z~2: An Epoch of Disk Assembly

We explore the evolution of the internal gas kinematics of star-forming galaxies from the peak of cosmic star-formation at $z\sim2$ to today. Measurements of galaxy rotation velocity $V_{rot}$, which quantify ordered motions, and gas velocity dispersion $\sigma_g$, which quantify disordered motions, are adopted from the DEEP2 and SIGMA surveys. This sample covers a continuous baseline in redshift from $z=2.5$ to $z=0.1$, spanning 10 Gyrs. At low redshift, nearly all sufficiently massive star-forming galaxies are rotationally supported ($V_{rot}>\sigma_g$). By $z=2$, the percentage of galaxies with rotational support has declined to 50$\%$ at low stellar mass ($10^{9}-10^{10}\,M_{\odot}$) and 70$\%$ at high stellar mass ($10^{10}-10^{11}M_{\odot}$). For $V_{rot}\,>\,3\,\sigma_g$, the percentage drops below 35$\%$ for all masses. From $z\,=\,2$ to now, galaxies exhibit remarkably smooth kinematic evolution on average. All galaxies tend towards rotational support with time, and it is reached earlier in higher mass systems. This is mostly due to an average decline in $\sigma_g$ by a factor of 3 since a redshift of 2, which is independent of mass. Over the same time period, $V_{rot}$ increases by a factor of 1.5 for low mass systems, but does not evolve for high mass systems. These trends in $V_{rot}$ and $\sigma_g$ with time are at a fixed stellar mass and should not be interpreted as evolutionary tracks for galaxy populations. When galaxy populations are linked in time with abundance matching, not only does $\sigma_g$ decline with time as before, but $V_{rot}$ strongly increases with time for all galaxy masses. This enhances the evolution in $V_{rot}/\sigma_g$. These results indicate that $z\,=\,2$ is a period of disk assembly, during which the strong rotational support present in today's massive disk galaxies is only just beginning to emerge.Comment: 12 pages, 8 figures, submitted to Ap

Direct Stimulation Of Human Fibroblasts By nCeO2 In Vitro Is Attenuated With An Amorphous Silica Coating

Background: Nano-scaled cerium oxide (nCeO2) is used in a variety of applications, including use as a fuel additive, catalyst, and polishing agent, yet potential adverse health effects associated with nCeO2 exposure remain incompletely understood. Given the increasing utility and demand for engineered nanomaterials (ENMs) such as nCeO2, “safety-bydesign” approaches are currently being sought, meaning that the physicochemical properties (e.g., size and surface chemistry) of the ENMs are altered in an effort to maximize functionality while minimizing potential toxicity. In vivo studies have shown in a rat model that inhaled nCeO2 deposited deep in the lung and induced fibrosis. However, little is known about how the physicochemical properties of nCeO2, or the coating of the particles with a material such as amorphous silica (aSiO2), may affect the bio-activity of these particles. Thus, we hypothesized that the physicochemical properties of nCeO2 may explain its potential to induce fibrogenesis, and that a nano-thin aSiO2 coating on nCeO2 may counteract that effect. Results: Primary normal human lung fibroblasts were treated at occupationally relevant doses with nCeO2 that was either left uncoated or was coated with aSiO2 (amsCeO2). Subsequently, fibroblasts were analyzed for known hallmarks of fibrogenesis, including cell proliferation and collagen production, as well as the formation of fibroblastic nodules. The results of this study are consistent with this hypothesis, as we found that nCeO2 directly induced significant production of collagen I and increased cell proliferation in vitro, while amsCeO2 did not. Furthermore, treatment of fibroblasts with nCeO2, but not amsCeO2, significantly induced the formation of fibroblastic nodules, a clear indicator of fibrogenicity. Such in vitro data is consistent with recent in vivo observations using the same nCeO2 nanoparticles and relevant doses. This effect appeared to be mediated through TGFβ signaling since chemical inhibition of the TGFβ receptor abolished these responses. Conclusions: These results indicate that differences in the physicochemical properties of nCeO2 may alter the fibrogenicity of this material, thus highlighting the potential benefits of “safety-by-design” strategies. In addition, this study provides an efficient in vitro method for testing the fibrogenicity of ENMs that strongly correlates with in vivo finding

Efficacy and safety of ipratropium bromide/albuterol compared with albuterol in patients with moderate-to-severe asthma: a randomized controlled trial

Abstract Background Many patients with asthma require frequent rescue medication for acute symptoms despite appropriate controller therapies. Thus, determining the most effective relief regimen is important in the management of more severe asthma. This study’s objective was to evaluate whether ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI) provides more effective acute relief of bronchospasm in moderate-to-severe asthma than albuterol hydrofluoroalkaline (ALB-HFA) alone after 4 weeks. Methods In this double-blind, crossover study, patients who had been diagnosed with asthma for ≥1 year were randomized to two sequences of study medication “as needed” for symptom relief (1–7 day washout before second 4-week treatment period): CVT-MDI/ALB-HFA or ALB-HFA/CVT-MDI. On days 1 and 29 of each sequence, 6-hour serial spirometry was performed after administration of the study drug. Co-primary endpoints were FEV 1 area under the curve (AUC 0–6 ) and peak (post-dose) forced expiratory volume in 1 s (FEV 1 ) response (change from test day baseline) after 4 weeks. The effects of “as needed” treatment with ALB-HFA/CVT-MDI were analyzed using mixed effect model repeated measures (MMRM). Results A total of 226 patients, ≥18 years old, with inadequately controlled, moderate-to-severe asthma were randomized. The study met both co-primary endpoints demonstrating a statistically significant treatment benefit of CVT-MDI versus ALB-HFA. FEV 1 AUC 0-6h response was 167 ml for ALB-HFA, 252 ml for CVT-MDI (p <0.0001); peak FEV 1 response was 357 ml for ALB-HFA, 434 ml for CVT-MDI (p <0.0001). Adverse events were comparable across groups. Conclusions CVT-MDI significantly improved acute bronchodilation over ALB-HFA alone after 4 weeks of “as-needed” use for symptom relief, with a similar safety profile. This suggests additive bronchodilator effects of β 2 -agonist and anticholinergic treatment in moderate-to-severe, symptomatic asthma. Trial registration ClinicalTrials.gov No.: NCT00818454; Registered November 16, 2009

Mechanisms of drug-induced lupus. IV. Comparison of procainamide and hydralazine with analogs in vitro and in vivo

Objective . T cells treated with DNA methylation inhibitors overexpress lymphocyte function-associated antigen 1 (LFA-1), which results in autoreactivity, and the autoreactive cells cause a lupus-like disease in vivo, suggesting a mechanism by which some agents may cause drug-induced lupus. This study compared the effects of procainamide (Pca) and hydralazine (Hyd) with those of structural analogs, to determine if the degree of LFA-1 overexpression and T cell autoreactivity correlated with the ability of the agents to induce autoimmunity. Methods . Cloned murine T helper 2 cells were treated with Pca, N -acetylprocainamide, Hyd, Phthalazine, or hydroxyurea (HU). The treated cells were then compared for LFA-1 overexpression, autoreactivity, and the ability to induce autoimmunity in vivo. Results . Pca and Hyd were more potent than their analogs or HU in all 3 assays. Conclusion . The results support a relationship between LFA-1 overexpression, T cell autoreactivity, and autoimmunity, and suggest a mechanism by which Pca and Hyd, but not the analogs, may cause drug-induced lupus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37814/1/1780400811_ftp.pd

Total and Active Rabbit Antithymocyte Globulin (rATG;Thymoglobulin®) Pharmacokinetics in Pediatric Patients Undergoing Unrelated Donor Bone Marrow Transplantation

AbstractRabbit antithymocyte globulin (rATG; Thymoglobulin®) is currently used to prevent or treat graft-versus-host disease (GVHD) during hematopoietic stem cell transplantation (HSCT). The dose and schedule of rATG as part of the preparative regimen for unrelated donor (URD) bone marrow transplantation (BMT) have not been optimized in pediatric patients. We conducted a prospective study of 13 pediatric patients with hematologic malignancies undergoing URD BMT at St. Jude Children's Research Hospital from October 2003 to March 2005, to determine the pharmacokinetics and toxicities of active and total rATG. The conditioning regimen comprised total body irradiation (TBI), thiotepa, and cyclophosphamide (Cy); cyclosporine (CsA) and methotrexate (MTX) were administered as GVHD prophylaxis. Patients received a total dose of 10 mg/kg rATG, and serial blood samples were assayed for total rATG by enzyme linked immunosorbent assay (ELISA) and active rATG by florescein activated cell sorting (FACS). We found that our weight-based dosing regimen for rATG was effective and well tolerated by patients. The half-lives of total and active rATG were comparable to those from previous studies, and despite high doses our patients had low maximum concentrations of active and total rATG. There were no occurrences of grade iii-iv GVHD even in patients having low peak rATG levels, and the overall incidence of grade II GVHD was only 15%. None of the patients had serious infections following transplantation. These data support the use of a 10 mg/kg dose of rATG in children with hematologic malignancies because it can be administered without increasing the risk of graft rejection, or serious infection in pediatric patients with a low rate of GVHD. These conclusions may not apply to patients with nonmalignant disorders

The Course of Quality of Life and Its Predictors in Nursing Home Residents With Young-Onset Dementia

OBJECTIVE: To explore the course of quality of life (QoL) and possible resident-related predictors associated with this course in institutionalized people with young-onset dementia (YOD). DESIGN: An observational longitudinal study. SETTING AND PARTICIPANTS: A total of 278 residents with YOD were recruited from 13 YOD special care units in the Netherlands. METHODS: Secondary analyses were conducted with longitudinal data from the Behavior and Evolution in Young-ONset Dementia (BEYOND)-II study. QoL was assessed with proxy ratings, using the Quality of Life in Dementia (QUALIDEM) questionnaire at 4 assessment points over 18 months. Predictors included age, gender, dementia subtype, length of stay, dementia severity, neuropsychiatric symptoms, and psychotropic drug use at baseline. Multilevel modeling was used to adjust for the correlation of measurements within residents and clustering of residents within nursing homes. RESULTS: The total QUALIDEM score (range: 0-111) decreased over 18 months with a small change of 0.65 (95% confidence interval -1.27, -0.04) points per 6 months. An increase in several domains of QoL regarding care relationship, positive self-image, and feeling at home was seen over time, whereas a decline was observed in the subscales positive affect, social relations, and having something to do. Residents with higher levels of QoL and more advanced dementia at baseline showed a more progressive decline in QoL over time. Sensitivity analyses indicated a more progressive decline in QoL for residents who died during the follow-up. CONCLUSION AND IMPLICATIONS: This study shows that although overall QoL in nursing home residents with YOD was relatively stable over 18 months, there were multidirectional changes in the QoL subscales that could be clinically relevant. Higher levels of QoL and more advanced stages of dementia at baseline predicted a more progressive decline in QoL over time. More longitudinal studies are needed to verify factors influencing QoL in YOD

Individualized decision aid for diverse women with lupus nephritis (IDEA-WON): A randomized controlled trial.

BackgroundTreatment decision-making regarding immunosuppressive therapy is challenging for individuals with lupus. We assessed the effectiveness of a decision aid for immunosuppressive therapy in lupus nephritis.Methods and findingsIn a United States multicenter, open-label, randomized controlled trial (RCT), adult women with lupus nephritis, mostly from racial/ethnic minority backgrounds with low socioeconomic status (SES), seen in in- or outpatient settings, were randomized to an individualized, culturally tailored, computerized decision aid versus American College of Rheumatology (ACR) lupus pamphlet (1:1 ratio), using computer-generated randomization. We hypothesized that the co-primary outcomes of decisional conflict and informed choice regarding immunosuppressive medications would improve more in the decision aid group. Of 301 randomized women, 298 were analyzed; 47% were African-American, 26% Hispanic, and 15% white. Mean age (standard deviation [SD]) was 37 (12) years, 57% had annual income of &lt;$40,000, and 36% had a high school education or less. Compared with the provision of the ACR lupus pamphlet (n = 147), participants randomized to the decision aid (n = 151) had (1) a clinically meaningful and statistically significant reduction in decisional conflict, 21.8 (standard error [SE], 2.5) versus 12.7 (SE, 2.0; p = 0.005) and (2) no difference in informed choice in the main analysis, 41% versus 31% (p = 0.08), but clinically meaningful and statistically significant difference in sensitivity analysis (net values for immunosuppressives positive [in favor] versus negative [against]), 50% versus 35% (p = 0.006). Unresolved decisional conflict was lower in the decision aid versus pamphlet groups, 22% versus 44% (p &lt; 0.001). Significantly more patients in the decision aid versus pamphlet group rated information to be excellent for understanding lupus nephritis (49% versus 33%), risk factors (43% versus 27%), medication options (50% versus 33%; p ≤ 0.003 for all); and the ease of use of materials was higher in the decision aid versus pamphlet groups (51% versus 38%; p = 0.006). Key study limitations were the exclusion of men, short follow-up, and the lack of clinical outcomes, including medication adherence.ConclusionsAn individualized decision aid was more effective than usual care in reducing decisional conflict for choice of immunosuppressive medications in women with lupus nephritis.Trial registrationClinicaltrials.gov, NCT02319525

Mechanisms of drug-induced lupus. III. Sex-specific differences in T cell homing may explain increased disease severity in female mice

Objective . To determine if sex-specific differences in lymphocyte trafficking could contribute to increased disease severity in female mice. Methods . A lupus-like disease was induced by injecting male and female mice with procainamide-treated T cell clones. Trafficking was examined by labeling the injected cells with 51 Cr or 5-chloromethylfluorescein diacetate. Results . Females developed more autoimmune liver disease and greater titers of anti-DNA antibodies than did males, and 2-7 times more cells accumulated in the female spleens. Splenectomy prevented the development of autoantibodies and renal and liver disease. Oophorectomy decreased the splenic homing, autoantibody titer, and liver disease severity, to levels found in males. Conclusion . T cells traffic differently to the spleen in male and female mice, and the spleen appears to be essential in the disease process. This suggests that differences in T cell homing could contribute to sex-specific disease severity in this murine model, and also possibly in human disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37813/1/1780400719_ftp.pd