Symbolic Software for the Painleve Test of Nonlinear Ordinary and Partial Differential Equations

The automation of the traditional Painleve test in Mathematica is discussed. The package PainleveTest.m allows for the testing of polynomial systems of ordinary and partial differential equations which may be parameterized by arbitrary functions (or constants). Except where limited by memory, there is no restriction on the number of independent or dependent variables. The package is quite robust in determining all the possible dominant behaviors of the Laurent series solutions of the differential equation. The omission of valid dominant behaviors is a common problem in many implementations of the Painleve test, and these omissions often lead to erroneous results. Finally, our package is compared with the other available implementations of the Painleve test.Comment: Published in the Journal of Nonlinear Mathematical Physics (http://www.sm.luth.se/math/JNMP/), vol. 13(1), pp. 90-110 (Feb. 2006). The software can be downloaded at either http://www.douglasbaldwin.com or http://www.mines.edu/fs_home/wherema

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background Liraglutide 3\ub70 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3\ub70 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2\ub77 times longer with liraglutide than with placebo (95% CI 1\ub79 to 3\ub79, p<0\ub70001), corresponding with a hazard ratio of 0\ub721 (95% CI 0\ub713\u20130\ub734). Liraglutide induced greater weight loss than placebo at week 160 (\u20136\ub71 [SD 7\ub73] vs 121\ub79% [6\ub73]; estimated treatment difference 124\ub73%, 95% CI 124\ub79 to 123\ub77, p<0\ub70001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3\ub70 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding Novo Nordisk, Denmark

Prevalence of diabetes, metabolic syndrome and metabolic abnormalities in schizophrenia over the course of the illness: a cross-sectional study

BACKGROUND: Patients with schizophrenia are at high risk of developing metabolic abnormalities. METHOD: A prospective study focusing on metabolic disturbances in patients with schizophrenia, including an oral glucose tolerance test, is currently ongoing at our University Hospital and affiliate services. The prevalence of metabolic abnormalities at baseline was assessed in a cohort of 415 patients with schizophrenia. The sample was divided into 4 groups according to duration of illness: first-episode patients (<1.5 years), recent-onset patients (between 1.5 and 10 years), subchronic patients (between 10 and 20 years) and chronic patients (>20 years). RESULTS: Metabolic abnormalities were already present in first-episode patients, and considerably increased with increasing duration of illness. When compared to the general population matched for age and gender, much higher rates of the metabolic syndrome (MetS) and diabetes were observed for patients with schizophrenia. For MetS, the increase over time was similar to that of the general population. In contrast, the difference in the prevalence of diabetes in patients with schizophrenia and the general population dramatically and linearly increased from 1.6% in the 15–25 age-band to 19.2% in the 55–65 age-band. CONCLUSION: Thus, the current data suggest that on the one hand metabolic abnormalities are an inherent part of schizophrenic illness, as they are already present in first-episode patients. On the other hand, however, our results suggest a direct effect of the illness and/or antipsychotic medication on their occurence. The data underscore the need for screening for metabolic abnormalities in patients diagnosed with schizophrenia, already starting from the onset of the illness

The endocanabinnoid system and diabetes - critical analyses of studies conducted with rimonabant

Rimonabant is the first CB1 receptor inhibitor available in the Brazilian market. This new drug has been approved for the treatment of obese or overweight patients associated with cardiovascular risk factors. In this article it is compared the effects of rimonabant treatment in obese patients with cardiovascular risk factors to usual obesity pharmacological treatment

Best Practices for Alchemical Free Energy Calculations

Alchemical free energy calculations are a useful tool for predicting free energy differences associated with the transfer of molecules from one environment to another. The hallmark of these methods is the use of "bridging" potential energy functions representing \emph{alchemical} intermediate states that cannot exist as real chemical species. The data collected from these bridging alchemical thermodynamic states allows the efficient computation of transfer free energies (or differences in transfer free energies) with orders of magnitude less simulation time than simulating the transfer process directly. While these methods are highly flexible, care must be taken in avoiding common pitfalls to ensure that computed free energy differences can be robust and reproducible for the chosen force field, and that appropriate corrections are included to permit direct comparison with experimental data. In this paper, we review current best practices for several popular application domains of alchemical free energy calculations, including relative and absolute small molecule binding free energy calculations to biomolecular targets.Comment: 48 pages, 14 figure

Is There Evidence That Oral Hypoglycemic Agents Reduce Cardiovascular Morbidity/Mortality? Yes

Athough type 2 diabetes is a heterogeneous condition encompassing multiple metabolic and vascular alterations, it can be easily described as a disease characterized by chronic hyperglycemia and increased cardiovascular (CV) risk. Hyperglycemia is the diagnostic criterion for diabetes, the target for antidiabetic therapy, and, together with A1C, the marker of glycemic control. Progressive worsening of glycemic control has been described in type 2 diabetic patients irrespective of initial form of treatment, leading the U.K. Prospective Diabetes Study (UKPDS) investigators to describe such changes as the “natural history” of the disease ( 1). Still, maintaining good glycemic control is crucial, since it is associated with marked reduction in the risk of developing retinopathy, nephropathy, and neuropathy in both type 1 ( 2) and type 2 diabetic patients ( 1). But it is CV disease that worsens long-term prognosis in type 2 diabetes ( 3), to the point that diabetes has been proposed as a CV risk equivalent owed to the observation that 10-year risk for major coronary events approximates the risk in CHD in patients without diabetes with previous CV events ( 4), increased case fatality rate after myocardial infarction, and worse overall prognosis after CHD ( 5). In diabetic patients, even after correction for known CV risk factors, the incidence of myocardial infarction or stroke is two- to threefold higher than in the nondiabetic population, with a twofold increase in risk of death ( 6), suggesting that some feature of diabetes must confer excessive propensity toward CV disease. Can this feature be hyperglycemia? No better issue can be chosen for debate. From an epidemiological point of view, there is evidence that the risk of CV mortality increases with the increase of plasma glucose concentrations ( 7) and A1C values ( 8). Moreover, multiple atherogenic mechanisms have been identified that can be activated by hyperglycemia ( 9)

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies

Insulin Detemir in the Treatment of Type 1 and Type 2 Diabetes

Insulin detemir is a soluble long-acting human insulin analogue at neutral pH with a unique mechanism of action. Following subcutaneous injection, insulin detemir binds to albumin via fatty acid chain, thereby providing slow absorption and a prolonged metabolic effect. Insulin detemir has a less variable pharmacokinetic profile than insulin suspension isophane or insulin ultralente. The use of insulin detemir can reduce the risk of hypoglycemia (especially nocturnal hypoglycemia) in type 1 and type 2 diabetic patients. However, overall glycemic control, as assessed by glycated hemoglobin, is only marginally and not significantly improved compared with usual insulin therapy. The weight gain commonly associated with insulin therapy is rather limited when insulin detemir is used. In our experience, this new insulin analogue is preferably administrated at bedtime but can be proposed twice a day (in the morning and either before the dinner or at bedtime). Detemir is a promising option for basal insulin therapy in type 1 or type 2 diabetic patients