplastic host tissue may have therapeutic implications for the rational use of chemotherapeutic and radiotherapeutic intervention.     

The ultrastructure of the avian Golgi tendon organ

The ultrastructure of the avian Golgi tendon organ (GTO) is described and compared with those of mammals using transverse sections through the myo-tendinous junctions of wing muscles of adult mallard ducks. The capsule, which is continuous with the perineural epithelial sheath of the Ib afferent nerve fiber, consists of four to seven flattened cellular lamellae. Two to four muscle fibers attach to large collagen bundles which enter the GTO through a tight collar at the proximal end of the fusiform capsule. These collagen bundles divide into many smaller bundles, which run longitudinally through the lumen in compartments formed by septal cells. The septal cells contain many prominent lipid accumulations. The Ib axon divides several times, and the unmyelinated branch axons weave between the small collagen bundles. Schwann cell processes or basement membrane usually intervene between the axons and collagen bundles. The small collagen bundles regroup into larger bundles, which pass through tight capsular collars and merge with the main muscle tendon. The size of the duck GTOs was measured and found to be smaller than the GTOs of man, cat or rat.     

Lung surfactant gelation induced by epithelial cells exposed to air pollution or oxidative stress

Lung surfactant lowers surface tension and adjusts interfacial rheology to facilitate breathing. A novel instrument, the interfacial stress rheometer (ISR), uses an oscillating magnetic needle to measure the shear viscosity and elasticity of a surfactant monolayer at the air-water interface. The ISR reveals that calf lung surfactant, Infasurf, exhibits remarkable fluidity, even when exposed to air pollution residual oil fly ash (ROFA), hydrogen peroxide (H2O2), or conditioned media from resting A549 alveolar epithelial cells (AEC). However, when Infasurf is exposed to a subphase of the soluble fraction of ROFA- or H2O2-treated AEC conditioned media, there is a prominent increase in surfactant elasticity and viscosity, representing two-dimensional gelation. Surfactant gelation is decreased when ROFA-AEC are pretreated with inhibitors of cellular reactive oxygen species (ROS), or with a mitochondrial anion channel inhibitor, as well as when A549-rho0 cells that lack mitochondrial DNA and functional electron transport are investigated. These results implicate both mitochondrial and nonmitochondrial ROS generation in ROFA-AEC-induced surfactant gelation. A549 cells treated with H2O2 demonstrate a dose-dependent increase in lung surfactant gelation. The ISR is a unique and sensitive instrument to characterize surfactant gelation induced by oxidatively stressed AEC.     

Calcineurin B1 is essential for positive but not negative selection during thymocyte development

During development, discrete cell fates often result from variation in the intensity of a particular signal. The mechanisms underlying these seemingly analog-to-digital switches are not understood. In developing T lymphocytes, low-intensity signals through the antigen receptor result in positive selection while more intense signals give rise to negative selection. By deleting the genetic locus encoding the regulatory B1 subunit of calcineurin specifically in thymocytes, we found an absolute requirement for calcineurin in positive selection. In contrast, calcineurin activity was dispensable in several models of negative selection. Unexpectedly, we found that removal of calcineurin activity from thymocytes results in inefficient ERK activation at the double-positive stage of thymocyte development, when selection occurs. These studies clarify the mechanism by which graded signals are converted to discrete outcomes in T cell development and further indicate that the developmental roles of calcineurin likely contribute to immunosuppression by calcineurin inhibitors.     

Specificity of cone mechanisms in lateral interaction

1. The increment threshold for a brief, small probing light flash was used as an indicator of the state of adaptation of the human fovea. It shows that illumination of a zone up to 7 min of arc in diameter desensitizes the retina and that the additional illumination of a surrounding zone acts to counteract the desensitization.

2. The red and green colour mechanisms were isolated by selecting light of appropriate wave-lengths for the adaptation and the increment stimuli and it was demonstrated that the desensitizing and sensitizing adaptation zones exist within each mechanism.

3. Using the constancy of the increment threshold for a brief, small probing flash as a null-indicator for equivalence of annuli of various wave-lengths to produce a given amount of sensitization, the action spectrum for the laterally interacting region was obtained for both the red and the green mechanisms.

4. For the red mechanism, the surrounding sensitizing zone has the action spectrum also of the red mechanism. For the green mechanism the surrounding sensitizing zone has a green action spectrum.

     

Education modifies the effect of apolipoprotein epsilon 4 on cognitive decline

OBJECTIVES: To assess the influence of education on the association between apolipoprotein E and cognitive change. DESIGN: Prospective cohort. PARTICIPANTS: HMO-based sample of 2168 non-demented community-dwelling elderly followed over 6 years. MEASUREMENTS: Generalized estimating equations were used with the difference between baseline and follow-up cognitive abilities screening instrument (CASI) as the outcome variable. RESULTS: At follow-up, 6% of the sample had a decline of 1.5 S.D. or greater on the CASI. Compared to individuals without an APOE4 allele, individuals with a single APOE4 allele did not have greater CASI decline. By contrast, individuals with two APOE4 alleles experienced greater decline in cognitive performance and the magnitude of that decline decreased as years of educational attainment increased. These relationships held after adjusting for age, gender, ethnicity, depression, diabetes, and history of vascular disease. CONCLUSION: Lower education was associated with steep 4-year cognitive decline for APOE4 homozygotes but not for APOE4 heterozygotes. Potentially modifiable host factors such as education could influence the association of high-risk genotypes and cognitive decline.     

Nano-C60 cytotoxicity is due to lipid peroxidation

This study examines the biological effects of water-soluble fullerene aggregates in an effort to evaluate the fundamental mechanisms that contribute to the cytotoxicity of a classic engineered nanomaterial. For this work we used a water-soluble fullerene species, nano-C₆₀, a fullerene aggregate that readily forms when pristine C₆₀ is added to water. Nano-C₆₀ was cytotoxic to human dermal fibroblasts, human liver carcinoma cells (HepG2), and neuronal human astrocytes at doses 50 ppb (LC₅₀=2–50 ppb, depending on cell type) after 48 h exposure. This water-soluble nano-C₆₀ colloidal suspension disrupts normal cellular function through lipid peroxidation; reactive oxygen species are responsible for the membrane damage. Cellular viability was determined through live/dead staining and LDH release. DNA concentration and mitochondrial activity were not affected by the nano-C₆₀ inoculations to cells in culture. The integrity of cellular membrane was examined by monitoring the peroxy-radicals on the lipid bilayer. Subsequently, glutathione production was measured to assess the cell's reaction to membrane oxidation. The damage to cell membranes was observed both with chemical assays, and confirmed physically by visualizing membrane permeability with high molecular weight dyes. With the addition of an antioxidant, l-ascorbic acid, the oxidative damage and resultant toxicity of nano-C₆₀ was completely prevented.     

Gluthatione-S-transferase P1 polymorphism I105V in familial and sporadic prostate cancer

Several reports suggest that the glutathione-S-transferase (GST) family of enzymes is involved in a variety of cancers, due to their carcinogen-detoxification properties. A polymorphism in codon 105 of the pi variant (GSTP1 I105V), which affects the enzymatic activity of the enzyme, has been linked to the incidence of cancers from different organs. However, the published data in prostate cancer (PCa) is controversial. Some studies report an association with the GSTP1 I105V polymorphism and sporadic PCa, whereas other studies report no association. Recently, one study showed a positive correlation between the GSTP1 I105V polymorphism and familial PCa in a Japanese population. In the present study, we assessed the correlation of the GSTP1 I105V polymorphism with familial and sporadic PCa in an American population. We analyzed DNA samples from 438 patients with familial PCa, 499 patients with sporadic PCa, and 510 controls. We found no significant association between the GSTP1 I105V polymorphism and familial or sporadic PCa when compared to the control group [odds ratio (OR) =1.0 (0.74-1.37); P=0.58]. Moreover, no association was found after stratification for age of diagnosis, Gleason grade, or lymph node involvement [OR =0.84 (0.65-1.09), P=0.37]. These data indicate that there is no associated risk for sporadic or familial PCa in American families containing the GSTP1 I105V polymorphism.