Gangliosides attenuate the delayed neurotoxicity of aspartic acid in vitro

The neurotoxic effects of L-aspartate were evaluated in rat cerebellar granule cell cultures. Acute (15 min) exposure to L-aspartate produced a time-dependent, delayed degeneration of neuronal cell bodies and neurites (LD50 about 40 microM) over 24 h. Aspartate neurotoxicity was prevented by competitive and non-competitive N-methyl-D-aspartate (NMDA) antagonists, but not by non-NMDA antagonists, suggesting a major involvement of NMDA receptors in this neuronal injury. Gangliosides, including GM1, were also effective in attenuating the cytotoxicity of L-aspartate. The neurotoxic potential of L-aspartate may thus contribute to pathologies involving the action of endogenous excitatory amino acids.     

B(0) and B(1)-insensitive uniform T(1)-weighting for quantitative, first-pass myocardial perfusion magnetic resonance imaging.

Myocardial perfusion can be estimated, in principle, from first-pass MR images by converting the T(1)-weighted signal-time curves to contrast agent concentration-time curves. Typically, T(1) weighting is achieved by saturating the magnetization with a nonselective radiofrequency (RF) pulse prior to the imaging sequence. The accuracy of the perfusion estimate derived from the single-point T(1)-weighted signal depends on the initial residual longitudinal magnetization (RLM) produced by the saturation pulse. In this study we demonstrate that single-shot, echo-planar imaging can be used to show initial RLM resulting from incomplete saturation due to static magnetic field and RF field inhomogeneities in the heart at 1.5 T. Three saturation pulses, single, composite simple, and composite B(1)-insensitive rotation (BIR-4) were evaluated in phantom and cardiac experiments. The RLM image was calculated by normalizing the saturated image by a proton-density-weighted image. Mean RLM produced by the three saturation pulses was significantly different in noncontrast cardiac imaging (RLM(single) = 0.108 +/- 0.078; RLM(composite) = 0.051 +/- 0.052; RLM(BIR-4) = 0.011 +/- 0.009; P < 0.001; n = 20). Using a BIR-4 pulse to perform saturation of magnetization seems promising for improving the effectiveness and uniformity of T(1) weighting for first-pass perfusion imaging.     

Genome scan of glomerular filtration rate and albuminuria: the HyperGEN study.

BACKGROUND: Albuminuria and reduced glomerular filtration rate (GFR) are markers of renal dysfunction associated with hypertension. We performed genome-wide scans to detect loci impacting these parameters in 1251 African American (AAs) and 1129 European American (EAs) hypertensive siblings from the Hypertension Genetic Epidemiology Network study. METHODS: GFR, estimated by the Modification of Diet in Renal Disease equation, and albuminuria, measured as albumin to creatinine ratio (ACR), were adjusted for gender, age, centre, mean blood pressure, anti-hypertensive medication class and diabetes status using SOLAR. Since albuminuria and abnormal GFR often coexist, we conducted bivariate linkage analyses to investigate the presence of pleiotropy. RESULTS: The phenotypic correlation between ACR and GFR was not significant in EAs (r = 0.04) and significantly negative in AAs (r = -0.17). Univariate analyses of ACR showed suggestive evidence of linkage on chromosomes 8, 16 and 17 (LOD: 2-2.8) in AAs, on chromosomes 18 and 19 (LOD = 2) in EAs, and on chromosome 19 (LOD = 2.6) when combining AAs and EAs. For GFR, suggestive linkage was found on chromosomes 7, 14 and 19 (LOD: 2.2-2.9) in AAs and on chromosomes 14, 15 and 16 (LOD: 2.1-3.3) in the combined group. Also, bivariate analyses showed a LOD score of 3.4 at 133 cM on chromosome 7 in AAs. CONCLUSIONS: Suggestive evidence for linkage to GFR and ACR was observed at many loci. The findings are consistent with previous studies. Also, indication of a pleiotropic locus was detected in chromosome 7 in AAs.     

Attrition in randomized controlled clinical trials: methodological issues in psychopharmacology.

Attrition is a ubiquitous problem in randomized controlled clinical trials (RCT) of psychotropic agents that can cause biased estimates of the treatment effect, reduce statistical power, and restrict the generalizability of results. The extent of the problem of attrition in central nervous system (CNS) trials is considered here and its consequences are examined. The taxonomy of missingness mechanisms is then briefly reviewed in order to introduce issues underlying the choice of data analytic strategies appropriate for RCTs with various forms of incomplete data. The convention of using last observation carried forward to accommodate attrition is discouraged because its assumptions are typically inappropriate for CNS RCTs, whereas multiple imputation strategies are more appropriate. Mixed-effects models often provide a useful data analytic strategy for attrition as do the pattern-mixture and propensity adjustments. Finally, investigators are encouraged to consider asking participants, at each assessment session, the likelihood of attendance at the subsequent assessment session. This information can be used to eliminate some of the very obstacles that lead to attrition, and can be incorporated in data analyses to reduce bias, but it will not eliminate all attrition bias.     

Clinical and pathologic prognostic indicators in colorectal cancer. A population-based study.

The institution of a colorectal Cancer Register in a health care district of Northern Italy gave the authors the opportunity to evaluate the prognostic relevance of several morphologic and clinical variables by univariate and multivariate analyses. Of the 134 patients registered in 1984, 132 were followed up until the end of 1989. Overall 5-year survival was 37%, but the figure increased to 43% when only colorectal cancer-related deaths were considered. Univariate analysis for clinical variables showed that TNM staging and age at diagnosis were significantly related to prognosis, whereas none of the other parameters were indicative of the clinical outcome. With a similar analysis, among the various morphologic variables, pattern of growth (infiltrating versus expanding) and extent of fibrosis (extensive versus little or absent) appeared to be indicators of prognosis. When the variables that were significant (stage, age, pattern of growth, and fibrosis) in the univariate analysis were entered into the Cox model of multivariate analysis, TNM staging was the only parameter that maintained an independent prognostic importance. The authors state that their results confirm the importance of stage in predicting survival for cancer of the large bowel and suggest that the possible prognostic value of clinical and morphologic variables should be investigated within each of the major TNM or Dukes' classes.     

Age-dependent changes in serotonergic modulation of yawning in the rat.

Serotonin (5-HT) effects on physostigmine (PHY)-induced yawning were studied in LY Sprague-Dawley rats by injecting Lu 10 171 (citalopram), a specific 5-HT uptake blocker, and two antagonists--methiothepine and ritanserin--which differ slightly in the selectivity of their actions on different 5-HT receptor subtypes. Infant and young rats show significant increases in PHY-induced yawning when preinjected with citalopram (5-10 mg/kg). Two-month-old animals show this effect only with 10 mg/kg. With adult animals (3-5 months old), the effect is the opposite: Yawning decreases. The facilitory effect in infant and young rats was counteracted by methiothepine but not by ritanserin, suggesting that it is mediated through 5-HT1A or 5-HT1B receptor subtypes. The inhibitory effect of citalopram in adult rats was unmodified by the two antagonists used, leaving open the possibility that it is mediated by 5-HT3 receptors.     

Triamcinolone acetonide aqueous nasal spray and fluticasone propionate are equally effective for relief of nasal symptoms in patients with seasonal allergic rhinitis.

OBJECTIVE: We compared 220 microg daily intranasal aqueous triamcinolone acetonide (TAA AQ) with 200 microg daily fluticasone propionate (FP) for relief of seasonal allergic rhinitis symptoms.Study design and setting Randomized, parallel-group, investigator-blind study included patients with symptomatic seasonal allergic rhinitis. After a baseline period, TAA AQ or FP was taken for about 21 days. Nasal symptom (discharge, stuffiness, itching, sneezing) severity was recorded twice daily; total nasal symptom score was calculated. Health-related quality of life was assessed by Rhinoconjunctivitis Quality of Life Questionnaire. RESULTS: Reductions in individual symptoms and total nasal symptom score were statistically significant versus baseline and were equivalent between treatments: -3.15 +/- 0.19 with TAA AQ (n = 148) and approximately 3.17 +/- 0.18 with FP (n = 147) (95% confidence interval for the difference, -0.7391 to 0.3693). Clinically and statistically significant improvements in Rhinoconjunctivitis Quality of Life Questionnaire scores were comparable. CONCLUSION: TAA AQ and FP were equally efficacious in relieving seasonal allergic rhinitis symptoms and improving health-related quality of life. SIGNIFICANCE: Differences in molecular potency of intranasal steroids do not confer differences in efficacy.