Infliximab-related weight gain in inflammatory bowel disease: associations and financial impacts.

Association between tumour necrosis alpha inhibitors and weight gain has been reported. We examined weight change in our cohort of inflammatory bowel disease patients treated with infliximab (IFX) for over 12 months, its associations and financial implications. Two-thirds of patients gained weight during the course of therapy. The mean change in weight after 12 months of IFX therapy was 3.3 (±6.5) kg.

Potential of mean force between oppositely charged nanoparticles: A comprehensive comparison between Poisson-Boltzmann theory and Monte Carlo simulations.

Ion-mediated interactions between like-charged polyelectrolytes have been paid much attention, and the Poisson-Boltzmann (PB) theory has been shown to fail in qualitatively predicting multivalent ion-mediated like-charge attraction. However, inadequate attention has been paid to the ion-mediated interactions between oppositely charged polyelectrolytes. In this work, the potentials of mean force (PMF) between oppositely charged nanoparticles in 1:1 and 2:2 salt solutions were investigated by Monte Carlo simulations and the PB theory. Our calculations show that the PMFs between oppositely charged nanoparticles are generally attractive in 1:1 and 2:2 salt solutions and that such attractive PMFs become weaker at higher 1:1 or 2:2 salt concentrations. The comprehensive comparisons show that the PB theory can quantitatively predict the PMFs between oppositely charged nanoparticles in 1:1 salt solutions, except for the slight deviation at very high 1:1 salt concentration. However, for 2:2 salt solutions, the PB theory generally overestimates the attractive PMF between oppositely charged nanoparticles, and this overestimation becomes more pronounced for nanoparticles with higher charge density and for higher 2:2 salt concentration. Our microscopic analyses suggest that the overestimation of the PB theory on the attractive PMFs for 2:2 salt solutions is attributed to the underestimation of divalent ions bound to nanoparticles.

Radial distribution function of semiflexible oligomers with stretching flexibility.

The radial distribution of the end-to-end distance Ree is crucial for quantifying the global size and flexibility of a linear polymer. For semiflexible polymers, several analytical formulas have been derived for the radial distribution of Ree ignoring the stretching flexibility. However, for semiflexible oligomers, such as DNA or RNA, the stretching flexibility can be rather pronounced and can significantly affect the radial distribution of Ree. In this study, we obtained an extended formula that includes the stretch modulus to describe the distribution of Ree for semiflexible oligomers on the basis of previous formulas for semiflexible polymers without stretching flexibility. The extended formula was validated by extensive Monte Carlo simulations over wide ranges of the stretch modulus and persistence length, as well as all-atom molecular dynamics simulations of short DNAs and RNAs. Additionally, our analyses showed that the effect of stretching flexibility on the distribution of Ree becomes negligible for DNAs longer than ∼130 base pairs and RNAs longer than ∼240 base pairs.

Screening for chronic kidney disease in Canadian indigenous peoples is cost-effective.

Canadian indigenous (First Nations) have rates of kidney failure that are 2- to 4-fold higher than the non-indigenous general Canadian population. As such, a strategy of targeted screening and treatment for CKD may be cost-effective in this population. Our objective was to assess the cost utility of screening and subsequent treatment for CKD in rural Canadian indigenous adults by both estimated glomerular filtration rate and the urine albumin-to-creatinine ratio. A decision analytic Markov model was constructed comparing the screening and treatment strategy to usual care. Primary outcomes were presented as incremental cost-effectiveness ratios (ICERs) presented as a cost per quality-adjusted life-year (QALY). Screening for CKD was associated with an ICER of $23,700/QALY in comparison to usual care. Restricting the model to screening in communities accessed only by air travel (CKD prevalence 34.4%), this ratio fell to $7,790/QALY. In road accessible communities (CKD prevalence 17.6%) the ICER was $52,480/QALY. The model was robust to changes in influential variables when tested in univariate sensitivity analyses. Probabilistic sensitivity analysis found 72% of simulations to be cost-effective at a $50,000/QALY threshold and 93% of simulations to be cost-effective at a $100,000/QALY threshold. Thus, targeted screening and treatment for CKD using point-of-care testing equipment in rural Canadian indigenous populations is cost-effective, particularly in remote air access-only communities with the highest risk of CKD and kidney failure. Evaluation of targeted screening initiatives with cluster randomized controlled trials and integration of screening into routine clinical visits in communities with the highest risk is recommended.

Computational polypharmacology: a new paradigm for drug discovery.

INTRODUCTION: Over the past couple of years, the cost of drug development has sharply increased along with the high rate of clinical trial failures. Such increase in expenses is partially due to the inability of the "one drug - one target" approach to predict drug side effects and toxicities. To tackle this issue, an alternative approach, known as polypharmacology, is being adopted to study small molecule interactions with multiple targets. Apart from developing more potent and effective drugs, this approach allows for studies of off-target activities and the facilitation of drug repositioning. Although exhaustive polypharmacology studies in-vitro or in-vivo are not practical, computational methods of predicting unknown targets or side effects are being developed. Areas covered: This article describes various computational approaches that have been developed to study polypharmacology profiles of small molecules. It also provides a brief description of the algorithms used in these state-of-the-art methods. Expert opinion: Recent success in computational prediction of multi-targeting drugs has established polypharmacology as a promising alternative approach to tackle some of the daunting complications in drug discovery. This will not only help discover more effective agents, but also present tremendous opportunities to study novel target pharmacology and facilitate drug repositioning efforts in the pharmaceutical industry.

Flexibility of short DNA helices with finite-length effect: From base pairs to tens of base pairs.

Flexibility of short DNA helices is important for the biological functions such as nucleosome formation and DNA-protein recognition. Recent experiments suggest that short DNAs of tens of base pairs (bps) may have apparently higher flexibility than those of kilo bps, while there is still the debate on such high flexibility. In the present work, we have studied the flexibility of short DNAs with finite-length of 5-50 bps by the all-atomistic molecular dynamics simulations and Monte Carlo simulations with the worm-like chain model. Our microscopic analyses reveal that short DNAs have apparently high flexibility which is attributed to the significantly strong bending and stretching flexibilities of ∼6 bps at each helix end. Correspondingly, the apparent persistence length lp of short DNAs increases gradually from ∼29 nm to ∼45 nm as DNA length increases from 10 to 50 bps, in accordance with the available experimental data. Our further analyses show that the short DNAs with excluding ∼6 bps at each helix end have the similar flexibility with those of kilo bps and can be described by the worm-like chain model with lp ∼ 50 nm.

A coarse-grained model with implicit salt for RNAs: predicting 3D structure, stability and salt effect.

To bridge the gap between the sequences and 3-dimensional (3D) structures of RNAs, some computational models have been proposed for predicting RNA 3D structures. However, the existed models seldom consider the conditions departing from the room/body temperature and high salt (1M NaCl), and thus generally hardly predict the thermodynamics and salt effect. In this study, we propose a coarse-grained model with implicit salt for RNAs to predict 3D structures, stability, and salt effect. Combined with Monte Carlo simulated annealing algorithm and a coarse-grained force field, the model folds 46 tested RNAs (≤45 nt) including pseudoknots into their native-like structures from their sequences, with an overall mean RMSD of 3.5 Å and an overall minimum RMSD of 1.9 Å from the experimental structures. For 30 RNA hairpins, the present model also gives the reliable predictions for the stability and salt effect with the mean deviation ∼ 1.0 °C of melting temperatures, as compared with the extensive experimental data. In addition, the model could provide the ensemble of possible 3D structures for a short RNA at a given temperature/salt condition.

Assessment of a pharmacokinetic and pharmacodynamic interaction between simvastatin and Ginkgo biloba extracts in healthy subjects.

1. Ginkgo biloba extract (GBE) is one of the most commonly used herbal remedies worldwide. It is usually concomitantly administrated with statins to treat diseases in geriatric patients. We aim to determine the influence of GBE on the pharmacokinetics (PK) and pharmacodynamics of simvastatin, which is currently unknown. 2. An open-label, randomized, two-period, two-treatment, balanced, crossover study was performed in 14 healthy volunteers. Subjects received simvastatin 40 mg once daily, co-treated with placebo or GBE 120 mg twice daily. Each treatment was administered for 14 d, separated by a wash-out period of 1 month. Simvastatin, simvastatin acid and lipoprotein concentrations were assessed. 3. GBE administration reduced mean simvastatin area under the curve (AUC)0-24, AUC0-∞ and Cmax by 39% (p = 0.000), 36%(p = 0.001) and 32% (p = 0.002), respectively, but did not cause significant differences in simvastatin acid PK or its cholesterol-lowering efficacy. 4. GBE consumption decreased simvastatin system exposure, but did not affect simvastatin acid PK. However, we cannot rule out the possibility for a pharmacodynamic interaction between GBE and simvastatin in vivo.

Inhibition of the organic anion-transporting polypeptide 1B1 by quercetin: an in vitro and in vivo assessment.

AIM: To investigate the effect of quercetin on organic anion transporting polypeptide 1B1 (OATP1B1) activities in vitro and on the pharmacokinetics of pravastatin, a typical substrate for OATP1B1 in healthy Chinese-Han male subjects. METHODS: Using human embryonic kidney 293 (HEK293) cells stably expressing OATP1B1, we observed the effect of quercetin on OATP1B1-mediated uptake of estrone-3-sulphate (E3S) and pravastatin. The influence of quercetin on the pharmacokinetics of pravastatin was measured in 16 healthy Chinese-Han male volunteers receiving a single dose of pravastatin (40 mg orally) after co-administration of placebo or 500 mg quercetin capsules (once daily orally for 14 days). RESULTS: Quercetin competitively inhibited OATP1B1-mediated E3S uptake with a K(i) value of 17.9 ± 4.6 µm and also inhibited OATP1B1-mediated pravastatin uptake in a concentration dependent manner (IC(50) , 15.9 ± 1.4 µm). In healthy Chinese-Han male subjects, quercetin increased the pravastatin area under the plasma concentration - time curve (AUC(0,10 h) and the peak plasma drug concentration (C(max)) to 24% (95% CI 15, 32%, P < 0.001) and 31% (95% CI 20, 42%, P < 0.001), respectively. After administration of quercetin, the elimination half-life (t(1/2) ) of pravastatin was prolonged by 14% (95% CI 4, 24%, P = 0.027), with no change in the time to reach C(max) (t(max) ). Moreover, quercetin decreased the apparent clearance (CL/F) of pravastatin by 18% (95% CI 75, 89%, P < 0.001). CONCLUSIONS: These findings suggest that quercetin inhibits the OATP1B1-mediated transport of E3S and pravastatin in vitro and also has a modest inhibitory influence on the pharmacokinetics of pravastatin in healthy Chinese-Han male volunteers. The effects of quercetin on other OATP1B1 substrate drugs deserve further investigation.

Multi-detector CT/CT angiogram assessment of acute pancreatic graft dysfunction.

Simultaneous pancreatic-kidney transplantation is the definitive treatment for patients with type 1 diabetes mellitus and renal failure. Pancreatic graft failure is an important postoperative complication and most commonly occurs as a result of pancreatitis, graft thrombosis or rejection. Distinguishing between these causes is necessary to determine timely, appropriate management and thereby potentially minimising graft loss. Multi-detector CT imaging may be used to identify the cause of pancreatic graft dysfunction when renal function is not markedly impaired.

Ion-mediated nucleic acid helix-helix interactions.

Salt ions are essential for the folding of nucleic acids. We use the tightly bound ion (TBI) model, which can account for the correlations and fluctuations for the ions bound to the nucleic acids, to investigate the electrostatic free-energy landscape for two parallel nucleic acid helices in the solution of added salt. The theory is based on realistic atomic structures of the helices. In monovalent salt, the helices are predicted to repel each other. For divalent salt, while the mean-field Poisson-Boltzmann theory predicts only the repulsion, the TBI theory predicts an effective attraction between the helices. The helices are predicted to be stabilized at an interhelix distance approximately 26-36 A, and the strength of the attractive force can reach -0.37 k(B)T/bp for helix length in the range of 9-12 bp. Both the stable helix-helix distance and the strength of the attraction are strongly dependent on the salt concentration and ion size. With the increase of the salt concentration, the helix-helix attraction becomes stronger and the most stable helix-helix separation distance becomes smaller. For divalent ions, at very high ion concentration, further addition of ions leads to the weakening of the attraction. Smaller ion size causes stronger helix-helix attraction and stabilizes the helices at a shorter distance. In addition, the TBI model shows that a decrease in the solvent dielectric constant would enhance the ion-mediated attraction. The theoretical findings from the TBI theory agree with the experimental measurements on the osmotic pressure of DNA array as well as the results from the computer simulations.

Electrostatic correlations and fluctuations for ion binding to a finite length polyelectrolyte.

A statistical mechanical model is presented which explicitly accounts for the fluctuations, the electrostatic, and the excluded volume correlations for ions bound to a polyelectrolyte such as DNA. The method can be employed to treat a wide range of ionic conditions including multivalent ions. The microscopic framework of the theory permits the use of realistic finite length and grooved structural model for the polyelectrolyte and modeling of the finite size of the bound ions. Test against Monte Carlo simulations suggests that the theory can give accurate predictions for the ion distribution and the thermodynamic properties. For multivalent ions, the theory makes improved predictions as compared with the mean-field approach. Moreover, for long polyelectrolyte and dilute salt concentration, the theory predicts ion binding properties that agree with the counterion condensation theory.

Random walk with memory enhancement and decay.

A model of random walk with memory enhancement and decay was presented on the basis of the characteristics of the biological intelligent walks. In this model, the movement of the walker is determined by the difference between the remaining information at the jumping-out site and jumping-in site. The amount of the memory information s(i)(t) at a site i is enhanced with the increment of visiting times to that site, and decays with time t by the rate e(-beta(t)), where beta is the memory decay exponent. When beta=0, there exists a transition from Brownian motion (BM) to the compact growth of walking trajectory with the density of information energy u increasing. But for beta>0, this transition does not appear and the walk with memory enhancement and decay can be considered as the BM of the mass center of the cluster composed of remembered sites in the late stage.