Metformin:historical overview

Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat's rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin's future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications

Linear numerical analysis of soil behaviour under shallow foundation using four node quadrilateral finite element with smoothed stress field

W pracy wykonano analizę zachowania się gruntu pod fundamentem bezpośrednim z wykorzystaniem metody elementów skończonych. Kod źródłowy programu został napisany w języku Mathematica. Grunt zamodelowano jako materiał liniowo sprężysty. Obliczenia zostały przeprowadzone dla trzech rodzajów stopy fundamentowej: podatnej gładkiej, sztywnej szorstkiej i sztywnej gładkiej. Wyniki przeprowadzonych analiz przyrównano z wynikami obliczeń programu Midas GTS NX.The paper present analysis of soil behavior under shallow foundation using finite element procedure. The source code have been written in Mathematica language. The soil is modeled as linear elastic material. Computations have been carried out for three types of foot: Smooth flexible, rough rigid and smooth rigid. The results of the performed analysis were compared to the results of calculations by the computer software Midas GTS NX

Locating critical circular and unconstrained failure surface in slope stability analysis with tailored genetic algorithm

This article presents an efficient search method for representative circular and unconstrained slip surfaces with the use of the tailored genetic algorithm. Searches for unconstrained slip planes with rigid equilibrium methods are yet uncommon in engineering practice, and little publications regarding truly free slip planes exist. The proposed method presents an effective procedure being the result of the right combination of initial population type, selection, crossover and mutation method. The procedure needs little computational effort to find the optimum, unconstrained slip plane. The methodology described in this paper is implemented using Mathematica. The implementation, along with further explanations, is fully presented so the results can be reproduced. Sample slope stability calculations are performed for four cases, along with a detailed result interpretation. Two cases are compared with analyses described in earlier publications. The remaining two are practical cases of slope stability analyses of dikes in Netherlands. These four cases show the benefits of analyzing slope stability with a rigid equilibrium method combined with a genetic algorithm. The paper concludes by describing possibilities and limitations of using the genetic algorithm in the context of the slope stability problem

Analysis of embedded retaining wall using the subgrade reaction method

This paper analyzes the distribution of internal forces and displacements of embedded retaining wall in Quaternary deposits and Tertiary clays. Calculations have been based on the Subgrade Reaction Method (SRM) for two different types of earth pressure behind the wall (active, at-rest) in order to show the differences resulting from adopting the limit values. An algorithm for calculation of “cantilever wall” using the Mathematica program was proposed

Adaptive control of discrete time Markov processes by the large deviations method

Some discrete time controlled Markov processes in a locally compact metric space whose transition operators depend on an unknown parameter are described. The adaptive controls are constructed using the large deviations of empirical distributions which are uniform in the parameter that takes values in a compact set. The adaptive procedure uses a finite family of continuous, almost optimal controls. Using the large deviations property it is shown that an adaptive control which is a fixed almost optimal control after a finite time is almost optimal with probability nearly 1