Yogurt consumption and risk of colorectal cancer in the Italian European prospective investigation into cancer and nutrition cohort

Fermented dairy products like yogurt have been suggested to protect against colorectal cancer (CRC). We conducted a prospective study on 45,241 (14,178 men; 31,063 women) volunteers of the EPIC-Italy cohort who completed a dietary questionnaire including specific questions on yogurt intake. During 12 years of follow-up, 289 volunteers were diagnosed with CRC. Hazard ratios (HRs) for the disease and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models, stratified by dietary questionnaire and adjusted for energy intake and other potential confounders. Yogurt intake was inversely associated with CRC risk. For the energy-adjusted model, HR for CRC in the highest versus lowest tertile of yogurt intake was 0.62 (95% CI, 0.46-0.83). In the full model adjusted for energy, simple sugar, calcium, fiber, animal fat, alcohol and red meat intake, as well as body mass index, smoking, education and physical activity, HR was 0.65 (95% CI, 0.48-0.89) in the highest versus lowest tertile. The protective effect of yogurt was evident in the entire cohort, but was stronger in men, although there was no interaction of sex with the yogurt-CRC association (p(interaction) 0.20, fully adjusted model). In our prospective study, high yogurt intake was significantly associated with decreased CRC risk, suggesting that yogurt should be part of a diet to prevent the disease. Investigation of larger cohorts is necessary to reveal any residual confounding of the association of yogurt intake with CRC risk.     

Type 1 diabetes-induced hyper-responsiveness to 5-hydroxytryptamine in rat pulmonary arteries via oxidative stress and induction of cyclooxygenase-2

Recent epidemiological data suggest that diabetes is a risk factor for pulmonary arterial hypertension. The aim of the present study was to analyze the link between type 1 diabetes and pulmonary arterial dysfunction in rats. Male Sprague-Dawley rats were randomly divided into a control group (saline) and a diabetic group (70 mg/kg streptozotocin). After 6 weeks, diabetic animals showed a down-regulation of the lung bone morphogenetic protein receptor type 2, up-regulation of 5-hydroxytryptamine (5-HT) 2A receptors and cyclooxygenase-2 (COX-2) proteins as measured by Western blot analysis, and increased contractile responses to 5-HT in isolated intrapulmonary arteries. The hyper-responsiveness to 5-HT was endothelium-independent and unaffected by inhibition of nitric-oxide synthase but prevented by indomethacin, the selective COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398), superoxide dismutase, and the NADPH oxidase inhibitor apocynin or chronic treatment with insulin. However, diabetic rats at 6 weeks did not develop elevated right ventricular pressure or pulmonary artery muscularization, whereas a longer exposure (4 months) to diabetes induced a modest, but significant, increase in right ventricular systolic pressure. In conclusion, type 1 diabetes mellitus in rats induces a number of changes in lung protein expression and pulmonary vascular reactivity characteristic of clinical and experimental pulmonary arterial hypertension but insufficient to elevate pulmonary pressure. Our results further strengthen the link between diabetes and pulmonary arterial hypertension.     

Combined use of urinary neutrophil gelatinase-associated lipocalin (uNGAL) and albumin as markers of early cardiac damage in primary hypertension

BackgroundNeutrophil Gelatinase-Associated Lipocalin (NGAL) is an early and specific marker of acute kidney dysfunction. Recent evidences suggest that NGAL may also be involved in chronic vascular remodeling during the development of atherosclerosis. Albuminuria, a powerful predictor of cardiovascular events, is thought to reflect widespread subclinical vascular abnormalities. We investigated the relationship between urinary NGAL (uNGAL), albuminuria and left ventricular mass (LVM) in patients with primary hypertension.MethodsA total of 120 untreated, non diabetic patients with primary hypertension (mean age 47 ± 9 years) were studied. uNGAL was measured by a chemiluminescent microparticle method, optimized on a fully automated analytical platform (ARCHITECT, Abbott Diagnostics Inc, Rome, IT). Albuminuria was measured by immunonephelometry on an Immage Immunochemistry System (Beckman Coulter, Inc., Fullerton, California, USA) and expressed as albumin/creatinine ratio (ACR). LVM was assessed by echocardiography and indexed to body surface area (LVM/BSA).ResultsNo significant correlation was found between uNGAL and ACR; however, both variables were directly related to clinic systolic blood pressure (rho = 0.241, p = 0.0085 and rho = 0.248, p = 0.0068 respectively), left ventricular relative wall thickness (rho = 0.251, p = 0.0156 and rho = 0.263, p = 0.0013 respectively), and LVM/BSA (rho = 0.285, p = 0.0062 and rho = 0.213, p = 0.0410 respectively). The uNGAL and ACR simultaneous increase above their respective median values was associated with higher LVM/BSA values (p = 0.0109) and with a higher prevalence of left ventricular hypertrophy (LVH) (p = 0.0017). Furthermore, logistic regression analysis showed that the risk of presenting LVH increased more than 4-fold when uNGAL and ACR were both above the median value, even after adjustment for age, gender and blood pressure values.ConclusionsThe simultaneous increase in uNGAL and ACR excretion is significantly associated with the increase of LVM in low risk patients with primary hypertension. This association is clinically significant for the early assessment of cardiac damage in hypertension.     

Simultaneous Golgi-Cox and immunofluorescence using confocal microscopy

Visualization of neuronal elements is of fundamental importance in modern neuroscience. Golgi-Cox impregnation is a widely employed method that provides detailed information about morphological characteristics of neurons, but none regarding their neurochemical features. Immunocytochemical procedures, on the other hand, can provide a high degree of biochemical specificity but poorer morphological details, in particular if compared to Golgi-Cox impregnation. Hence, the combined use of these two approaches is highly desirable, especially for confocal microscopy that can exploit the advantages of both methods simultaneously. Here we show an innovative procedure of perfusion and fixation of brain tissue, that allows, by applying Golgi-Cox impregnation and immunofluorescence in the same histological section, to obtain high-quality histological material, with a very simple and inexpensive method. This procedure is based on three simple fixation steps: (1) a paraformaldehyde perfusion followed by a standard post-fixation to stabilize the subsequent immunofluorescence reaction; (2) the classical Golgi-Cox impregnation and (3) an immunofluorescence reaction in previously impregnated material. This combination allows simultaneous visualization of (a) the structural details (Golgi-Cox impregnated neurons), (b) the antigens’ characterization, (c) the anatomical interactions between discrete neuronal elements and (d) the 3D reconstruction and modeling. The method is easy to perform and can be reproducibly applied by small laboratories and expanded through the use of different antibodies. Overall, the method presented in this study offers an innovative and powerful approach to study the nervous system, especially by using confocal microscopy.     

Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: further structure-activity relationships, in vivo studies, and preliminary toxicity profiling

Despite recent progress in the fight against malaria, the emergence and spread of drug-resistant parasites remains a serious obstacle to the treatment of infections. We recently reported the development of a novel antimalarial drug that combines the 4-aminoquinoline pharmacophore of chloroquine with that of clotrimazole-based antimalarials. Here we describe the optimization of this class of hybrid drug through in-depth structure-activity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasite's 'chloroquine resistance transporter' were investigated in a Xenopus laevis oocyte expression system. These tests indicated that piperazine derivatives 4b and 4d may be suitable for coadministration with chloroquine against chloroquine-resistant parasites. The potential for metabolism of the drugs by cytochrome P450 was determined in silico, and the lead compounds were tested for toxicity and mutagenicity. A preliminary pharmacokinetic analysis undertaken in mice indicated that compound 4b has an optimal half-life.     

Fluorinated and pegylated polyaspartamide derivatives to increase solubility and efficacy of Flutamide

New fluorinated amphiphilic copolymers based on a biocompatible polyaspartamide have been prepared in order to obtain polymeric micelles useful for delivering anticancer drugs. In particular, α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) has been derivatized with polyethylene glycol (PEG(2000)) and ethylendiamine (EDA). Both these portions form the hydrophilic part of the copolymer, while the hydrophobic moiety is given by 1,2,4-oxadiazoles: 5-pentafluorophenyl-3-perfluoroheptyl-1,2,4-oxadiazole (PPOX) or 3-carboxyethyl-5-pentadecafluoroheptyl-1,2,4-oxadiazole (CPOX). Copolymers named PHEA-PEG(2000)-EDA-PPOX and PHEA-PEG(2000)-EDA-CPOX have been prepared with various degrees of derivatization and characterized by spectroscopic analyses. Size exclusion chromatography, pyrene colorimetric assay, light scattering analysis and scanning electron microscopy have evidenced the occurrence of a self-association process in aqueous medium. The ability of these aggregates to incorporate a hydrophobic drug and increase its solubility has been evaluated by using Flutamide, a fluorinated anticancer agent. Moreover, the activity of Flutamide-loaded micelles on proliferation of dihydrotestosterone stimulated LNCaP cells has been determined and compared to that of free drug.     

High sensitivity troponin T concentrations in patients undergoing noncardiac surgery: a prospective cohort study

Objectives

To determine the proportion of noncardiac surgery patients exceeding the published 99th percentile or change criteria with the high sensitivity Troponin T (hs-TnT) assay.

Design and methods

We measured hs-TnT preoperatively and postoperatively on days 1, 2 and 3 in 325 adults.

Results

Postoperatively 45% (95% CI: 39–50%) of patients had hs-TnT ≥ 14 ng/L and 22% (95% CI:17–26%) had an elevation (≥ 14 ng/L) and change (> 85%) in hs-TnT.

Conclusion

Further research is needed to inform the optimal hs-TnT threshold and change in this setting.