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BACKGROUND: Characterizing blood profile of alopecia areata (AA) is important not only for treatment advancements, but also for possibly identifying peripheral biomarkers that will eliminate the need for scalp biopsies. We aimed to compare frequencies of skin homing (CLA+ ) vs systemic (CLA- ) "polar" CD4+ and CD8+ and activated T-cell subsets in AA vs atopic dermatitis (AD) and control blood. METHODS: Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4+ and CD8+ T cells. Inducible co-stimulator molecule (ICOS) and HLA-DR were used to define mid- and long-term T-cell activation. We compared peripheral blood from 32 moderate-to-severe AA adults with 43 moderate-to-severe AD patients and 30 age-matched controls. RESULTS: AA patients had increased CLA+ /CLA- Th2 (P < .007), CLA+ Tc2 (P = .04), and CLA+ Th22 (P < .05) frequencies than controls. Except of CLA- Tc1 cells (P = .03), IFN-γ levels were mostly similar between AA, AD, and controls (P > .1). ICOS and HLA-DR activation were significantly higher in AA than controls (P < .05). T regulatory cells were significantly decreased in AA patients than controls (P < .01) and were correlated with activated CD8+ T cells and with multiple cytokine subsets (P < .05). While Th2 and Tc2 clustered with disease severity, IFN-γ producing cells were linked with AA duration. CONCLUSIONS: Alopecia areata is accompanied by Th2/Tc2 activation in skin-homing and systemic subsets, correlating with disease severity, while IFN-γ is linked to disease chronicity. These data hint for a possible role of diverse T-cells subsets in disease pathogenesis and emphasize the systemic nature of AA supporting the need for systemic therapeutic strategies in severe patients.

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Combined scanning tunneling microscopy, temperature programmed desorption, photo stimulated desorption, and density functional theory studies have probed the formation and reactivity of highly-hydroxylated rutile TiO(2)(110) surfaces, which were prepared via a novel, photochemical route using trimethyl acetic acid (TMAA) dissociative adsorption and subsequent photolysis at 300 K. Deprotonation of TMAA molecules upon adsorption produces both surface bridging hydroxyls (OH(b)) and bidentate trimethyl acetate (TMA) species with a saturation coverage of nearly 0.5 monolayers (ML). Ultra-violet light irradiation selectively removes TMA species, producing a highly-hydroxylated surface with up to ~0.5 ML OH(b) coverage. At high coverages, the OH(b) species typically occupy second-nearest neighbor sites along the bridging oxygen row locally forming linear (2 × 1) structures of different lengths, although the surface is less ordered on a long scale. The annealing of the highly-hydroxylated surface leads to hydroxyl recombination and H(2)O desorption with ~100% yield, thus ruling out the diffusion of H into the bulk that has been suggested in the literature. In agreement with experimental data, theoretical results show that the recombinative H(2)O desorption is preferred over both H bulk diffusion and H(2) desorption processes.

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BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract associated with dysregulation of the immune response. It is caused by a combination of environmental and genetic factors. Patients with CD have a TH1-type inflammatory response characterized by nuclear factor kappa B (NFkappaB) activation. Mutations in the bacterial pattern recognition receptors NOD2/CARD15 and Toll-like receptor 4 (TLR4) genes, which lead to activation of NFkappaB under normal circumstances, have been associated with increased susceptibility for CD. NFkappaB plays a critical role in the immune response and is down-regulated by NFkappaB inhibitor alpha (NFKBIA). NFKBIA was found to be a susceptibility gene for German CD patients lacking NOD2/CARD15 mutations. MATERIALS AND METHODS: A cohort of 231 Israeli CD patients previously genotyped for the single nucleotide polymorphisms (SNPs) in the CARD15, TLR4 susceptibility genes for CD, was analyzed for the 3'-untranslated region (UTR) SNP of the NFKBIA gene in comparison to 100 healthy ethnically matched controls. We evaluated the contribution of the 3'-UTR SNP in NFKBIA in patients with or without other SNPs in CARD15 to age of onset, disease location, and disease behavior (Vienna classification). RESULTS: We did not identify a significant difference in allele and genotype frequencies between either groups or an effect on phenotype. No interactions were found between NFKBIA and any NOD2. CONCLUSIONS: The contribution of population diversity to susceptibility genes for CD plays an important role in disease-associated variants and is important for better understanding of the pathologic mechanisms of the polymorphism.

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In this work, an oxidation model for alpha-uranium is presented. It describes the internally lateral stress field built in the oxide scale during the reaction. The thickness of the elastic, stress-preserving oxide (UO(2+x)) scale is less than 0.5 microm. A lateral, 6.5 GPa stress field has been calculated from strains derived from line shifts (delta(2theta)) as measured by the X-ray diffraction of UO(2). It is shown that in the elastic growth domain, (110) is the main UO(2) growth plane for gas-solid oxidation. The diffusion-limited oxidation mechanism discussed here is based on the known "2:2:2" cluster theory which describes the mechanism of fluorite-based hyperstoichiometric oxides. In this study, it is adapted to describe oxygen-anion hopping. Anion hopping toward the oxide-metal interface proceeds at high rates in the [110] direction, hence making this pipeline route the principal growth direction in UO(2) formation. It is further argued that growth in the pure elastic domain of the oxide scale should be attributed entirely to anion hopping in 110. Anions, diffusing isotropically via grain boundaries and cracks, are shown to have a significant impact on the overall oxidation rate in relatively thick (>0.35 microm) oxide scales if followed by an avalanche break off in the postelastic regime. Stress affects oxidation in the elastic domain by controlling the hopping rate directly. In the postelastic regime, stress weakens hopping, indirectly, by enhancing isotropic diffusion. Surface roughness presents an additional hindering factor for the anion hopping. In comparison to anisotropic hopping, diffusion of isotropic hopping has a lower activation energy barrier. Therefore, a relatively stronger impact at lower temperatures due to isotropic diffusion is displayed.

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While genetic factors clearly play a role in conferring breast cancer risk, the contribution of ATM gene mutations to breast cancer is still unsettled. To shed light on this issue, ATM haplotypes were constructed using eight SNPs spanning the ATM gene region (142 kb) in ethnically diverse non-Ashkenazi Jewish controls (n=118) and high-risk (n=142) women. Of the 28 haplotypes noted, four were encountered in frequencies of 5% or more and accounted for 85% of all haplotypes. Subsequently, ATM haplotyping of high-risk, non-Ashkenazi Jews was performed on 66 women with breast cancer and 76 asymptomatic. One SNP (rs228589) was significantly more prevalent among breast cancer cases compared with controls (P=4 x 10(-9)), and one discriminative ATM haplotype was significantly more prevalent among breast cancer cases (33.3%) compared with controls (3.8%), (P< or =10(-10)). There was no significant difference in the SNP and haplotype distribution between asymptomatic high-risk and symptomatic women as a function of disease status. We conclude that a specific ATM SNP and a specific haplotype are associated with increased breast cancer risk in high-risk non-Ashkenazi Jews.

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Dosimetry calculations characterizing the spatial variation of the energy deposited by the slowing and stopping of energetic electrons are reported and compared with experimental measurements from an electron microbeam facility. The computations involve event-by-event, detailed-histories Monte Carlo simulations of low-energy electrons interacting in water vapor. Simulations of electron tracks with starting energies from 30 to 80 keV are used to determine energy deposition distributions in thin cylindrical rings as a function of penetration and radial distance from a beam source. Experimental measurements of the spatial distribution of an electron microbeam in air show general agreement with the density-scaled simulation results for water vapor at these energies, yielding increased confidence in the predictions of Monte Carlo track-structure simulations for applications of the microbeam as a single-cell irradiator.

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In developing exposure standards, an assumption is often made in the case of less-than-lifetime exposures that the probability of response depends on the cumulative exposure, i.e., the product of exposure concentration and duration. Over the last two decades, the general applicability of this assumption, referred to as Haber's Law, has begun to be questioned. This study examined the interaction of exposure concentration and duration on embryonic development during a portion of organogenesis. Embryos were exposed in whole embryo culture to various temperature-duration combinations and evaluated for alterations in development 24 h later. The specific purpose of the study was to assess whether the developmental responses followed Haber's Law, or whether an additional component of exposure was needed to model the relationship. The current study demonstrated that the response of the developing embryo to hyperthermia, with rare exception, was dependent on an additional component of exposure beyond the cumulative exposure. For the vast majority of the parameters measured in this study, the probability of an effect was greater at higher temperatures for short durations than at lower temperatures for long durations, given the same cumulative exposure. Thus, Haber's Law did not adequately describe the results of our study.

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Significant advancements have been made toward the use of all relevant scientific information in health risk assessments. This principle has been set forth in risk-assessment guidance documents of international agencies including those of the World Health Organization's International Programme on Chemical Safety, the U.S. Environmental Protection Agency, and Health Canada. Improving the scientific basis of risk assessment is a leading strategic goal of the Society of Toxicology. In recent years, there has been a plethora of mechanistic research on modes of chemical toxicity that establishes mechanistic links between noncancer responses to toxic agents and subsequent overt manifestations of toxicity such as cancer. The research suggests that differences in approaches to assessing risk of cancer and noncancer toxicity need to be resolved and a common broad paradigm for dose-response assessments developed for all toxicity endpoints. In November 1999, a workshop entitled "Harmonization of Cancer and Noncancer Risk Assessment" was held to discuss the most critical issues involved in developing a more consistent and unified approach to risk assessment for all endpoints. Invited participants from government, industry, and academia discussed focus questions in the areas of mode of action as the basis for harmonization, common levels of adverse effect across toxicities for use in dose-response assessments, and scaling and uncertainty factors. This report summarizes the results of those discussions. There was broad agreement, albeit not unanimous, that current science supports the development of a harmonized set of principles that guide risk assessments for all toxic endpoints. There was an acceptance among the participants that understanding the mode of action of a chemical is ultimately critical for nondefault risk assessments, that common modes of action for different toxicities can be defined, and that our approach to assessing toxicity should be biologically consistent.

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This work group report addresses the central question: What are the critical windows during development (preconception through puberty) when exposure to xenobiotics may have the greatest adverse impact on subsequent reproductive health? The reproductive system develops in stages, with sex-specific organogenesis occurring prenatally and further maturational events occurring in the perinatal period and at puberty. Complex endocrine signals as well as other regulatory factors (genetics, growth factors) are involved at all stages. Evidence from animal models and human studies indicates that many specific events can be perturbed by a variety of toxicants, with endocrine-mediated mechanisms being the more widely studied. Prioritized research needs include basic studies on the cellular-molecular and endocrine regulation of sexual differentiation and development; increased efforts regarding potential adverse effects on development in females, including breast development; expanded animal studies on different classes of chemicals, comparing responses during development (prenatal and postnatal) with responses in adults; and, more extensive explorations regarding the reproductive biology and toxicology of puberty in humans.

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In risk assessment, evaluating a health effect at a duration of exposure that is untested involves assuming that equivalent multiples of concentration (C) and duration (T) of exposure have the same effect. The limitations of this approach (attributed to F. Haber, Zur Geschichte des Gaskrieges [On the history of gas warfare], in Funf Vortrage aus den Jahren 1920-1923 [Five lectures from the years 1920-1923], 1924, Springer, Berlin, pp. 76-92), have been noted in several studies. The study presented in this paper was designed to specifically look at dose-rate (C x T) effects, and it forms an ideal case study to implement statistical models and to examine the statistical issues in risk assessment. Pregnant female C57BL/6J mice were exposed, on gestational day 7, to ethylene oxide (EtO) via inhalation for 1.5, 3, or 6 h at exposures that result in C x T multiples of 2100 or 2700 ppm-h. EtO was selected because of its short half-life, documented developmental toxicity, and relevance to exposures that occur in occupational settings. Concurrent experiments were run with animals exposed to air for similar periods. Statistical analysis using models developed to assess dose-rate effects revealed significant effects with respect to fetal death and resorptions, malformations, crown-to-rump length, and fetal weight. Animals exposed to short, high exposures of EtO on day 7 of gestation were found to have more adverse effects than animals exposed to the same C x T multiple but at longer, lower exposures. The implication for risk assessment is that applying Haber's Law could potentially lead to an underestimation of risk at a shorter duration of exposure and an overestimation of risk at a longer duration of exposure. Further research, toxicological and statistical, are required to understand the mechanism of the dose-rate effects, and how to incorporate the mechanistic information into the risk assessment decision process.

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Epidemiologic studies strongly suggest that in utero exposure to hyperthermia results in developmental defects in humans. Rats, mice, guinea pigs, and other species exposed to hyperthermia also exhibit a variety of developmental defects. Studies in our laboratory have focused on exposure to hyperthermia on Gestation Day (GD) 10 of rats in vivo or in vitro. Within 24 h after in vivo or in vitro exposure, delayed or abnormal CNS, optic cup, somite, and limb development can be observed. At birth, only rib and vertebral malformations are seen after hyperthermia on GD 10, and these have been shown to be due to alterations in somite segmentation. Unsegmented somites have been thought to result from a cell-cycle block in the presomitic mesoderm, from which somites emerge individually during normal development. In the present study, DNA fragmentation (terminal deoxynucleotidyl transferase (TdT) catalyzed fluorescein-12-dUTP DNA end-labelling), indicative of apoptotic cell death, and changes in cell proliferation were examined in vitro in 37 degrees C control and heat treated (42 degrees C for 15 min) GD 10 CD rat embryos. Embryos were returned to 37 degrees C culture following exposure and evaluated 5, 8, or 18 h later. A temperature-related increase in TdT labelled cells was observed in the CNS, optic vesicle, neural tube, and somites. Increased cell death in the presomitic mesoderm also was evident. Changes in cell proliferation were examined using the cell-specific abundance of proliferating cell nuclear antigen (PCNA) and the quantification of mitotic figures. In neuroectodermal cells in the region of the optic cup, a change in the abundance of PCNA was not apparent, but a marked decrease in mitotic figures was observed. A significant change in cell proliferation in somites was not detected by either method. These results suggest that acute hyperthermia disrupts embryonic development through a combination of inappropriate cell death and/or altered cell proliferation in discrete regions of the developing rat embryo. Furthermore, postnatal vertebral and rib defects following disrupted somite development may be due, in part, to abundant cell death occurring in the presomitic mesoderm.

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SK&F107647 is a synthetic hematoregulatory peptide (HP) increases both the number and function of progenitor cells, enabling improved survival after lethal myelosuppression, lethal fungal infection, and lethal herpes simplex virus infection in murine models. This Phase I single-blind placebo-controlled dose-rising crossover trial examined the efficacy of SK&F107647 in patients who had incurable solid tumor malignancies. Sixteen patients were treated. Six adverse events in 3 patients were considered to be possibly related to SK& F107647; all were mild to moderate in nature (mild nervousness and agitation at 0.01 ng/kg, moderate fever and mild nausea at 0.1 ng/kg, elevated hepatic enzymes at 0.1 ng/kg, and mild vomiting at 1.0 ng/kg). Plasma half-life was 2.44 hours (+/-1.07 standard deviation). The observed area volume of distribution was 16.7 L (+/-7.7 standard deviation) and clearance was 5.04 L/hour (+/-1.83 standard deviation). When administered as a single 2-hour intravenous infusion at doses ranging from 0.01 to 100 ng/kg, SK&F107647 is safe and well tolerated.

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Exposure of mouse zygotes to ethylene oxide (EtO) has been shown to increase the incidence of external malformations among late fetuses [Generoso et al. (1987) Mutat. Res., 176:267-274; Rutledge and Generoso, (1989) Teratology, 39:563-572]. The present study was designed to determine whether EtO also affects the skeletal system. We report here the effects of varying times of exposure during the zygotic period on skeletal development. Female hybrid mice were injected intraperitoneally (IP) with 125 mg/kg EtO at 1, 3, 5, or 7 hr postmating. A positive control group consisted of female mice that were injected IP with 150 mg/kg EtO once daily between the 6th to 8th days of gestation. Day 17 fetuses were double-stained for "blind" examination of skeletal deviations and degree of ossification. Zygotic exposure to EtO significantly increased loss of conceptuses as well as the incidence of external defects, skeletal anomalies, and retarded ossification in live day 17 fetuses. An increase in the number of exposed fetuses with cleft sternum was observed with the highest rate (58.5%) occurring in fetuses whose mothers were exposed to EtO 3 hours postmating. Cleft sternum was seen in only 5% of fetuses exposed during the period of organogenesis and less than 1% of control fetuses. It is concluded that zygotic exposure to EtO produces a pattern of skeletal defects that differs from those observed following treatment with EtO during organogenesis.

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This summary report focuses on current studies on reproductive effects reported at the workshop on Perinatal Exposure to Dioxin-like Compounds and supporting data noted in the discussion. Recent laboratory studies have suggested that altered development (e.g., low birth weight, spontaneous abortion, congenital malformation) and reproductive health (e.g., fertility, sex organ development, reproductive behavior) may be among the most sensitive end points when examining the effects of dioxinlike compounds. Thus, future research should target the reproductive health of both males and females exposed postnatally and prenatally. Studies in humans are needed and are on-going. In animal models, postnatal exposure to dioxin or dioxinlike compounds has been associated with abnormal spermatogenesis and abnormal testicular morphology and size in males and with reduced fertility and endometriosis in females. In utero exposure may also produce profound reproductive consequences in both males and females including delays in sexual maturation, abnormalities in development of sexual organs, and abnormal sexual behavior. The mechanism by which dioxin-like compounds cause reproductive effects is not well delineated.

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The effects of in vivo heat exposure on gestation day (GD) 10 rat embryos were evaluated on GD 11 to determine the relationships between morphological sequelae following in vivo and in vitro exposures and between effects detected on GD 11 and those observed in postnatal day (PND) 3 pups. Anesthetized rats were exposed to 42 degrees C in a warm air incubator until their rectal temperatures reached 41 degrees C or until a rectal temperature of 42-42.5 degrees C had been maintained for 5 minutes. Heat-exposed embryos exhibited a significant decrease in growth parameters including head length, somite number, and protein content/embryo versus controls. These changes correlated well with in vitro effects from an earlier study (G.L. Kimmel et al., '93). Among the morphological endpoints which were slightly delayed in development were the caudal neural tube, branchial bars, forelimb and hindlimb. The only effect on the embryos that could not be explained as a transient delay in development induced by heat was the induction of unsegmented somites. Additional embryos were exposed to 42 degrees C for 15-20 min in vitro and examined specifically for unsegmented somites, which were observed in 47% of embryos exposed to 42 degrees C in vivo or in vitro. This phenomenon was observed in somites 9-20, i.e., those that give rise to cervical and thoracic vertebrae and ribs. These results correlated well with the axial skeletal malformations observed in PND 3 pups exposed to the same heat treatment (C.A. Kimmel et al., '93).

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Several reports have suggested that soluble nickel salts may affect development. In this study female Long-Evans rats drank nickel chloride solutions (0, 10, 50, or 250 ppm Ni) for 11 weeks prior to mating and then during two successive gestation (G1, G2) and lactation (L1, L2) periods. Pups were observed until weaning; breeder males were unexposed. Dams drinking 250 ppm consumed less liquid and more food per kilogram body weight than did controls (liquid: prebreeding, G1, and G2; food: prebreeding, G2 and L2). Maternal weight gain was reduced during G1 in the high- and middle-dose groups; indices of reproductive performance were comparable across groups. Pup birth weight was unaltered by treatment and weight gain was reduced only in male pups exposed to 50 ppm Ni during L1. The frequency of perinatal death is the most significant toxicologic finding of the study. The proportion of dead pups per litter was significantly elevated at the high dose in L1 and at 10 and 250 ppm in L2 (50 ppm, P = 0.076), with a dose-related response in both experimental segments. The number of dead pups per litter was significantly increased at each dose in L2. Prolactin levels in pups were unchanged by treatment and were reduced in dams at the high dose. We conclude that 10 ppm Ni represents the lowest observed adverse effect level (LOAEL) in this study.

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The purpose of this paper is to present a statistical model for analyzing the joint effects of exposure on fetal death, fetal weight, and malformation in a developmental toxicity study. In addition to allowing for the usual litter effect, the model allows for correlations between different outcomes measured on the same fetus. Fitting the model requires first focusing on non-live outcomes by modeling the probability of fetal death or resorption as a function of dose. Then outcomes among live fetuses are modeled using a two-stage regression approach. The first stage models fetal weight as a function of dose and the second stage models fetal malformation as a function of dose, as well as residuals from the weight model. The regression coefficients from the malformation model have intuitive interpretations in terms of correlations between littermates and between different outcomes measured within the same fetus. Not only does the approach provide a useful way to investigate the relationship between adverse fetal outcomes, it also yields a natural framework for conducting quantitative risk assessment. A procedure is proposed for quantifying overall risk by incorporating the three outcomes in order to estimate safe dose levels and corresponding lower confidence limits. The method is illustrated using data from an experiment in mice conducted through the National Toxicology Program.

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