The mechanism of Ara-C-induced apoptosis of differentiating cerebellar granule neurons

Neurotoxicity is one of the side-effects of the therapeutically useful antitumour agent, Ara-C (or 1-beta-d-arabinofuranosyl-cytosine, cytarabine). This agent is also reported to induce cell death of cultured neurons. In this study, we show that Ara-C-induced death of differentiating rat cerebellar granule neurons is prevented by cycloheximide at concentrations corresponding to its action in preventing protein synthesis. The death is accompanied by cleavage of the caspase substrate poly ADP ribose polymerase (PARP) and c-Abl-dependent activation of the stress-activated protein kinases c-Jun N-terminal kinase and p38. However, c-Jun levels do not rise and the activation of the stress-activated protein kinases is not required for this form of neuronal death. Cyclin-dependent kinase (cdk) activity and inappropriate cell-cycle re-entry have been implicated in some forms of death in differentiated neurons. Here we show that Ara-C-induced death of cerebellar granule neurons is prevented by an inhibitor of cdk4, whereas inhibition of cdk1, -2 and -5 mimics the death, and non-cdk4/6 cdks are inhibited by Ara-C treatment. Cdk1 and -2 are dramatically down-regulated during neuronal differentiation, and neither Ara-C nor inhibition of these cdks induces death in mature neurons. This mechanism could also play a significant role in the neurotoxicity associated with the therapeutic use of Ara-C, as cdk levels can be upregulated in stressed neurons of adult brain. We propose that the balance between cdk4/6 and cdk1/2/5 activity may determine the survival of early differentiating neurons, and that DNA-damaging agents may induce neuronal death by inhibiting cdk1/2/5 under conditions which require these activities for survival.     

Panel on cost-effectiveness in health and medicine recommendations: identifying costs

The assignment of costs in a cost-effectiveness analysis is a complex and disputed issue. The Panel on Cost-Effectiveness in Health and Medicine was convened to discuss standards that could be applied across a range of areas of cost-effectiveness. Additionally, the Panel had a mandate to resolve some controversial issues about the practice of cost-effectiveness that created difficulty in making comparisons across studies. The Panel proposed these guidelines: (1) Do at least some of the analysis from a social perspective; (2) Assign values to resources that reflect their opportunity costs; (3) Avoid zero counting of resources; (4) Avoid double counting of resources; (5) Make analyses only as exacting as necessary in a study. Difficulties in data collection were discussed. Among other questions considered by the panel were how to assign a value to the patient's time and which productivity costs to include in a cost-effectiveness analysis. With tools and suggestions from the Panel on Cost-Effectiveness in Health and Medicine, the cost analyst can report costs accurately and provide accurate comparisons of cost performance across states, trial modalities, or diseases.     

Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B

1. Of the four major phosphodiesterase 4 (PDE4) subtypes, PDE4A, PDE4B and PDE4D are widely expressed in human inflammatory cells, including monocytes and T lymphocytes. We explored the functional role of these subtypes using ten subtype-selective PDE4 inhibitors, each belonging to one of two classes: (i) dual PDE4A/PDE4B inhibitors or (ii) PDE4D inhibitors. 2. These compounds were evaluated for their ability to inhibit antigen-stimulated T-cell proliferation and bacterial lipopolysaccharide (LPS)-stimulated tumour necrosis factor alpha (TNFalpha) release from peripheral blood monocytes. 3. All compounds inhibited T-cell proliferation in a concentration-dependent manner; with IC50 values distributed over an approximately 50 fold range. These compounds also inhibited TNFalpha release concentration-dependently, with a wider ( approximately 1000 fold) range of IC50 values. 4. In both sets of experiments, mean IC50 values were significantly correlated with compound potency against the catalytic activity of recombinant human PDE4A or PDE4B when analysed by either linear regression of log IC50 values or by Spearman's rank-order correlation. The correlation between inhibition of inflammatory cell function and inhibition of recombinant PDE4D catalytic activity was not significant in either analysis. 5. These results suggest that PDE4A and/or PDE4B may play the major role in regulating these two inflammatory cell functions but do not rule out PDE4D as an important mediator of other activities in mononuclear leukocytes and other immune and inflammatory cells. Much more work is needed to establish the functional roles of the PDE4 subtypes across a broader range of cellular functions and cell types.     

Children in single-father families in demographic perspective

The purpose of this article is to examine single-parent families headed by fathers. "We use specially constructed child files from the 1960-1990 Public Use Microdata Samples data from the Census of Population to address two general questions: (a) To what extent has both the likelihood and the demographic characteristics of these families changed over time? (b) What are the consequences for children of living in different kinds of father-only families? We find that single-father families are comparatively rare, but increasing rapidly, especially since 1980. Increasingly, these families are formed by fathers who are young, never married, with low incomes, and fewer children. Analysis of the 1990 data reveals wide diversity in living arrangements among children in single-father families. Furthermore, the social capital of children's fathers, the availability of adults, and children's economic well-being vary markedly across these types of families."     

Bladder Cancer and Arsenic Exposure： Differences in the Two Populations Enrolled in A Study in Southwest Taiwan

Objective Analyses of bladder cancer mortality in the Black Foot Disease (BFD) endemic area of southwest Taiwan conducted by Morales et al. showed a discontinuity in risk at 400 μg/L arsenic in the drinking water in a stratified analysis and no discontinuity in a continuous analysis.