The inhibitory mGluR agonist, S-4-carboxy-3-hydroxy-phenylglycine selectively attenuates NMDA neurotoxicity and oxygen-glucose deprivation-induced neuronal death

We examined the effect of two novel phenylglycine derivative drugs on excitotoxicity in murine cortical cell cultures: S-4-carboxy-3-hydroxy-phenylglycine (4C3HPG), a selective agonist of mGluRs 2/3 and an antagonist at mGluRs 1/5, and S-3 hydroxy-phenylglycine (3HPG), an agonist of mGluRs 1/5. 4C3HPG attenuated slowly-triggered NMDA-induced excitotoxic neuronal death, as well as the death induced by combined oxygen-glucose deprivation, but did not affect slowly-triggered excitotoxicity induced by AMPA or kainate. As expected, 4C3HPG also reduced NMDA-induced increases in cAMP in near-pure neuronal cultures, and the protective effect of 4C3HPG on NMDA toxicity could be reversed by adding 8-(4-chlorophenylthio)-adenosine 3':5'-cyclic-monophosphate (CPT cAMP) to the exposure medium. In contrast, 3HPG did not did not have any protective effects in these paradigms; in fact, slowly-triggered NMDA-induced excitotoxicity and the neuronal cell death induced by oxygen-glucose deprivation were potentiated. These results are consistent with the idea that the "inhibitory" mGluRs 2/3 exert a negative modulatory action on NMDA receptor-mediated excitotoxicity via reduction in neuronal cAMP levels.     

Clinicopathologic analysis of bcl-2 immunostaining in breast carcinoma

Tissue sections of 81 breast carcinomas and 19 benign breast tissues were immunostained with a monoclonal antibody to the bcl-2 gene product, a cytoplasmic protein that regulates apoptosis. The degree of immunoreactivity was then compared with clinicopathologic parameters and to immunostaining for mutated p53 gene product. Immunoreactivity for bcl-2 was present consistently in lymphocyte populations and in residual benign lobules. Apocrine metaplasia (n = 6) and lactating breast (n = 1) exhibited minimal bcl-2 expression, whereas duct hyperplasia (n = 10) showed staining of cells primarily at the periphery of the involved structure and adenosis (n = 7) displayed staining in a majority of cells. Neoplastic epithelial bcl-2 immunoreactivity was negative or minimally positive (staining in 1-5% of cells) in 42% of cases, heterogeneous (staining in 6-30% of cells) in 27% of cases, and diffuse (> 30% of cells) in 31% of cases. Immunostaining for bcl-2 correlated with the presence of estrogen receptor (bcl-2 negative, 16% estrogen receptor positive versus bcl-2 positive, 88% estrogen receptor-positive; P < 0.001), with differentiation (bcl-2 negative, 62% poorly differentiated versus bcl-2 positive, 8% poorly differentiated; P < 0.001) and with better disease-free survival (bcl-2 negative, 82% recurrence versus bcl-2 positive, 28% recurrence; P = 0.0001; 52-mo mean follow-up). Immunostaining for p53 in greater than 5% of tumor cells was observed in 39% of cases and was more frequent in bcl-2-negative tumors (18/35, 51%) as opposed to bcl-2-positive tumors (14/46, 30%); P = NS. Disease recurrence correlated with p53 staining, which was observed in 51% of tumors that relapsed versus only 22% of tumors that did not recur. We conclude that bcl-2 is expressed in benign breast tissues that retain proliferative capacity and partial differentiation. Moreover, in neoplastic breast tissue, it is better correlated with a differentiated, "hormonally responsive," prognostically favorable phenotype than with disabled p53 gene function.     

Phosphatidate phosphohydrolase and signal transduction

A Mg(2+)-independent and N-ethylmaleimide-insensitive phosphatidate phosphohydrolase (PAP-2) has been identified in the plasma membrane of cells and it has been purified. The enzyme is a multi-functional phosphohydrolase that can dephosphorylate phosphatidate, lysophosphatidate, sphingosine 1-phosphate and ceramide 1-phosphate and these substrates are competitive inhibitors of the reaction. The action of PAP-2 could terminate signalling by these bioactive lipids and at the same time generates compounds such as diacylglycerol, sphingosine and ceramide which are also potent signalling molecules. In relation to phosphatidate metabolism, sphingosine (or sphingosine 1-phosphate) stimulates phospholipase D and thus the formation of phosphatidate. At the same time sphingosine inhibits PAP-2 activity thus further increasing phosphatidate concentrations. By contrast, ceramides inhibit the activation of phospholipase D by a wide variety of agonists and increase the dephosphorylation of phosphatidate, lysophosphatidate, sphingosine 1-phosphate and ceramide 1-phosphate. These actions demonstrate "cross-talk' between the glycerolipid and sphingolipid signalling pathways and the involvement of PAP-2 in modifying the balance of the bioactive lipids generated by these pathways during cell activation.     

Cross-national interrater reliability of dementia diagnosis in the elderly and factors associated with disagreement

Thirteen researchers from five centers in Australia, Germany, the Netherlands, United Kingdom, and United States applied DSM-III-R and Clinical Dementia Rating (CDR) syndrome-level dementia criteria to written vignettes of 100 elderly people identified in clinics or community surveys. Subjects ranged in type from cognitively intact to severely demented and many were also frail, partially sighted, or deaf. This paper concerns reliability within and between centers, and the relationship between reliability and factors such as diagnostic criteria, dementia severity, and respondents' clinical characteristics. Within-center interrater reliability was high, more so for "yes-no" DSM-III-R diagnoses than the multi-level CDR. Between-center rates were lower but still moderate to good. Concordance was lower for intermediate dementia levels than for no dementia and severe dementia. Physical disability made an additional contribution to uncertainty but deafness, poor vision, anxiety, and depression had no discernible effects. Reliability levels are likely to be lower in representative aged populations than in carefully selected clinical groups.     

A comparison of moderate and high users of Alberta's universal dental plan for the elderly

The characteristics and service utilization of 2,071 high and 2,337 moderate users of Alberta's dental plan from 1978-79 to 1990-91 are reported. High users are those who used the plan for 14 consecutive years; moderate users are those who used the plan in seven of the 14 years. Both groups were over 74 years of age in 1991-92. Compared to high users, moderate users lived in less urbanized regions, visited denturists more often and received far more complete dentures and fewer partial dentures. As a percentage of their total annual plan expenditures, moderate users spent less on diagnostic, preventive, periodontal and restorative services and much more on removable prosthodontic and denturists' services. However, during the study period, the moderate users increased their annual relative expenditures for diagnostic, preventive and, especially, periodontal services, and decreased them for prosthodontic services. With respect to specific preventive and periodontal services, the percentage of total annual expenditures for dental prophylaxis, topical fluoride applications, periodontal scaling, gingival curettage, and combinations of these, was much higher for the high user group. Despite these differences favoring the high user group, during the 14 year period, the moderate user group considerably increased its relative expenditures for dental prophylaxis, topical fluoride and periodontal scaling services. While the observed differences in service expenditures between high and moderate users were anticipated, the shift over time to using more preventive and periodontal services by both groups was an encouraging harbinger of the "new elderly" dental patients.     

Supporting decision making process with “ideal” software agents - What do business executives want?

According to Simon’s (1977) decision making theory, intelligence is the first and most important phase in the decision making process. With the escalation of information resources available to business executives, it is becoming imperative to explore the potential and challenges of using agent-based systems to support the intelligence phase of decision-making. This research examines UK executives’ perceptions of using agent-based support systems and the criteria for design and development of their “ideal” intelligent software agents. The study adopted an inductive approach using focus groups to generate a preliminary set of design criteria of “ideal” agents. It then followed a deductive approach using semi-structured interviews to validate and enhance the criteria. This qualitative research has generated unique insights into executives’ perceptions of the design and use of agent-based support systems. The systematic content analysis of qualitative data led to the proposal and validation of design criteria at three levels. The findings revealed the most desirable criteria for agent based support systems from the end users’ point view. The design criteria can be used not only to guide intelligent agent system design but also system evaluation.     

Reduced interlitter variability in rats resulting from a restricted mating period, and reassessment of the "litter effect''

Rats were mated for two or 15 hours and variability of day-12-embryos in weight, protein content, and [3H]thymidine incorporation was compared in the long mating period (LMP) and short mating period (SMP) groups by a 2-level nested analysis of variance. Variability in day-20 fetal weight was similarly compared. In both groups day-12 embryonic weight was relatively more variable than day-20 fetal weight, and variability was less in SMP than LMP animals for each comparison made, although statistical significance was attained only for thymidine incorporation. "Litter effects' were noted but not of the magnitude reported by other investigators. It was concluded that inappropriate statistical methods have encouraged the belief that among-litter variability usually exceeds within-litter fetal weight variability. The teratological implications of reduced development variability and the "litter effect' are discussed.