Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors α- and γ-mediated gene expression via liver fatty acid binding protein: A signaling path to the nucleus

Peroxisome proliferator-activated receptor α (PPARα) is a key regulator of lipid homeostasis in hepatocytes and target for fatty acids and hypolipidemic drugs. How these signaling molecules reach the nuclear receptor is not known; however, similarities in ligand specificity suggest the liver fatty acid binding protein (L-FABP) as a possible candidate. In localization studies using laser-scanning microscopy, we show that L-FABP and PPARα colocalize in the nucleus of mouse primary hepatocytes. Furthermore, we demonstrate by pull-down assay and immunocoprecipitation that L-FABP interacts directly with PPARα. In a cell biological approach with the aid of a mammalian two-hybrid system, we provide evidence that L-FABP interacts with PPARα and PPARγ but not with PPARβ and retinoid X receptor-α by protein–protein contacts. In addition, we demonstrate that the observed interaction of both proteins is independent of ligand binding. Final and quantitative proof for L-FABP mediation was obtained in transactivation assays upon incubation of transiently and stably transfected HepG2 cells with saturated, monounsaturated, and polyunsaturated fatty acids as well as with hypolipidemic drugs. With all ligands applied, we observed strict correlation of PPARα and PPARγ transactivation with intracellular concentrations of L-FABP. This correlation constitutes a nucleus-directed signaling by fatty acids and hypolipidemic drugs where L-FABP acts as a cytosolic gateway for these PPARα and PPARγ agonists. Thus, L-FABP and the respective PPARs could serve as targets for nutrients and drugs to affect expression of PPAR-sensitive genes.

Les lipides et les cancers urologiques - approches épidémiologiques. L’importance du temps immortel

Objectif: Définir l’effet des lipides et du traitement de la dyslipidémie sur les cancers de la prostate et de la vessie en utilisant différents devis d’étude et en tenant compte de la présence de plusieurs biais, particulièrement le biais du temps immortel. Devis: Le premier volet utilise un devis rétrospectif de type cas témoins. Un questionnaire semi-quantitatif de fréquence de consommation alimentaire validé a été utilisé. Le génotype COX2 de neuf polymorphisme nucléotidique unique (SNP) a été mesuré avec une plateforme Taqman. Des modèles de régression logistique non conditionnelle ont été utilisés pour comparer le risque de diagnostic d’un cancer de la prostate et l’interaction. Le deuxième volet utilise un devis rétrospectif de type cohorte basée sur les données administratives de la Régie de l’assurance-maladie du Québec (RAMQ). Des modèles de régression de Cox ont été employés pour mesurer l’association entre les statines et l’évolution du cancer de la vessie. Le troisième volet, porte un regard méthodologique sur le biais du temps immortel en examinant sa présence dans la littérature oncologique. Son importance est illustrée avec les données de la cohorte du deuxième volet, et les méthodes de correction possibles son appliquées. Résultats: L’étude du premier volet démontre qu’une diète riche en acides gras oméga-3 d’origine marine était fortement associée à un risque diminué de cancer de la prostate agressif (p<0.0001 pour la tendance). Le ratio de cote pour le cancer de la prostate du quartile supérieur d’oméga-3 était de 0.37 (IC 95% = 0.25 à 0.54). L’effet diététique était modifié par le génotype COX-2 SNP rs4648310 (p=0.002 pour l’interaction). En particulier, les hommes avec faible apport en oméga-3 et la variante rs4648310 avait un risque accru de cancer de la prostate (ratio de cote = 5.49, IC 95%=1.80 à 16.7), effet renversé par un apport en oméga-3 plus grand. L’étude du deuxième volet a observé que l’utilisation de statines est associée à une diminution du risque de progression du cancer de la vessie (risque relatif = 0.44, IC 95% = 0.20 à 0.96, p=0.039). Cette association était encore plus forte pour le décès de toute cause (HR = 0.57, 95% CI = 0.43 to 0.76, p=0.0001). L’effet des statines semble être dose-dépendant. L’étude du troisième volet démontre que le biais du temps immortel est fréquent et important dans les études épidémiologiques oncologiques. Il comporte plusieurs aspects dont certains sont mieux prévenus au stade du choix du devis d’étude et différentes méthodes statistiques permettent un contrôle de ce biais. Conclusion: 1) Une diète riche en oméga-3 aurait un effet protecteur pour le cancer de la prostate. 2) L’utilisation de statines aurait un effet protecteur sur la progression du cancer non invasif de la vessie. Les lipides semblent avoir un effet sur les cancers urologiques.

Effects of phthalic acid esters on the liver and thyroid

The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P-450 isoenzyme(s) catalyzing omega oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fail to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid. The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.

The influence of local administration of simvastatin in calvarial bone healing in rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

β-conglycinin combined with fenofibrate or rosuvastatin have exerted distinct hypocholesterolemic effects in rats

Background: There is increasing interest in non-pharmacological control of cholesterol and triglyceride levels in the plasma and diet-drug association represent an important area of studies. The objective of this study was to observe the hypocholesterolemic effect of soybean β-conglycinin (7S protein) alone and combined with fenofibrate and rosuvastatin, two hypolipidemic drugs. Methods. The protein and drugs were administered orally once a day to rats and the effects were evaluated after 28 days. Wistar rats were divided into six groups (n = 9): hypercholesterolemic diet (HC), HC+7S protein (300 mg.kg-1 day-1) (HC-7S), HC+fenofibrate (30 mg.kg-1 day-1)(HC-FF), HC+rosuvastatin (10 mg.kg-1 day-1)(HC-RO), HC+7S+fenofibrate (HC-7S-FF) and HC+7S+rosuvastatin (HC-7S-RO). Results: Animals in HC-7S, HC-FF and HC-RO exhibited reductions of 22.9, 35.8 and 18.8% in total plasma cholesterol, respectively. In HC-7S-FF, animals did not show significant alteration of the level in HC+FF while the group HC-7S-RO showed a negative effect in comparison with groups taking only protein (HC-7S) or drug (HC-RO). The administration of the protein, fenofibrate and rosuvastatin alone caused increases in the plasma HDL-C of the animals, while the protein-drug combinations led to an increase compared to HC-FF and HC-RO. The plasma concentration of triacylgycerides was significantly reduced in the groups without association, while HC-7S-FF showed no alteration and HC-7S-RO a little reduction. Conclusion: The results of our study indicate that conglycinin has effects comparable to fenofibrate and rosuvastatin on the control of plasma cholesterol, HDL-C and triacylglycerides, when given to hypercholesterolemic rats, and suggests that the association of this protein with rosuvastatin alters the action of drug in the homeostasis of cholesterol. © 2012 Ferreira et al; licensee BioMed Central Ltd.

Screening for drugs in oral fluid : illicit drug use and drug driving in a sample of urban and regional Queensland motorists

Police services in a number of Australian states and overseas jurisdictions have begun to implement or consider random road-side drug testing of drivers. This paper outlines research conducted to provide an estimate of the extent of drug driving in a sample of Queensland drivers in regional, rural and metropolitan areas. Oral fluid samples were collected from 2657 Queensland motorists and screened for illicit substances including cannabis (delta 9 tetrahydrocannibinol [THC]), amphetamines, ecstasy, and cocaine. Overall, 3.8% of the sample (n = 101) screened positive for at least one illicit substance, although multiple drugs were identified in a sample of 23 respondents. The most common drugs detected in oral fluid were ecstasy (n = 53), and cannabis (n = 46) followed by amphetamines (n = 23). A key finding was that cannabis was confirmed as the most common self-reported drug combined with driving and that individuals who tested positive to any drug through oral fluid analysis were also more likely to report the highest frequency of drug driving. Furthermore, a comparison between drug vs. drink driving detection rates for one region of the study, revealed a higher detection rate for drug driving (3.8%) vs. drink driving (0.8%). This research provides evidence that drug driving is relatively prevalent on Queensland roads, and may in fact be more common than drink driving. This paper will further outline the study findings’ and present possible directions for future drug driving research.

Alcohol and other drugs in the Australian construction industry : A national evaluation and the best way forward

Anecdotal evidence highlights issues of alcohol and other drugs (AODs) and its association with safety risk on construction sites. Information is limited however regarding the prevalence of AODs in the workplace and there is limited evidential guidance regarding how to effectively address it. This research aimed to scientifically evaluate the use of AODs within the Australian construction industry in order to reduce the potential resulting safety and performance impacts and engender a cultural change in the workforce. A national qualitative and quantitative evaluation of the use of AODs was conducted with approximately 500 employees. Results indicate that as in the general population, a proportion of those sampled in the construction sector may be at risk of hazardous alcohol consumption and support the need for evidence-based, tailored responses. This is the first known study to scientifically evaluate the use of AODs and potential workplace safety impacts in the construction sector.

New findings with old drugs for osteoporosis

Background : Postmenopausal osteoporosis is common and is associated with stooped posture, loss of height, back pain and fractures. Objectives/methods : This evaluation is of clinical outcome trials with tibolone (Long-Term Intervention of Fractures with Tibolone) and strontium ranelate (Spinal Osteoporosis Therapeutic Intervention) in postmenopausal osteoporosis. Results : Although the Long-Term Intervention of Fractures with Tibolone trial established that tibolone decreased the incidence of vertebral and non-vertebral fractures in postmenopausal osteoporosis, it also showed that tibolone caused a small increase in the incidence of stoke. The Spinal Osteoporosis Therapeutic Intervention trial established that strontium ranelate decreased the incidence of vertebral fractures, but had little effect on the incidence of non-vertebral fractures. Conclusions : As some of the bisphosphonates (alendronate, risedronate, zoledronic acid) have been shown to prevent hip fractures without increasing the incidence of stroke, they should be preferred to tibolone and strontium in the treatment of postmenopausal osteoporosis.

Safeguarding rural Australia : addressing masculinity and violence in rural settings. Data report No. 4 - Risky behaviour - misuse of alcohol, illicit drugs, firearms use and abuse, other risky behaviour

This report focuses on our examination of extant data which have been sourced with respect to personally and socially risky behaviour associated with males living in regional and remote Australia . The AIHW (2008: PHE 97:89) defines personally risky behaviour, on the one hand, as working, swimming, boating, driving or operating hazardous machinery while intoxicated with alcohol or an illicit drug. Socially risky behaviour, on the other hand, is defined as creating a public disturbance, damaging property, stealing or verbally or physically abusing someone while intoxicated with alcohol or an illicit drug. Additional commentary resulting from exploration, examination and analyses of secondary data is published online in complementary reports in this series.

Drugs, dental professionals and the law

Dentists have the privilege of possessing, administering and prescribing drugs, including highly addictive medications, to their patients. But because drugs are often vulnerable to being abused by all members of society, including dentists and their patients, and because drugs can be dangerous, they are tightly regulated in Canada by the federal and provincial/territorial governments. Regulatory and professional dental bodies also provide guidance for their members about how to best administer and prescribe drugs. This chapter outlines the regulation by federal and provincial/territorial governments in this area, examines the professional practice requirements set out by regulatory/professional bodies and the issue of drug abuse by dental professional and patients. It is important to note from the outset that governmental and professional regulations, policies and practices differ from province to province and territory to territory. This chapter aims to alert dentists to possible legal and professional issues surrounding the possession, administration and prescription of drugs. For detailed specific information about regulation, policies, ethical standards and professional practice standards in Canada or their province/ territory, dentists should contact their insurer or professional association.

Safety impacts of alcohol and other drugs in the construction industry : a research methodology

Anecdotal evidence from the infrastructure and building sectors highlights issues of drugs and alcohol and its association with safety risk on construction sites. Operating machinery and mobile equipment, proximity to live traffic together with congested sites, electrical equipment and operating at heights conspire to accentuate the potential adverse impact of drugs and alcohol in the workplace. While most Australian jurisdictions have identified this as a critical safety issue, information is limited regarding the prevalence of alcohol and other drugs in the workplace and there is limited evidential guidance regarding how to effectively and efficiently address such an issue. No known study has scientifically evaluated the relationship between the use of drugs and alcohol and safety impacts in construction, and there has been only limited adoption of nationally coordinated strategies, supported by employers and employees to render it socially unacceptable to arrive at a construction workplace with impaired judgement from drugs and alcohol. A nationally consistent collaborative approach across the construction workforce - involving employers and employees; clients; unions; contractors and sub-contractors is required to engender a cultural change in the construction workforce – in a similar manner to the on-going initiative in securing a cultural change to drink-driving in our society where peer intervention and support is encouraged. This study has four key objectives. Firstly, using the standard World Health Organisation AUDIT, a national qualitative and quantitative assessment of the use of drugs and alcohol will be carried out. This will build upon similar studies carried out in the Australian energy and mining sectors. Secondly, the development of an appropriate industry policy will adopt a non-punitive and rehabilitative approach developed in consultation with employers and employees across the infrastructure and building sectors, with the aim it be adopted nationally for adoption at the construction workplace. Thirdly, an industry-specific cultural change management program will be developed through a nationally collaborative approach to reducing the risk of impaired performance on construction sites and increasing workers’ commitment to drugs and alcohol safety. Finally, an implementation plan will be developed from data gathered from both managers and construction employees. Such an approach stands to benefit not only occupational health and safety, through a greater understanding of the safety impacts of alcohol and other drugs at work, but also alcohol and drug use as a wider community health issue. This paper will provide an overview of the background and significance of the study as well as outlining the proposed methodology that will be used to evaluate the safety impacts of alcohol and other drugs in the construction industry.

Safety impacts of alcohol and other drugs in the construction industry : Preliminary findings

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Safety impacts of alcohol and other drugs in construction : a mid term report

Estimated 640,700 persons suffered a work-related injury or illness in 2009-2010 and 444 lost their lives as a result in 2008-2009, in Australia Very little is known about what proportion of accidents are directly attributable to the effects of AOD Anecdotal evidence highlights issues of AOD and its association with safety risk on construction sites

New drugs for the treatment of coronary artery syndromes

Background: Acute coronary syndromes are a major cause of mortality and morbidity. Objectives/Methods: The objective of this evaluation is to review the clinical trials of two new drugs being developed for the treatment of acute coronary syndromes. The first drug is the anti-coagulant otamixaban, and the trial compared otamixaban with unfractionated heparin and eptifibatide in acute coronary syndromes. The second drug is the anti-platelet ticagrelor, and the trial compared ticagrelor with clopidogrel in acute coronary syndromes. Results: In the SEPIA-ACS1 TIMI 42 trial, the primary efficacy endpoint occurred in 6.2% of subjects treated with unfractionated heparin and eptifibatide, and to a significantly lesser extent with otamixaban. In the PLATO trial, the primary efficacy endpoint had occurred less in the ticagrelor group (9.8%) than in the clopidogrel group (11.7%) at 12 months. Conclusions: Two new drugs for acute coronary syndromes, otamixaban and ticagrelor, have recently been shown to have benefits in subjects undergoing percutaneous interventions compared to the present standard regimens for this condition.