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Introduction People with Down syndrome (DS) are at high risk for Alzheimer's disease (AD). Defects in monoamine neurotransmitter systems are implicated in DS and AD but have not been comprehensively studied in DS. Methods Noradrenaline, adrenaline, and their metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid; and serotonin and its metabolite 5-hydroxyindoleacetic acid were quantified in 15 brain regions of DS without AD (DS, n = 4), DS with AD (DS+AD, n = 17), early-onset AD (EOAD, n = 11) patients, and healthy non-DS controls (n = 10) in the general population. Moreover, monoaminergic concentrations were determined in cerebrospinal fluid (CSF)/plasma samples of DS (n = 37/149), DS with prodromal AD (DS+pAD, n = 13/36), and DS+AD (n = 18/40). Results In brain, noradrenergic and serotonergic compounds were overall reduced in DS+AD versus EOAD, while the dopaminergic system showed a bidirectional change. For DS versus non-DS controls, significantly decreased MHPG levels were noted in various brain regions, though to a lesser extent than for DS+AD versus EOAD. Apart from DOPAC, CSF/plasma concentrations were not altered between groups. Discussion Monoamine neurotransmitters and metabolites were evidently impacted in DS, DS+AD, and EOAD. DS and DS+AD presented a remarkably similar monoaminergic profile, possibly related to early deposition of amyloid pathology in DS. To confirm whether monoaminergic alterations are indeed due to early amyloid β accumulation, future avenues include positron emission tomography studies of monoaminergic neurotransmission in relation to amyloid deposition, as well as relating monoaminergic concentrations to CSF/plasma levels of amyloid β and tau within individuals., Highlights • Monoaminergic changes are found in Alzheimer's disease (AD) and Down syndrome (DS). • We characterized 15 brain regions of DS, DS+AD, early-onset AD, and non-DS controls. • Noradrenergic and serotonergic compounds were reduced in DS+AD versus early-onset AD postmortem brain tissue. • DS and DS+AD cases presented rather similar monoaminergic profiles in postmortem brain tissue. • Monoaminergic CSF/plasma levels were not related to clinical dementia status in DS.

Background Exenatide (exendin-4) exhibits dose-dependent glucoregulatory activity, but causes dose-limiting nausea and vomiting. This study was designed to formally assess the possibility of inducing tolerance to the side effects of nausea and vomiting at therapeutic doses of exenatide, using a dose-escalation methodology. Methods In this two-arm, triple-blind, multicenter study, 123 subjects with type 2 diabetes were enrolled and randomized; 99 (80.5%) of them completed the study. Subjects in the exenatide-primed arm received subcutaneous exenatide, starting at 0.02 µg/kg three times a day (TID) and increasing in 0.02 µg/kg per dose increments every 3 days for 35 days. Subjects in the exenatide-naive arm received placebo TID for 35 days. At the end of this 35-day regimen, subjects in both arms received the same highest dose of exenatide (0.24 µg/kg TID) for 3 days. Thus, the exenatide-naive arm received exenatide for the first time on Day 35. Results The exenatide-primed arm had a lower proportion of subjects experiencing nausea and vomiting in response to exposure to the highest dose of exenatide (27 vs 56% in the exenatide-naive arm; p = 0.0018). Kaplan–Meier estimates of cumulative incidence were 0.28 in the exenatide-primed arm, compared with 0.68 in the exenatide-naive arm (p ≤ 0.001). As predicted by the study design, fewer subjects in the exenatide-primed arm reported severe nausea (29%) and vomiting (10%) than those in the exenatide-naive arm (48 and 31%, respectively). In the exenatide-primed arm, fasting serum glucose progressively declined over the first 35 days of dosing, but was unchanged in the exenatide-naive arm (placebo phase) during the same interval. Conclusion Gradual dose-escalation of exenatide successfully reduced the proportion of subjects experiencing dose-limiting nausea and vomiting, with no loss of glucoregulatory activity, thus demonstrating the value of gradual dose-escalation in mitigating the gastrointestinal side effects of exenatide. Copyright © 2004 John Wiley & Sons, Ltd.

Summary • Previously we have cloned sucrose: fructan-6-fructosyltransferase (6-SFT) from barley (Hordeum vulgare) and proposed that synthesis of fructans in grasses depends on the concerted action of two main enzymes: sucrose: sucrose-1-fructosyltransferase (1-SST), as in other fructan producing plants, and 6-SFT, found only in grasses. • Here we report the cloning of barley 1-SST, verifying the activity of the encoded protein by expression in Pichia pastoris. As expected, the barley 1-SST is homologous to invertases and fructosyltransferases, and in particular to barley 6-SFT. • The gene expression pattern of 1-SST and 6-SFT, along with the corresponding enzyme activities and fructan levels, were investigated in excised barley leaves subjected to a light–dark regime known to sequentially induce fructan accumulation and mobilization. The turnover of transcripts and enzyme activities of 1-SST and 6-SFT was compared, using appropriate inhibitors. • We found the 1-SST transcripts and enzymatic activity respond quickly, being subject to a rapid turnover. By contrast, the 6-SFT transcripts and enzymatic activity were found to be much more stable. The much higher responsiveness of 1-SST to regulatory processes, as compared with 6-SFT, clearly indicates that 1-SST plays the role of the pacemaker enzyme of fructan synthesis in barley leaves.

This survey assesses the current status of foreign languages and international education studies in Colorado, and describes the critical needs of those academic areas. As intended, this survey resulted in the formulation of specific recommendations for curriculum improvement at the elementary and secondary levels. Our assessment was made in direct response to the published Report of the President's Commission on Foreign Languages and International Studies.

Water exchange on hexaaquavanadium (III) has been studied as a function of temperature (255 to 413 K) and pressure (up to 250 MPa, at several temperatures) by 17O-NMR spectroscopy at 8.13 and 27.11 MHz. The samples contained V3+ (0.30–1.53 m), H+ (0.19–2.25 m) and 17O-enriched (10–20%) H2O. The trifluoromethanesulfonate was used as counter-ion, and, contrary to the previously used chloride or bromide, CF3SO is shown to be non-coordinating. The following exchange parameters were obtained: k = (5.0 ± 0.3) · 102 s−1, ΔH* = (49.4 ± 0.8) kJ mol−1, ΔS* = −(28 ± 2) JK−1 mol−1, ΔV* = −(8.9 ± 0.4) cm3 mol−1 and Δβ* = −(1.1 ± 0.3) · 10−2 cm3 mol−1 MPa−1. They are in accord with an associative interchange mechanism, Ia. These results for H2O exchange are discussed together with the available data for complex formation reactions on hexaaquavanadium(III). A semi-quantitative analysis of the bound H2O linewidth led to an estimation of the proportions of the different contributions to the relaxation mechanism in the coordinated site: the dipole-dipole interaction hardly contributes to the relaxation (less than 7%); the quadrupolar relaxation, and the scalar coupling mechanism are nearly equally efficient at low temperature (∼ 273 K), but the latter becomes more important at higher temperature (75–85% contribution at 360 K).