The neuropathology of the effects of ethanol on the developing central nervous system are similar to those of patients with mutations in L1, a neural cell adhesion molecule. This observation suggests that inhibition of L1 plays a role in the pathogenesis of alcohol-related neurodevelopmental disorders. Here we examine the effects of ethanol on L1 homophilic binding and on L1-mediated neurite outgrowth. Ethanol had no effect on cell adhesion or aggregation in a myeloma cell line expressing full-length human L1. In contrast, the rate of L1-mediated neurite outgrowth of rat postnatal day 6 cerebellar granule cells grown on a substratum of Ng-CAM, the chick homologue of L1, was inhibited by 48.6% in the presence of ethanol with a half-maximal concentration of 4.7 mM. The same effect was found with soluble L1-Fc, thus showing that the inhibitory effect is not dependent on cell adhesion. In contrast, neither laminin nor N-cadherin-mediated neurite outgrowth was inhibited by physiologic concentrations of ethanol. We conclude that one mechanism of ethanol's toxicity to the developing central nervous system may be the inhibition of L1-mediated neurite outgrowth.Ethanol is a known human teratogen of immense public health concern. The characteristic pattern of malformations now called fetal alcohol syndrome (FAS) 1 was first described in 1968 (1). The criteria for diagnosis, established by the Fetal Alcohol Syndrome Study Group, are as follows: 1) pre-or postnatal growth retardation, 2) craniofacial dysmorphology including microphthalmia, and 3) neurologic abnormalities including mental retardation (2). Conservative estimates place the overall rate of FAS at 0.33/1000, with 1200 children/year born with FAS (3). Alcohol-related birth and neurodevelopmental defects are thought to be anywhere from 3-4 times as common as FAS (4). The Institute of Medicine has recently divided FAS and other effects into five separate categories, including a category for patients with only neurodevelopmental pathology, alcohol-related neurodevelopmental disorder (5). Although multiple organ systems are affected in FAS, the central nervous system appears to be particularly sensitive. The list of neuropathological anomalies found in FAS infants and children include neuronal-glial heterotopias, cerebellar dysplasia, agenesis of the corpus callosum, hydrocephalus, enlarged lateral ventricles, and microcephaly (2,4,6). Magnetic resonance imaging in 10 patients with FAS revealed central nervous system anomalies in all 10 (7). Six of these patients had midline defects including partial to complete agenesis of the corpus callosum, hypoplastic corpus callosum, cavum septum pellucidi, and cavum vergae. The other four had microcephaly.Overlap of the neuropathological abnormalities observed in FAS with those of patients with L1 mutations has led to the hypothesis that ethanol acts via disruption of L1-mediated events (8). L1 is a member of the Ig superfamily of cell adhesion molecules (9). L1 was initially identified when antibodies to L1 disrupted migratio...

The presence of ethyl linoleate in meconium is the first reported biological marker for maternal ethanol use during pregnancy. Because of the inherent inaccuracy associated with the use of self-reporting, the establishment of true values of sensitivity and specificity will require validation where the presence, quantity, and timing of exposure to alcohol is known. Further validation of this marker will permit identification and intervention of at-risk infants.

Low-dose UVB exposure induces antigen-specific unresponsiveness to antigen(s) introduced through UV-irradiated skin (tolerance). Analysis of cytokine expression in murine draining lymph nodes (DLNs) revealed that IL-12p40 mRNA and protein expression as well as IL-12p70 protein were upregulated after application of the contact sensitizer 2,4 dinitro-1-fluorobenzene (DNFB) to normal skin. The cellular source of IL-12p40 mRNA was CD11c+ cells. By contrast, following DNFB application to UV-irradiated skin (UV+DNFB), IL-12p40 mRNA was not upregulated, and DLN IL-12p40 and p70 proteins were reduced. UVB irradiation alone did not upregulate IL-10 mRNA, but UV+DNFB upregulated IL-10 mRNA as early as 3-6 hours after DNFB application, immediately preceding a decrease of IL-12p40 mRNA from the level induced by UVB. The infiltration of F4/80+ cells into UV-irradiated skin was followed by a rapid and remarkable increase of F4/80+CD11c(-) cells in DLN 3 hours following DNFB application. FITC/DNFB skin painting and subsequent enzyme-linked immunospot assay demonstrated that flow-sorted FITC+F4/80+CD11c(-) cells from the DLN produce IL-10. Thus, monocytes/macrophages that infiltrated into the skin following UVB exposure migrate to the DLN triggered by contact sensitizers. Production of IL-10 by migrating macrophages, in conjunction with IL-12 inhibition in the DLN, likely reflects a role as mobile suppressive mediators for locally induced UV tolerance.

Background: Type I interferons (IFNs) are common therapeutics for several diseases, including viral infections and multiple sclerosis (MS). Although numerous studies have implicated type I INFs with the production of autoantibodies and the development of certain autoimmune disorders, interferon beta has not previously been described in association with dermatomyositis, to our knowledge. Previous microarray studies of muscle biopsy specimens from patients with dermatomyositis disclosed a type I IFN-induced gene expression profile. The central role of plasmacytoid dendritic cell precursors, together with increased type I IFN production, suggests a pivotal role for type I IFNs in dermatomyositis. We report a case of dermatomyositis exacerbated or induced by interferon beta therapy for MS and provide evidence that demonstrates enhanced type I IFN signaling in this patient. Observations:We observed new-onset dermatomyositis in a 57-year-old patient treated with interferon beta Conclusions: To our knowledge, this is the first description of dermatomyositis exacerbated or induced by interferon beta treatment. Our results demonstrate enhanced type I IFN signaling following interferon beta treatment in our patient with dermatomyositis.

The presence of ethyl linoleate in meconium is the first reported biological marker for maternal ethanol use during pregnancy. Because of the inherent inaccuracy associated with the use of self-reporting, the establishment of true values of sensitivity and specificity will require validation where the presence, quantity, and timing of exposure to alcohol is known. Further validation of this marker will permit identification and intervention of at-risk infants.

Quantitative analysis of Lp-PLA concentration and activity by LC-MS/MS assays provided key insight into resolving the well-documented discordance between Lp-PLA concentration (determined by immunoassay) and activity. Quantitative detection of Lp-PLA by immunoassay appears to be strongly inhibited by interaction of Lp-PLA with lipoprotein. Together, the results illustrate the advantages of quantitative LC-MS/MS for measurement of Lp-PLA concentration (by SISCAPA) and activity (by direct product detection).

SummaryBackground-Photodynamic therapy (PDT) has been shown to be effective in the treatment of malignancies of a variety of organ systems, including the lungs, bladder, gastrointestinal tract and skin. Cutaneous lesions serve as ideal targets of PDT because of the accessibility of the skin to light. To achieve optimum results, the photosensitizer must be delivered effectively into the target layers of the skin within a practical timeframe, via noninvasive methods.

Plateau-phase A549 cells exhibit a high capacity for repair of potentially lethal radiation damage (PLD) when allowed to recover in their own spent medium. Addition of either insulin or insulin-like growth factor-1 (IGF-1) to the spent medium 60 to 120 min before irradiation significantly inhibits PLD repair. The 9-h recovery factor (survival with holding/survival without holding) is reduced from 10.8 +/- 0.7 to 3.4 +/- 0.3 by insulin and to 3.0 +/- 0.4 by IGF-1. Neither growth factor alters the cell age distribution of the plateau-phase cells, increases the rate of incorporation of 5-bromo-2'-deoxyuridine into DNA, or alters the extent of radiation-induced mitotic delay in cells subcultured immediately after irradiation. Both insulin and IGF-1 alter the kinetics for rejoining of DNA double-strand breaks (DSBs), slowing the fast component of rejoining significantly. However, these growth factors have no effect on the initial level of DSBs or on the percentage of residual unrejoined breaks at 120 min postirradiation. Both growth factors affect repair of lesions leading to dicentric, but not to acentric, chromosome aberrations significantly. In control cells (treated with phosphate-buffered saline, 90 min prior to irradiation), the half-time for disappearance of dicentrics was 4.1 h (3.4 to 5.1 h), and 47.1 +/- 3.7% of the residual damage remained at 24 h postirradiation. Insulin and IGF-1 increased the half-time for disappearance of dicentrics to 5.2 h (3.9 to 7.7 h) and 5.7 h (5.5 to 5.9 h), respectively, and increased residual damage to 56.1 +/- 5.9% and 60.8 +/- 6.0%, respectively. Overall, these data show that insulin and IGF-1 inhibit PLD repair in A549 cells by mechanisms which are independent of changes in cell cycle parameters. The data suggest that the growth factors act by inducing changes in chromatin conformation which promote misrepair of radiation-damaged DNA.