Degradation and glycemic effects of His(7)-glucitol glucagon-like peptide-1(7-36)amide in obese diabetic ob/ob mice

Glucagon-like peptide-1(7-36)amide (tGLP-1) has attracted considerable potential as a possible therapeutic agent for type 2 diabetes. However, tGLP-1 is rapidly inactivated in vivo by the exopeptidase dipeptidyl peptidase IV (DPP IV), thereby terminating its insulin releasing activity. The present study has examined the ability of a novel analogue, His(7)-glucitol tGLP-1 to resist plasma degradation and enhance the insulin-releasing and antihyperglycemic activity of the peptide in 20-25-week-old obese diabetic ob/ob mice. Degradation of native tGLP-1 by incubation at 37 degreesC with obese mouse plasma was clearly evident after 3 h (35% intact). After 6 h, more than 87% of tGLP-1 was converted to GLP-1(9-36)amide and two further N-terminal fragments, GLP-1(7-28) and GLP-1(9-28). In contrast, His7-glucitol tGLP-1 was completely resistant to N-terminal degradation. The formation of GLP-1(9-36)amide from native tGLP-1 was almost totally abolished by addition of diprotin A, a specific inhibitor of DPP IV. Effects of tGLP-1 and His7-glucitol tGLP-1 were examined in overnight fasted obese mice following i.p. injection of either peptide (30 nmol/kg) together with glucose (18 mmol/kg) or in association with feeding. Plasma glucose was significantly lower and insulin response greater following administration of His7-glucitol tGLP-1 as compared to glucose alone. Native tGLP-1 lacked antidiabetic effects under the conditions employed, and neither peptide influenced the glucose-lowering action of exogenous insulin (50 units/kg). Twice daily s.c. injection of ob/ob mice with His(7)-glucitol tGLP-1 (10 nmol/kg) for 7 days reduced fasting hyperglycemia and greatly augmented the plasma insulin response to the peptides given in association with feeding. These data demonstrate that His(7)-glucitol tGLP-1 displays resistance to plasma DPP IV degradation and exhibits antihyperglycemic activity and substantially enhanced insulin-releasing action in a commonly used animal model of type 2 diabetes. (C) 2001 Elsevier Science B.V. All rights reserved.

Computer simulating a trial of a load-bearing implant: example of an intramedullary prosthesis

Computational modelling is becoming ever more important for obtaining regulatory approval for new medical devices. An accepted approach is to infer performance in a population from an analysis conducted for an idealised or ‘average’ patient; we present here a method for predicting the performance of an orthopaedic implant when released into a population—effectively simulating a clinical trial. Specifically we hypothesise that an analysis based on a method for predicting the performance in a population will lead to different conclusions than an analysis based on an idealised or ‘average’ patient. To test this hypothesis we use a finite element model of an intramedullary implant in a bone whose size and remodelling activity is different for each individual in the population. We compare the performance of a low Young’s modulus implant (View the MathML source) to one with a higher Young’s modulus (200 GPa). Cyclic loading is applied and failure is assumed when the migration of the implant relative to the bone exceeds a threshold magnitude. The analysis for an idealised of ‘average’ patient predicts that the lower modulus device survives longer whereas the analysis simulating a clinical trial predicts no statistically-significant tendency (p=0.77) for the low modulus device to perform better. It is concluded that population-based simulations of implant performance–simulating a clinical trial–present a very valuable opportunity for more realistic computational pre-clinical testing of medical devices.

Sedative load of medications prescribed for older people with dementia in care homes

The objective of this study was to determine the sedative load and use of sedative and psychotropic medications among older people with dementia living in (residential) care homes.

Scaling in the time-dependent failure of a fiber bundle with local load sharing

We study the scaling behaviors of a time-dependent fiber-bundle model with local load sharing. Upon approaching the complete failure of the bundle, the breaking rate of fibers diverges according to r(t)proportional to(T-f-t)(-xi) where T-f is the lifetime of the bundle and xi approximate to 1.0 is a universal scaling exponent. The average lifetime of the bundle [T-f] scales with the system size as N-delta, where delta depends on the distribution of individual fiber as well as the breakdown rule. [S1063-651X(99)13902-3].

Failure of fiber bundles with local load sharing

We develop a recursion-relation approach for calculating the failure probabilities of a fiber bundle with local load sharing. This recursion relation is exact, so it provides a way to test the validity of the various approximate methods. Applying the exact calculation to uniform and Weibull threshold distributions, we find that the most probable failure load coincides with the average strength as the size of the system N --> infinity.

BURST-SIZE DISTRIBUTION IN FIBER-BUNDLES WITH LOCAL LOAD-SHARING

A critical load x(c) is introduced into the fiber-bundle model with local load-sharing. The critical load is defined as the average load per fiber that causes the final complete failure. It is shown that x(c) --> 0 when the size of the system N --> infinity. A power law for the burst-size distribution, D(DELTA) is-proportional-to DELTA(-xi) is approximately correct. The exponent xi is not universal, since it depends on the strength distribution as well as the size of the system.

Genetic variants influencing human aging from late-onset Alzheimer's disease (LOAD) genome-wide association studies (GWAS)

Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 × 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.

Delamination threshold load for dynamic impact on plates

A criterion is derived for delamination onset in transversely isotropic laminated plates under small mass, high velocity impact. The resulting delamination threshold load is about 21% higher than the corresponding quasi-static threshold load. A closed form approximation for the peak impact load is then used to predict the delamination threshold velocity. The theory is validated for a range of test cases by comparison with 3D finite element simulation using LS-DYNA and a newly developed interface element to model delamination onset and growth. The predicted delamination threshold loads and velocities are in very good agreement with the finite element simulations. Good agreement is also shown in a comparison with published experimental results. In contrast to quasi-static impacts, delamination growth occurs under a rapidly decreasing load. Inclusion of finite thickness effects and a proper description of the contact stiffness are found to be vital for accurate prediction of the delamination threshold velocity

Predicting the ultimate load of a CFRP wingbox

The finite element method in conjunction with the Soutis-Fleck model is used to predict the residual strength after impact of a carbon-fibre reinforced plastic wingbox subjected to a cantilever type loading. The maximum stress failure criterion further validates the Soutis-Fleck model predictions. The Soutis-Fleck model predicts that the wingbox fails at a tip load of 99.2 kN, approximately 5.5% less than the experimental observation

Design technique for mm-wave IC realization of the load network of switched-mode class-EF power amplifier

Analysis and synthesis of the new Class-EF power amplifier (PA) are presented in this paper. The proposed circuit offers means to alleviate some of the major issues faced by existing Class-EF and Class-EF PAs, such as (1) substantial power losses due to parasitic resistance of the large inductor in the Class-EF load network, (2) unpredictable behaviour of practical lumped inductors and capacitors at harmonic frequencies, and (3) deviation from ideal Class-EF operation mode due to detrimental effects of device output inductance at high frequencies. The transmission-line load network of the Class-EF PA topology elaborated in this paper simultaneously satisfies the Class-EF optimum impedance requirements at fundamental frequency, second, and third harmonics as well as simultaneously providing matching to the circuit optimum load resistance for any prescribed system load resistance. Furthermore, an elegant solution using an open and short-circuit stub arrangement is suggested to overcome the problem encountered in the mm-wave IC realizations of the Class-EF PA load network due to lossy quarter-wave line. © 2010 IEICE Institute of Electronics Informati.