Search

Exercise is important in the management of type 1 diabetes mellitus (T1DM). Modern diabetes care includes the goal that all youth meet guidelines for regular physical activity. Evidence suggests regular physical activity improves cardiovascular health, lipid profiles, psychosocial wellbeing and, possibly, glycemic control in youth with T1DM. However, exercise is especially problematic for children and adolescents because wide glycemic excursions commonly occur during and after exercise and may increase the risk of severe hypoglycemia. In addition, youth with T1DM have abnormal counterregulatory hormone responses, further increasing the risk of exercise-associated hypoglycemia. Recent studies have demonstrated that this risk is present during, and many hours after exercise, and have tested strategies to prevent exercise-induced hypoglycemia in youth. Despite these recent studies, the fear of hypoglycemia remains a major impediment to achieving target glycemic control in youth, targets that have recently been tightened. Equally, data suggests fear of hypoglycemia is the major impediment to participation in regular daily exercise in T1DM. Recent advances in insulin delivery systems and in real time continuous glucose monitoring have improved care for youth with T1DM, allowing safer participation in exercise programs. The impending development and approval of “closed loop” insulin delivery systems (the artificial pancreas) holds great promise for the safe participation in exercise for all youth with T1DM.

Here we present a study of five analogues of a fragment from the shaft domain of the adenovirus fibre protein that readily form fibrils under a range of conditions. Using atomic force microscopy the fibrillisation of these peptides at the liquid/solid interface utilizing ordered crystalline substrates has been investigated. Our results demonstrate that the assembly pathway at the liquid/solid interface enables only the formation of truncated fibrillar structures, which align along the substrates underlying atomic lattice during growth. Furthermore, that the concentration and volume of solution applied can be used to directly control the density of fibrillar coverage at the surface.

In the present study, numerical simulations of turbulent flow with free-surface vortex in unbaffled vessels agitated by a paddle impeller and a Rushton turbine, which were investigated experimentally by Nagata (John Wiley & Sons:  New York, 1974) and Ciofalo et al. (Chem. Eng. Sci.1996, 51, 3557−3573), respectively, have been carried out. A homogeneous multiphase flow model coupled with a volume-of-fluid (VOF) method for interface capturing has been applied to determine the shapes of the gas−liquid interface and to compute the turbulent flow fields in unbaffled vessels. Turbulence is modeled using the k−/k− based shear-stress transport model (Menter, F. R. AIAA J.1994, 32, 1598−1605) and a second-moment differential Reynolds-stress transport model. Calculations are carried out using the ANSYS CFX-5.7 CFD code (ANSYS:  Canonsburg, PA, 2004). Validation of the predictions is effected against the measured free-surface profiles (Nagata, 1974; Ciofalo et al., 1996), and the mean velocity distributions (Nagata, 1974). The predicted liquid surface profiles using the VOF method in conjunction with both turbulence models are generally in good agreement with measurements. As for the mean velocity components, the Reynolds-stress transport model predictions are superior than those obtained using the shear-stress transport model.

We describe here the first example of an iterative convergent strategy for the synthesis of dendritically branched polymers involving condensation coupling reactions of AB2 macromonomers. The macromonomers were synthesized by living anionic polymerization, initiated with 3-tert-butyldimethylsiloxy-1-propyllithium and end capped with 1,1-bis(4-tert-butyldimethylsiloxyphenyl) ethylene. Following a deprotection reaction, the macromonomer, functionalized with two phenol groups and one primary alcohol group, can be built up into a dendritic structure by a series of Williamson coupling reactions and subsequent end group modification reactions. Since the dendritic structures are built up from macromonomers we have coined the term “DendriMac” to describe these branched polymers. In this paper, we will discuss the synthesis of the macromonomer, the iterative reaction sequence and merits of a convergent strategy. Some preliminary characterization data will also be reported.

Structure−activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of alkynamide analogues of quinazoline- and pyrido[3,4-d]pyrimidine-based compounds. The compounds were prepared by coupling the appropriate 6-aminoquinazolines or 6-aminopyrido[3,4-d]pyrimidines with alkynoic acids, using EDCI·HCl in pyridine. The compounds showed pan-erbB enzyme inhibition but were on average about 10-fold more potent against erbB1 than against erbB2 and erbB4. For cellular inhibition, the nature of the alkylating side chains was an important determinant, with 5-dialkylamino-2-pentynamide type Michael acceptors providing the highest potency. This is suggested to be due to an improved ability of the amine to participate in an autocatalysis of the Michael reaction with enzyme cysteine residues. Pyrido[3,4-d]pyrimidine analogue 39 was selected for in vivo evaluation and achieved tumor regressions at 10 mg/kg in the A431 human epidermoid carcinoma and at 40 mg/kg for the SF767 human glioblastoma and the SKOV3 human ovarian carcinoma. Complete stasis was observed at 40 mg/kg in the BXPC3 human pancreatic carcinoma as well as in the H125 human non-small-cell lung carcinoma.

Presents letters to the editor concerning medicine.

In this study, we characterized the effects of activation of cyclic AMP-dependent protein kinase (PKA) on the internalization and functional coupling of the metabotropic glutamate receptor (mGluR1) splice variants mGluR1a and mGluR1b. Using an enzyme-linked immunosorbent assay technique to assess receptor internalization, we found that the glutamate-induced internalization of mGluR1a or mGluR1b transiently expressed in human embryonic kidney (HEK) 293 cells was inhibited by coactivation of endogenous beta2-adrenoceptors with isoprenaline or by direct activation of adenylyl cyclase with forskolin. The PKA inhibitor N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride (H89) blocked the effects of both isoprenaline and forskolin. The heterologous internalization of the mGluR1 splice variants triggered by carbachol was also inhibited by isoprenaline and forskolin in a PKA-sensitive fashion, whereas the constitutive (agonist-independent) internalization of mGluR1a was inhibited only modestly by PKA activation. Using inositol phosphate (IP) accumulation in cells prelabeled with [3H]inositol to assess receptor coupling, PKA activation increased basal IP accumulation in mGluR1a receptor-expressing cells and also increased glutamate-stimulated IP accumulation in both mGluR1a- and mGluR1b-expressing cells, but only at short times of glutamate addition. Furthermore, PKA activation completely blocked the carbachol-induced heterologous desensitization of glutamate-stimulated IP accumulation in both mGluR1a- and mGluR1b-expressing cells. In coimmunoprecipitation experiments, the ability of glutamate to increase association of GRK2 and arrestin-2 with mGluR1a and mGluR1b was inhibited by PKA activation with forskolin. Together, these results indicate that PKA activation inhibits the agonist-induced internalization and desensitization of mGluR1a and mGluR1b, probably by reducing their interaction with GRK2 and nonvisual arrestins.