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Arrival of the Fukushima radioactivity plume in North American continental waters
The large discharge of radioactivity into the northwest Pacific Ocean from the 2011 Fukushima Dai-ichi nuclear reactor accident has generated considerable concern about the spread of this material across the ocean to North America. We report here the first systematic study to our knowledge of the transport of the Fukushima marine radioactivity signal to the eastern North Pacific. Time series measurements of ¹³⁴Cs and ¹³⁷Cs in seawater revealed the initial arrival of the Fukushima signal by ocean current transport at a location 1,500 km west of British Columbia, Canada, in June 2012, about 1.3 y after the accident. By June 2013, the Fukushima signal had spread onto the Canadian continental shelf, and by February 2014, it had increased to a value of 2 Bq/m ³ throughout the upper 150 m of the water column, resulting in an overall doubling of the fallout background from atmospheric nuclear weapons tests. Ocean circulation model estimates that are in reasonable agreement with our measured values indicate that future total levels of ¹³⁷Cs (Fukushima-derived plus fallout ¹³⁷Cs) off the North American coast will likely attain maximum values in the 3–5 Bq/m ³ range by 2015–2016 before declining to levels closer to the fallout background of about 1 Bq/m ³ by 2021. The increase in ¹³⁷Cs levels in the eastern North Pacific from Fukushima inputs will probably return eastern North Pacific concentrations to the fallout levels that prevailed during the 1980s but does not represent a threat to human health or the environment.
Significance The radionuclide results in this report represent the first systematic study, to our knowledge, of the arrival of the Fukushima radioactivity signal in continental waters off North America. The present time series results are critical to an understanding of the circulation of Fukushima tracers in the eastern North Pacific and to the tuning and validation of ocean circulation models that are being used to predict the future evolution of this signal. They are also important for informing the public of the magnitude of the Fukushima radioactivity signal in North American continental waters and enabling a science-based assessment of the significance of its potential effects on human health and the environment.
Journal Article
Lipoarabinomannan-Reactive Human Secretory Immunoglobulin A Responses Induced by Mucosal Bacille Calmette-Guérin Vaccination
The ability of 17 recombinant mycobacterial proteins, native antigen 85 complex, lipoarabinomannan (LAM), and Mycobacterium tuberculosis lysate to detect antibody responses induced by bacille Calmette-Guérin (BCG) vaccination and active tuberculosis infection were studied in enzyme-linked immunosorbent assays. Only LAM-reactive serum immunoglobulin G responses were significantly increased in both BCG-vaccinated patients and patients with active tuberculosis (P<.05), and oral BCG vaccination also induced significant increases in LAM-reactive secretory immunoglobulin A (P<.05). LAM-reactive antibody assays can serve as markers of humoral and mucosal immunity in future trials of BCG and newer attenuated mycobacterial vaccines
Journal Article
Preclinical Characterization of Once Weekly Basal Insulin Fc (BIF)
Weekly basal insulin injections may increase treatment adherence in subjects with diabetes and an appropriately engineered weekly basal insulin may reduce daily pharmacokinetic (PK)/pharmacodynamic (PD) fluctuations compared to currently available daily basal insulins. Therefore, a weekly insulin has the potential to not only ease the burden of insulin therapy, but also improve outcomes for subjects with diabetes in a real-world setting. Basal insulin Fc (BIF, LY3209590) is an insulin Fc-fusion protein in clinical testing as a once weekly treatment for type 1 and type 2 diabetes mellitus (T1DM, T2DM). BIF is comprised of a human single-chain insulin fused to a human IgG2 Fc domain through a peptide linker. The in vitro evaluation determined that BIF exhibited reduced insulin receptor (IR) potency with full agonism, selectivity against human insulin-like growth factor-1 receptor (hIGF-1R), and functional properties similar to native human insulin. The binding affinity of BIF for hIR isoform A, Ki = 25 nM (SEM = 4, n=10), and hIR isoform B, Ki = 26 nM (SEM = 4, n=10), was more than two orders of magnitude weaker than human insulin. BIF stimulated IR phosphorylation in cells with reduced potency, but full agonism, and showed a significantly faster hIR dephosphorylation profile than either human insulin or AspB10 insulin. BIF stimulated de novo lipogenesis in 3T3-L1 adipocytes and cell proliferation in SAOS-2 and H4IIE cells with at least a 70-fold reduction in potency compared to human insulin. BIF possessed markedly reduced binding and activation of hIGF-1R making definitive mitogenic measurements unattainable. In preclinical in vivo pharmacology studies using streptozotocin (STZ)-treated diabetic rats, a statistically significant decrease in blood glucose compared to vehicle-treated animals was seen 24 hours post-injection and persisted through 336 hours post-injection following a single subcutaneous administration (30 nmol/kg) of BIF. In STZ-treated rats, BIF reached a Tmax at 48 hours, possessed an apparent clearance rate of ~0.85 mL/hr/kg, and t1/2 of ~120 hrs. Collectively, these results demonstrate that BIF possesses selective IR agonism with a pharmacological profile similar to native insulin, however with a significantly reduced potency, and a significantly extended time action profile in preclinical animal models supporting once weekly testing in the clinic.
Journal Article
Mucosal Bacille Calmette-Guérin Vaccination of Humans Inhibits Delayed-Type Hypersensitivity to Purified Protein Derivative but Induces Mycobacteria-Specific Interferon-γ Responses
We conducted a placebo-controlled, double-dose-escalation trial of oral bacille Calmette-Guérin (BCG) vaccination in 48 healthy volunteers. Seven of 32 BCG recipients became purified protein derivative (PPD)-positive after dose 1, and only 1 remained positive after dose 2, which suggeststhat oral BCG has inhibitory effects on delayed-type hypersensitivity (DTH) responses. Ten of the original placebo recipients and 11 oral BCG recipients were recruited to return for an intradermal BCG booster vaccination. Five of 10 original placebo recipients developed PPD responses ≥10 mm, but none of 11 oral BCG recipients developed PPD induration after they received an intradermal BCG booster (P < .05; Fisher's exact test). These results document persistent inhibitory effects of oral BCG vaccination on mycobacteria-specific DTH responses. Despite inhibition of DTH, oral BCG induced significant increases in mycobacteria-specific interferon (IFN)-γ responses in peripheral blood mononuclear cells. More detailed studies of cytokine and homing molecule expression indicated that differential mucosal versus cutaneous trafficking may explain the dissociation between IFN-γ and DTH responses.
Journal Article
Jordan in the Late Middle Ages: Transformation of the Mamluk Frontier
Brown reviews Jordan in the Late Middle Ages: Transformation of the Mamluk Frontier by Bethany J. Walker.
Book Review