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Background and Objectives Exenatide is a glucagon-like peptide-1 receptor agonist, available in an immediate-release (IR), twice-daily formulation, which improves glycaemic control through enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated postprandial glucagon secretion, slowing of gastric emptying and reduction of food intake. The objectives of these studies were to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an extended-release (ER) exenatide formulation in patients with type 2 diabetes mellitus. Patients and Methods Patients with type 2 diabetes participated in either a single-dose trial (n=62) or a repeated-administration trial (n = 45). The pharmacokinetic and safety effects of single-dose subcutaneous administration of exenatide ER (2.5 mg, 5 mg, 7 mg or 10 mg) versus placebo were studied over a period of 12 weeks in patients with type 2 diabetes. These results were used to predict the dose regimen of exenatide ER required to achieve steady-state therapeutic plasma exenatide concentrations. A second clinical study investigated the pharmacokinetics, pharmacodynamics and safety of weekly exenatide ER subcutaneous injections (0.8 mg or 2 mg) versus placebo in patients with type 2 diabetes over a period of 15 weeks. Furthermore, population-based analyses of these studies were performed to further define the exposure-response relationships associated with exenatide ER. Results Exenatide exposure increased with dose (2.5 mg, 5 mg, 7 mg or 10 mg) and exhibited a multiple-peak profile over approximately 10 weeks. Multiple-dosing pharmacokinetics were predicted from superpositioning of single-dose data; weekly administration of exenatide ER 0.8 mg and 2 mg for 15 weeks confirmed the predictions. Weekly dosing resulted in steady-state plasma exenatide concentrations after 6–7 weeks. Fasting plasma glucose levels were reduced similarly with both doses after 15 weeks (−42.7 ±15.7 mg/dL with the 0.8mg dose and −39.0±9.3mg/dL with the 2mg dose; both p<0.001 vs placebo), and the integrated exposure-response analysis demonstrated that the drug concentration producing 50% of the maximum effect (EC 50 ) on fasting plasma glucose was 56.8 pg/mL (a concentration achieved with both the 0.8 mg and 2mg doses of exenatide ER). The 2 mg dose reduced bodyweight (−3.8 ± 1.4kg; p<0.05 vs placebo) and postprandial glucose excursions. Glycosylated haemoglobin (HbA lc ) levels were reduced with the 0.8 mg dose (−1.4±0.3%; baseline 8.6%) and with the 2mg dose (−1.7 ± 0.3%; baseline 8.3%) [both p<0.001 vs placebo]. Adverse events were generally transient and mild to moderate in intensity. Conclusion These studies demonstrated that (i) a single subcutaneous dose of exenatide ER resulted in dose-related increases in plasma exenatide concentrations; (ii) single-dose exposure successfully predicted the weekly-dosing exposure, with 0.8 mg and 2 mg weekly subcutaneous doses of exenatide ER eliciting therapeutic concentrations of exenatide; and (iii) weekly dosing with either 0.8 or 2 mg of exenatide ER improved fasting plasma glucose control, whereas only the 2 mg dose was associated with improved postprandial glucose control and weight loss. [Clinicaltrials.gov Identifier: NCT00103935]

OBJECTIVE: Human regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL). RESEARCH DESIGN AND METHODS: This was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects. RESULTS: Both overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC0-t’]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tRmax50, tRlast) were prolonged for U-500R versus U-100R at both doses (P < 0.05). CONCLUSIONS: Overall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes.

The Tropical Composition, Cloud and Climate Coupling Experiment (TC4), was based in Costa Rica and Panama during July and August 2007. The NASA ER‐2, DC‐8, and WB‐57F aircraft flew 26 science flights during TC4. The ER‐2 employed 11 instruments as a remote sampling platform and satellite surrogate. The WB‐57F used 25 instruments for in situ chemical and microphysical sampling in the tropical tropopause layer (TTL). The DC‐8 used 25 instruments to sample boundary layer properties, as well as the radiation, chemistry, and microphysics of the TTL. TC4 also had numerous sonde launches, two ground‐based radars, and a ground‐based chemical and microphysical sampling site. The major goal of TC4 was to better understand the role that the TTL plays in the Earth's climate and atmospheric chemistry by combining in situ and remotely sensed data from the ground, balloons, and aircraft with data from NASA satellites. Significant progress was made in understanding the microphysical and radiative properties of anvils and thin cirrus. Numerous measurements were made of the humidity and chemistry of the tropical atmosphere from the boundary layer to the lower stratosphere. Insight was also gained into convective transport between the ground and the TTL, and into transport mechanisms across the TTL. New methods were refined and extended to all the NASA aircraft for real‐time location relative to meteorological features. The ability to change flight patterns in response to aircraft observations relayed to the ground allowed the three aircraft to target phenomena of interest in an efficient, well‐coordinated manner.

ABSTRACT In our effort to complete the census of low-mass stars and brown dwarfs in the immediate solar neighborhood, we present spectra, photometry, proper motions, and distance estimates for 42 low-mass star and brown dwarf candidates discovered by the Wide-field Infrared Survey Explorer (WISE). We also present additional follow-up information on 12 candidates selected using WISE data but previously published elsewhere. The new discoveries include 15 M dwarfs, 17 L dwarfs, five T dwarfs, and five objects of other types. Among these discoveries is a newly identified \"unusually red L dwarf\" (WISE J223527.07 + 451140.9), four peculiar L dwarfs whose spectra are most readily explained as unresolved L + T binary systems, and a T9 dwarf (WISE J124309.61 + 844547.8). We also show that the recently discovered red L dwarf WISEP J004701.06 + 680352.1 may be a low-gravity object and hence young and potentially low-mass (< 25 MJup).

Background and Objectives: To quantify whole grain intake in pregnant women in Singapore in order to provide the first detailed analysis of whole grain intake in an Asian country and in pregnant women. Methods and Study Design: Analysis of 24-h diet recalls in a cross-sectional cohort study and analysis of a biomarker of whole grain intake (plasma alkylresorcinols) in a subset of subjects. The Growing Up in Singapore Towards healthy Outcomes-mother offspring cohort study based in Singapore. 998 pregnant mothers with complete 24-h recalls taken during their 26-28th week of gestation. Plasma samples from a randomly select subset of 100 subjects were analysed for plasma alkylresorcinols. Results: Median (IQR) whole grain intake for the cohort and the 30% who reported eating whole grains were 0 (IQR 0, 9) and 23.6 (IQR 14.6, 44.2) g/day respectively. Plasma alkylresorcinol concentrations were very low [median (IQR)=9 (3, 15) nmol/L], suggesting low intake of whole grain wheat in this population. Plasma alkylresorcinols were correlated with whole grain wheat intake (Spearman's r=0.35; p<0.01). Conclusions: Whole grain intake among pregnant mothers in Singapore was well below the 2-3 (60-95 g) servings of whole grains per day recommended by the Singapore Health Promotion Board. Efforts to increase whole grain intake should be supported to encourage people to choose whole grains over refined grains in their diet.

High ice cloud horizontal inhomogeneity is examined using optical depth retrievals from four midlatitude datasets. Three datasets include ice cloud microphysical profiles derived from millimeter cloud radar at the Southern Great Plains Atmospheric Radiation Measurement site in Oklahoma. A fourth dataset combines lidar and midinfrared radiometry (LIRAD), and is from the Facility for Atmospheric Remote Sensing at the University of Utah, Salt Lake City, Utah. Plane-parallel homogeneous (PPH) calculations of domain-averaged solar albedo for these four datasets are compared to independent column approximation (ICA) results. A solar albedo bias up to 25% is found over a low reflective surface at a high solar zenith angle. A spherical solar albedo bias as high as 11% is shown. The gamma-weighted radiative transfer (GWRT) scheme is shown to be an effective correction for the solar albedo bias suitable for GCM applications. The GWRT result was, in all cases, within 1–2 W m−2of the ICA outgoing solar flux. The GWRT requires a parameterization of the standard deviation of cloud optical depth. It is suggested that the domain-averaged cloud optical depth and ice water path together can be used in a parameterization to account for 80% of the standard deviation in optical depth.

In our effort to complete the census of low-mass stars and brown dwarfs in the immediate solar neighborhood, we present spectra, photometry, proper motions, and distance estimates for 42 low-mass star and brown dwarf candidates discovered by the Wide-field Infrared Survey Explorer (WISE). We also present additional follow-up information on 12 candidates selected usingWISEdata but previously published elsewhere. The new discoveries include 15 M dwarfs, 17 L dwarfs, five T dwarfs, and five objects of other types. Among these discoveries is a newly identified “unusually red L dwarf” (WISE J223527.07 + 451140.9 J 223527.07 + 451140.9 ), four peculiar L dwarfs whose spectra are most readily explained as unresolvedL + T L + T binary systems, and a T9 dwarf (WISE J124309.61 + 844547.8 J 124309.61 + 844547.8 ). We also show that the recently discovered red L dwarfWISEP J004701.06 + 680352.1 J 004701.06 + 680352.1 may be a low-gravity object and hence young and potentially low-mass (< 25 M Jup < 25     M Jup ).

From Commedia dell'Arte came archetypal characters that are still with us today, such as Harlequin and Pantalone, and the rediscovered craft of writing comic dramas and masked theatre. From it came the forces that helped create and influence Opera, Ballet, Pantomime, Shakespeare, Moliere, Lopes de Vega, Goldoni, Meyerhold, and even the glove puppet, Mr Punch.The Routledge Companion to Commedia dell'Arte is a wide-ranging volume written by over 50 experts, that traces the history, characteristics, and development of this fascinating yet elusive theatre form. In synthesizing the elements of Commedia, this book introduces the history of the Sartori mask studio; presents a comparison between Gozzi and Goldoni's complicated and adversarial approaches to theatre; invites discussions on Commedia's relevance to Shakespeare, and illuminates re-interpretations of Commedia in modern times. The authors are drawn from actors, mask-makers, pedagogues, directors, trainers and academics, all of whom add unique insights into this most delightful of theatre styles. Notable contributions include: Donato Sartori on the 20th century Sartori mask Rob Henke on form and freedom Anna Cottis on Carlo Boso Didi Hopkins on One Man, Two Guv'nors Kenneth Richards on acting companies Antonio Fava on Pulcinella Joan Schirle on Carlo Mazzone-Clementi and women in Commedia and M.A. Katritzky on imagesOlly Crick is a performer, trainer and director, having trained in Commedia under Barry Grantham and Carlo Boso. He is founder of The Fabulous Old Spot Theatre Company. Judith Chaffee is Associate Professor of Theatre at Boston Un

We present a Hubble Space Telescope/Wide-Field Camera 3 near infrared spectrum of the archetype Y dwarf WISEP 182831.08+265037.8. The spectrum covers the 0.9-1.7 um wavelength range at a resolving power of lambda/Delta lambda ~180 and is a significant improvement over the previously published spectrum because it covers a broader wavelength range and is uncontaminated by light from a background star. The spectrum is unique for a cool brown dwarf in that the flux peaks in the Y, J, and H band are of near equal intensity in units of f_lambda. We fail to detect any absorption bands of NH_3 in the spectrum, in contrast to the predictions of chemical equilibrium models, but tentatively identify CH_4 as the carrier of an unknown absorption feature centered at 1.015 um. Using previously published ground- and spaced-based photometry, and using a Rayleigh Jeans tail to account for flux emerging longward of 4.5 um, we compute a bolometric luminosity of log (L_bol/L_sun)=-6.50+-0.02 which is significantly lower than previously published results. Finally, we compare the spectrum and photometry to two sets of atmospheric models and find that best overall match to the observed properties of WISEP 182831.08+265037.8 is a ~1 Gyr old binary composed of two T_eff~325 K, ~5 M_Jup brown dwarfs with subsolar [C/O] ratios.