Adherence to a Mediterranean diet is associated with a lower risk of later-onset Crohn's disease:Results from two large prospective cohort studies

Objective: To examine the relationship between Mediterranean diet and risk of later-onset Crohn's disease (CD) or ulcerative colitis (UC). Design: We conducted a prospective cohort study of 83 147 participants (age range: 45-79 years) enrolled in the Cohort of Swedish Men and Swedish Mammography Cohort. A validated food frequency questionnaire was used to calculate an adherence score to a modified Mediterranean diet (mMED) at baseline in 1997. Incident diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modelling to calculate HRs and 95% CI. Results: Through December of 2017, we confirmed 164 incident cases of CD and 395 incident cases of UC with an average follow-up of 17 years. Higher mMED score was associated with a lower risk of CD (Ptrend=0.03) but not UC (Ptrend=0.61). Compared with participants in the lowest category of mMED score (0-2), there was a statistically significant lower risk of CD (HR=0.42, 95% CI 0.22 to 0.80) but not UC (HR=1.08, 95% CI 0.74 to 1.58). These associations were not modified by age, sex, education level, body mass index or smoking (all Pinteraction >0.30). The prevalence of poor adherence to a Mediterranean diet (mMED score=0-2) was 27% in our cohorts, conferring a population attributable risk of 12% for later-onset CD. Conclusion: In two prospective studies, greater adherence to a Mediterranean diet was associated with a significantly lower risk of later-onset CD

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

The new combination between the nucleoside analogue gemcitabine and the cholesterol-lowering drug fluvastatin was investigated in vitro and in vivo on the human pancreatic tumour cell line MIAPaCa-2. The present study demonstrates that fluvastatin inhibits proliferation, induces apoptosis in pancreatic cancer cells harbouring a p21ras mutation at codon 12 and synergistically potentiates the cytotoxic effect of gemcitabine. The pharmacologic activities of fluvastatin are prevented by administration of mevalonic acid, suggesting that the shown inhibition of geranyl-geranylation and farnesylation of cellular proteins, including p21rhoA and p21ras, plays a major role in its anticancer effect. Fluvastatin treatment also indirectly inhibits the phosphorylation of p42ERK2/mitogen-activated protein kinase, the cellular effector of ras and other signal transduction peptides. Moreover, fluvastatin administration significantly increases the expression of the deoxycytidine kinase, the enzyme required for the activation of gemcitabine, and simultaneously reduces the 5′-nucleotidase, responsible for deactivation of gemcitabine, suggesting a possible additional role of these enzymes in the enhanced cytotoxic activity of gemcitabine. Finally, a significant in vivo antitumour effect on MIAPaCa-2 xenografts was observed with the simultaneous combination of fluvastatin and gemcitabine, resulting in an almost complete suppression and a marked delay in relapse of tumour growth. In conclusion, the combination of fluvastatin and gemcitabine is an effective cytotoxic, proapoptotic treatment in vitro and in vivo against MIAPaCa-2 cells by a mechanism of action mediated, at least in part, by the inhibition of p21ras and rhoA prenylation. The obtained experimental findings might constitute the basis for a novel translational research in humans

Analysis of Alfven eigenmodes destabilization by energetic particles in TJ-II using a Landau-closure model

Alfven Eigenmodes (AE) can be destabilized by energetic particles in neutral beam injection (NBI) heated plasmas through inverse Landau damping and couplings with gap modes in the shear Alfven continua. We describe the linear evolution of the poloidal flux and the toroidal component of the vorticity in a full 3D system using the reduced MHD equations, density and parallel velocity moments for the energetic particles as well as the geodesic acoustic wave dynamics. A closure relation adds the Landau damping and resonant destabilization effects in the model. We apply the model to study the Alfven modes stability in TJ-II, performing a parametric analysis in a range of realistic values of energetic particle beta (beta(f)), ratios of thermal/Alfven velocities (V-th/V-A0), energetic particle density profiles and toroidal modes (n) including toroidal and helical couplings. The study predicts a large helical coupling between different toroidal modes and the destabilization of helical Alfven eigenmodes (HAE) with frequencies similar to the AE activity measured in TJ-II, between 50-400 kHz. The analysis has also revealed the destabilization of GAE (global Alfven eigenmodes), TAE (toroidal Alfven eigenmodes) and EPM (energetic particle modes). For the modes considered here, optimized TJ-II operations require a t profile in the range of [0.845, 0.979] to stabilize AEs in the inner and middle plasma. AEs in the plasma periphery cannot be fully stabilized, although for a configuration with t = [0.945, 1.079], only n = 7, 11, 15 AE are unstable with a growth rate 4 times smaller compared to the standard t = [1.54, 1.68] case and a frequency of 100 kHz. We reproduce the frequency sweeping evolution of the AE frequency observed in TJ-II as the t profile is varied. The AE frequency sweeping is caused by consecutive changes of the instability dominant modes between different helical families.This material based on work is supported both by the U.S. Department of Energy, Office of Science, under Contract DE-AC05-00OR22725 with UT-Battelle, LLC. This research was sponsored in part by the Ministerio of Economia y Competitividad of Spain under project no. ENE2015-68265-P. We also want to acknowledge Alexander Melnikov and the TJ-II group at CIEMAT for providing us the initial VMEC equilibria and useful discussions regarding the experimental phenomena

Short-Term Synaptic Plasticity in the Dentate Gyrus of Monkeys

The hippocampus plays an important role in learning and memory. Synaptic plasticity in the hippocampus, short-term and long-term, is postulated to be a neural substrate of memory trace. Paired-pulse stimulation is a standard technique for evaluating a form of short-term synaptic plasticity in rodents. However, evidence is lacking for paired-pulse responses in the primate hippocampus. In the present study, we recorded paired-pulse responses in the dentate gyrus of monkeys while stimulating to the medial part of the perforant path at several inter-pulse intervals (IPIs) using low and high stimulus intensities. When the stimulus intensity was low, the first pulse produced early strong depression (at IPIs of 10–30 ms) and late slight depression (at IPIs of 100–1000 ms) of field excitatory postsynaptic potentials (fEPSPs) generated by the second pulse, interposing no depression IPIs (50–70 ms). When the stimulus intensity was high, fEPSPs generated by the second pulse were depressed by the first pulse at all IPIs except for the longest one (2000 ms). Population spikes (PSs) generated by the second pulse were completely blocked or strongly depressed at shorter IPIs (10–100 or 200 ms, respectively), while no depression or slight facilitation occurred at longer IPIs (500–2000 ms). Administration of diazepam slightly increased fEPSPs, while it decreased PSs produced by the first pulse. It also enhanced the facilitation of PSs produced by the second stimulation at longer IPIs. The present results, in comparison with previous studies using rodents, indicate that paired-pulse responses of fEPSPs in the monkey are basically similar to those of rodents, although paired-pulse responses of PSs in the monkey are more delayed than those in rodents and have a different sensitivity to diazepam

Fast Particle Effects on the Internal Kink, Fishbone and Alfven Modes

The issues of linear stability of low frequency perturbative and nonperturbative modes in advanced tokamak regimes are addressed based on recent developments in theory, computational methods, and progress in experiments. Perturbative codes NOVA and ORBIT are used to calculate the effects of TAEs on fast particle population in spherical tokamak NSTX. Nonperturbative analysis of chirping frequency modes in experiments on TFTR and JT-60U is presented using the kinetic code HINST, which identified such modes as a separate branch of Alfven modes - resonance TAE (R-TAE). Internal kink mode stability in the presence of fast particles is studied using the NOVA code and hybrid kinetic-MHD nonlinear code M3D

A multidisciplinary program for achieving lipid goals in chronic hemodialysis patients

BACKGROUND: There is little information on how target lipid levels can be achieved in end stage renal disease (ESRD) patients in a systematic, multidisciplinary fashion. METHODS: We retrospectively reviewed a pharmacist-directed hyperlipidemia management program for chronic hemodialysis (HD) patients. All 26 adult patients on chronic HD at a tertiary care medical facility were entered into the program. A clinical pharmacist was responsible for laboratory monitoring, patient counseling, and the initiation and dosage adjustment of an appropriate 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) using a dosing algorithm and monitoring guidelines. The low-density lipoprotein (LDL) cholesterol goal was ≤ 100 mg/dl. A renal dietitian provided nutrition counseling and the nephrologist was notified of potential or existing drug interactions or adverse drug reactions (ADRs). Patients received a flyer containing lipid panel results to encourage compliance. Data was collected at program initiation and for 6 months thereafter. RESULTS: At the start of the program, 58% of patients were at target LDL cholesterol. At 6 months, 88% had achieved target LDL (p = 0.015). Mean LDL cholesterol decreased from 96 ± 5 to 80 ± 3 mg/dl (p < 0.01), and mean total cholesterol decreased from 170 ± 7 to 151 ± 4 mg/dl (p < 0.01). Fifteen adjustments in drug therapy were made. Eight adverse drug reactions were identified; 2 required drug discontinuation or an alternative agent. Physicians were alerted to 8 potential drug-drug interactions, and appropriate monitoring was performed. CONCLUSIONS: Our findings demonstrate both feasibility and efficacy of a multidisciplinary approach in management of hyperlipidemia in HD patients

Simvastatin impairs murine melanoma growth

<p>Abstract</p> <p>Background</p> <p>Statins induces cell cycle arrest, apoptosis, reduction of angiogenic factors, inhibition of the endothelial growth factor, impairing tissue adhesion and attenuation of the resistance mechanisms. The aim of this study was evaluate the anti-tumoral activity of simvastatin in a B16F10 melanoma-mouse model.</p> <p>Methods</p> <p>Melanoma cells were treated with different concentrations of simvastatin and assessed by viability methods. Melanoma cells (5 × 10⁴) were implanted in two month old C57Bl6/J mice. Around 7 days after cells injection, the oral treatments were started with simvastatin (5 mg/kg/day, p.o.). Tumor size, hematological and biochemical analyses were evaluated.</p> <p>Results</p> <p>Simvastatin at a concentration of 0.8 μM, 1.2 μM and 1.6 μM had toxic effect. Concentration of 1.6 μM induced a massive death in the first 24 h of incubation. Simvastatin at 0.8 μM induces early cell cycle arrest in G0/G1, followed by increase of hypodiploidy. Tumor size were evaluated and the difference of treated group and control, after ten days, demonstrates that simvastatin inhibited the tumor expansion in 68%.</p> <p>Conclusion</p> <p>Simvastatin at 1.6 μM, presented cytototoxicity after 72 h of treatment, with an intense death. <it>In vivo</it>, simvastatin being potentially useful as an antiproliferative drug, with an impairment of growth after ten days.</p