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No abstract

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Nitric oxide produced by inducible nitric-oxide synthase (iNOS) in different brain cells in response to various cytokines plays an important role in the pathophysiology of stroke and other neurodegenerative diseases. This study underlines the importance of cAMP in inhibiting the induction of NO production by lipopolysaccharide (LPS) and cytokines in rat primary astrocytes. Compounds (forskolin, 8-bromo-cAMP, and (S p )-cAMP) that increase cAMP and activate protein kinase A (PKA) were found to inhibit LPS-and cytokine-mediated production of NO as well as the expression of iNOS, whereas compounds (H-89 and (R p )-cAMP) that decrease cAMP and PKA activity stimulated the production of NO and the expression of iNOS in rat primary astrocytes. Forskolin, but not the inactive analogue 1,9-dideoxyforskolin, inhibited NO production and iNOS expression in a dose-dependent manner in astrocytes. The inhibition of LPS-and/or cytokine-induced NO production in rat C 6 glial cells by forskolin suggest that similar to astrocytes, iNOS expression in C 6 cells is also regulated by similar mechanisms. In contrast, in rat peritoneal macrophages the cAMP analogues stimulated the LPS-and cytokineinduced production of NO. In vitro, the PKA had no effect on iNOS activity in LPS-treated astrocytes or macrophages, suggesting that PKA modulates the intracellular signaling events associated with the induction of iNOS biogenesis rather than the post-translational modification of iNOS. The compounds which activate PKA activity, blocked the activation of NF-␤ in astrocytes but stimulated the activation of NF-␤ in macrophages. This differential regulation of NF-␤ activation in two different cell types (astrocytes and macrophages) by the same second messenger (cAMP) indicates that intracellular events or pathways in the activation of NF-␤ may be different. Moreover, this inhibition of iNOS expression in LPS-and cytokine-treated astrocytes by cAMP may be of therapeutic potential in NOmediated cytotoxicity in neurodegenerative diseases.

We examined age differences in the effort required to perform the basic cognitive operations needed to achieve a specified objective outcome and how hypothesized increases in effort requirements in later life are related to intrinsic motivation associated with enjoyment of and participation in effortful cognitive activities. Young (N = 59; 20–40 years) and older (N = 57; 64–85 years) adults performed a memory-search task varying in difficulty across trials, with systolic blood pressure responsivity—calculated as the increase over baseline during task performance—used as a measure of effort expenditure and task engagement. Consistent with expectations, older adults exhibited greater levels of responsivity (i.e., effort) at all levels of objective task difficulty, and this increase was reflected in subjective perceptions of difficulty. Older adults also exhibited greater levels of disengagement (i.e., effort withdrawal) than younger adults at higher levels of task difficulty, conceivably reflecting the disproportionately greater effort required for successful performance in the former group. We also found that, relative to younger adults, older adults’ engagement was more sensitive to the importance attached to the task (i.e., motivation to do well). Finally, we also obtained evidence that increased costs associated with cognitive engagement in later life were negatively associated with intrinsic levels of motivation to engage in effortful cognitive activity. The results support the general conclusion that the costs of cognitive activity increase with age in adulthood, and that these costs influence individuals’ willingness to engage resources in support of demanding cognitive activities.

An implantable integrated stimulator and telemetry system has been developed. The system is capable of fulfilling the stimulus and telemetry needs of advanced functional neuromuscular stimulation (FNS) applications requiring multiple channels of stimulation and multiple channels of sensor or biopotential sensing. This system provides a command control structure, an inductive radio frequency link providing power to the implant device as well as two-way transcutaneous communication, an ASIC for decoding the command and for providing functional control within the implant, and modular circuitry providing the application specific implant functions. Biocompatible hermetic packaging, lead systems, and in-line connectors suitable for long-term implantation, provide encapsulation for the circuitry and access to the electrodes and sensors used in the application. The first implant configuration realized from this modular system is targeted for clinical implementation in persons with tetraplegia at the C6 level for restoration of hand function, using wrist position as the command control source. The implant device realized has ten channels of stimulation and telemetry used to control and sense a joint angle transducer implanted in the radio-carpal joint of the wrist. A prototype device has been fabricated and is undergoing testing in an animal.

Dental caries remains the most common chronic childhood disease. Despite strong evidence of genetic components, there have been few studies of candidate genes and caries. In this analysis we tried to assess genetic and environmental factors contributing to childhood caries in the Iowa Fluoride Study. Environmental factors (age, sex, race, tooth-brushing frequencies and water fluoride level) and three dental caries scores (d₂fs-total, d₂fs-pit/fissure, and d₂fs-smooth surface) were assessed in 575 unrelated children (mean age 5.2 years). Regression analyses were applied to assess environmental correlates. The Family-Based Association Test was used to test genetic associations for 23 single nucleotide polymorphism (SNP) markers in 7 caries candidate genes on 333 Caucasian parent-child trios. We evaluated the associations between caries status and the level of both single and multiple SNPs (haplotype) respectively. Permutation procedure was performed for correction of inflated type I errors due to multiple testing. Age, tooth-brushing frequency and water fluoride level were significantly correlated to at least one carious score. Caries on pit and fissure surfaces was substantially higher than on smooth surfaces (61 vs. 39%). SNPs in three genes (DSPP, KLK4 and AQP5) showed consistent associations with protection against caries. Of note, KLK4 and AQP5 were also highlighted by subsequent haplotype analysis. Our results support the concept that genes can modify the susceptibility of caries in children. Replication analysis in independent cohorts is highly needed in order to verify the validity of our findings.