The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two B7 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T cell activation. To elucidate the in vivo function of CTLA-4, we generated CTLA-4-deficient mice. These mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age. The phenotype of the CTLA-4-deficient mouse strain is supported by studies that have suggested a negative role for CTLA-4 in T cell activation. The severe phenotype of mice lacking CTLA-4 implies a critical role for CTLA-4 in down-regulating T cell activation and maintaining immunologic homeostasis. In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.

Evidence about the total cost of health, absence, short-term disability, and productivity losses was synthesized for 10 health conditions. Cost estimates from a large medical/absence database were combined with findings from several published productivity surveys. Ranges of condition prevalence and associated absenteeism and presenteeism (on-the-job-productivity) losses were used to estimate condition-related costs. Based on average impairment and prevalence estimates, the overall economic burden of illness was highest for hypertension ($392 per eligible employee per year), heart disease ($368), depression and other mental illnesses ($348), and arthritis ($327). Presenteeism costs were higher than medical costs in most cases, and represented 18% to 60% of all costs for the 10 conditions. Caution is advised when interpreting any particular source of data, and the need for standardization in future research is noted.

We investigated the hypothesis that neural stem cells (NSCs) possess an intrinsic capacity to "rescue" dysfunctional neurons in the brains of aged mice. The study focused on a neuronal cell type with stereotypical projections that is commonly compromised in the aged brain-the dopaminergic (DA) neuron. Unilateral implantation of murine NSCs into the midbrains of aged mice, in which the presence of stably impaired but nonapoptotic DA neurons was increased by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was associated with bilateral reconstitution of the mesostriatal system. Functional assays paralleled the spatiotemporal recovery of tyrosine hydroxylase (TH) and dopamine transporter (DAT) activity, which, in turn, mirrored the spatiotemporal distribution of donor-derived cells. Although spontaneous conversion of donor NSCs to TH(+) cells contributed to nigral reconstitution in DA-depleted areas, the majority of DA neurons in the mesostriatal system were "rescued" host cells. Undifferentiated donor progenitors spontaneously expressing neuroprotective substances provided a plausible molecular basis for this finding. These observations suggest that host structures may benefit not only from NSC-derived replacement of lost neurons but also from the "chaperone" effect of some NSC-derived progeny.

We sought to provide evidence for the relationship between health risks and self-reported productivity, including health-related absence and impaired performance on the job. A cross-sectional analysis was implemented consisting of 2264 employees of a large national employer located in the Northeast. Participants responded to a health risk assessment and work productivity scale. Mean productivity loss was compared for individuals with different levels of risk factors using analysis of variance. Multivariate analyses, including logistic and linear regression, were used to determine the significance of health risks on productivity loss. Participants with more risk factors reported greater productivity loss (P < 0.001). The odds of any productivity loss were most significant for individuals with diabetes (absenteeism) and stress (presenteeism). In conclusion, higher risks are strongly associated with greater productivity loss, and different risks are associated with absenteeism than with presenteeism.

We have examined the pathological lesions and sites of infection in mice inoculated with a highly neurovirulent recombinant wild mouse ecotropic retrovirus (FrCasE). The spongiform lesions appeared initially as swollen postsynaptic neuronal processes, progressing to swelling in neuronal cell bodies, all in the absence of detectable gliosis. Infection of neurons in regions of vacuolation was not detected. However, high level infection of cerebellar granule neurons was observed in the absence of cytopathology, wherein viral protein was found associated with both axons and dendrites. Infection of ramified and amoeboid microglial cells was associated with cytopathology in the brain stem, and endothelial cell-pericyte infection was found throughout the CNS. No evidence of defective retroviral expression was observed. These results are consistent with an indirect mechanism of retrovirus-induced neuropathology.

Caldesmon is an F-actin cross-linking protein of chicken gizzard smooth muscle whose F-actin binding activity can be regulated in vitro by Ca2+- calmodulin (Sobue, K., Y. Muramoto, M. Fujita, and S. Kakiuchi, 1981, Proc. Natl. Acad. Sci. USA, 78:5652-5655). It is a rod-shaped, heat- stable, F-actin bundling protein and is the most abundant F-actin cross- linking protein of chicken gizzard smooth muscle presently known (Bretscher, A., 1984, J. Biol. Chem., 259:12873-12880). We report the use of polyclonal antibodies to caldesmon to investigate its distribution and localization in other cells. Using immune blotting procedures, we have detected immunoreactive, heat-stable forms of caldesmon in cultured cells having either approximately the same apparent polypeptide molecular weight as gizzard caldesmon (120,000- 140,000) or a substantially lower molecular weight (71,000-77,000). Through use of affinity-purified antibodies in indirect immunofluorescence microscopy, we have localized the immunoreactive forms to the terminal web of the brush border of intestinal epithelial cells and to the stress fibers and ruffling membranes of cultured cells. At the light microscope level caldesmon is distributed in a periodic fashion along stress fibers that is coincident with the distribution of tropomyosin and complementary to the distribution of alpha-actinin.

We sought to examine the relationship between changes in health risks and changes in work productivity. Pre- and postanalysis was conducted on 500 subjects who participated in a wellness program at a large national employer. Change in health risks was analyzed using McNemar chi-square tests, and change in mean productivity was analyzed using paired t tests. A repeated measures regression model examined whether a change in productivity was associated with a change in health risks, controlling for age and gender. Individuals who reduced one health risk improved their presenteeism by 9% and reduced absenteeism by 2%, controlling for baseline risk level, age, gender, and interaction of baseline risk and risk change. In conclusion, reductions in health risks are associated with positive changes in work productivity. Self-reported work productivity may have utility in the evaluation of health promotion programs.

An ESR spectrometer operating at 250-GHz frequency ( l.22-mm wavelength) and 9-T magnetic field is described. The utilization of far-infrared (FIR) technology greatly simplifies its design and performance. Good frequency and field stability are achieved by unique designs which also conveniently permit the magnetic field to be swept. The potential utility ofFIR-ESR is illustrated with examples of spectra from polycrystalline and liquid samples. In the latter case the increased spectral sensitivity to motional dynamics is stressed. Several ways in which the FIR-ESR spectrometer may be improved are also discussed.