Lowering blood alcohol content levels to save lives: The european experience

Road safety has become an increasing concern in developed countries due to the significant amount of mortal victims and the economic losses derived. Only in 2005 these losses rose to 200.000 million euros, a significant amount - approximately the 2% of its GDP- that easily justifies any public intervention. One tool used by governments to face this challenge is the enactment of stricter policies and regulations. Since drunk driving is one of the most important concerns of public authorities on this field, several European countries decided to lower their illegal Blood Alcohol Content levels to 0.5 mg/ml during the last decade. This study evaluates for the first time the effectiveness of this transition using European panel-based data (CARE) for the period 1991-2003 using the Differences-in-Differences method in a fixed effects estimation that allows for any pattern of correlation (Cluster-Robust). My results show the existence of positive impacts on certain groups of road users and for the whole population when the policy is accompanied by some enforcement interventions. Moreover, a time lag of more than two years is found in that effectiveness. Finally, I also assert the importance of controlling for serial correlation in the evaluation of this kind of policies.

Association between conventional risk factors and different ultrasound-based markers of atherosclerosis at carotid and femoral levels in a middle-aged population.

Ultrasound detection of sub-clinical atherosclerosis (ATS) may help identify individuals at high cardiovascular risk. Most studies evaluated intima-media thickness (IMT) at carotid level. We compared the relationships between main cardiovascular risk factors (CVRF) and five indicators of ATS (IMT, mean and maximal plaque thickness, mean and maximal plaque area) at both carotid and femoral levels. Ultrasound was performed on 496 participants aged 45-64 years randomly selected from the general population of the Republic of Seychelles. 73.4 % participants had ≥ 1 plaque (IMT thickening ≥ 1.2 mm) at carotid level and 67.5 % at femoral level. Variance (adjusted R2) contributed by age, sex and CVRF (smoking, LDL-cholesterol, HDL-cholesterol, blood pressure, diabetes) in predicting any of the ATS markers was larger at femoral than carotid level. At both carotid and femoral levels, the association between CVRF and ATS was stronger based on plaque-based markers than IMT. Our findings show that the associations between CVRF and ATS markers were stronger at femoral than carotid level, and with plaque-based markers rather than IMT. Pending comparison of these markers using harder cardiovascular endpoints, our findings suggest that markers based on plaque morphology assessed at femoral artery level might be useful cardiovascular risk predictors.

Serum uric acid levels in Chagas' disease

Uricemia was studied in a sample of 192 individuals from a highly endemic site for Chagas' disease (Bambuí, State of Minas Gerais, Brazil). The sample had serologically negative individuals (controls) and the positive ones were classified on the basis of the presence of electrocardiographic alterations (63), altered esophageal emptying (16), or without any sign on sympton of the disease (76). Only the individuals with the digestive form of chronic Chagas' disease showed hyperuricemia, when compared with the appropriate controls. Family data suggest that hyperuricemia is an effect of the digestive pathology, rather than a cause, since the non-infected sibs of the megaesophagous patients did not show elevated levesl of serum uric acid. Possible mechanisms responsible for these findings are postulated.

Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels.

IDX-1 (islet/duodenum homeobox-1) is a transcription factor expressed in the duodenum and pancreatic beta and delta cells. It is required for embryonic development of the pancreas and transactivates the Glut2, glucokinase, insulin, and somatostatin genes. Here we show that exposure of isolated rat pancreatic islets to palmitic acid induced a approximately 70% decrease in IDX-1 mRNA and protein expression as well as 40 and 65% decreases in the binding activity of IDX-1 for its cognate cis-regulatory elements of the Glut2 and insulin promoters, respectively. The inhibitory effect of palmitic acid required its mitochondrial oxidation since it was prevented by the carnitine palmitoyltransferase I inhibitor bromopalmitic acid. The palmitic acid effect on IDX-1 was correlated with decreases in GLUT2 and glucokinase expression of 40 and 25%, respectively, at both the mRNA and protein levels. Insulin and somatostatin mRNA expression was also decreased by 40 and 60%, whereas glucagon mRNA expression was not modified. After 48 h of exposure to fatty acids, total islet insulin, somatostatin, and glucagon contents were decreased by 85, 55, and 65%, respectively. At the same time, total hormone release was strongly stimulated (13-fold) for glucagon, whereas its was only marginally increased for insulin and somatostatin (1.5- and 1.7-fold, respectively). These results indicate that elevated fatty acid levels 1) negatively regulate Idx-1 expression; 2) decrease the expression of genes transactivated by IDX-1 such as those for GLUT2, glucokinase, insulin, and somatostatin; and 3) lead to an important increase in glucagon synthesis and secretion. Fatty acids thus have pleiotropic effects on pancreatic islet gene expression, and the negative control of Idx-1 expression may be an initial event in the development of these multiple defects.

Affirmative Action Policy and Effort Levels. Sequential-Move Contest Game Argument

In this paper we analyse a simple two-person sequential-move contest game with heterogeneous players. Assuming that the heterogeneity could be the consequence of past discrimination, we study the effects of implementation of affirmative action policy, which tackles this heterogeneity by compensating discriminated players, and compare them with the situation in which the heterogeneity is ignored and the contestants are treated equally. In our analysis we consider different orders of moves. We show that the order of moves of contestants is a very important factor in determination of the effects of the implementation of the affirmative action policy. We also prove that in such cases a significant role is played by the level of the heterogeneity of individuals. In particular, in contrast to the present-in-the-literature predictions, we demonstrate that as a consequence of the interplay of these two factors, the response to the implementation of the affirmative action policy option may be the decrease in the total equilibrium effort level of the contestants in comparison to the unbiased contest game.

Payoff levels, loss avoidance, and equilibrium selection in the Stag Hunt: an experimental study

Game theorists typically assume that changing a game’s payoff levels—by adding the same constant to, or subtracting it from, all payoffs—should not affect behavior. While this invariance is an implication of the theory when payoffs mirror expected utilities, it is an empirical question when the “payoffs” are actually money amounts. In particular, if individuals treat monetary gains and losses differently, then payoff–level changes may matter when they result in positive payoffs becoming negative, or vice versa. We report the results of a human–subjects experiment designed to test for two types of loss avoidance: certain–loss avoidance (avoiding a strategy leading to a sure loss, in favor of an alternative that might lead to a gain) and possible–loss avoidance (avoiding a strategy leading to a possible loss, in favor of an alternative that leads to a sure gain). Subjects in the experiment play three versions of Stag Hunt, which are identical up to the level of payoffs, under a variety of treatments. We find differences in behavior across the three versions of Stag Hunt; these differences are hard to detect in the first round of play, but grow over time. When significant, the differences we find are in the direction predicted by certain– and possible–loss avoidance. Our results carry implications for games with multiple equilibria, and for theories that attempt to select among equilibria in such games.

No interaction between alcohol consumption and HDL-related genes on HDL cholesterol levels.

OBJECTIVE: To assess the relationships and possible interactions between polymorphisms related to HDL levels and alcohol consumption. METHODS: Cross-sectional population-based study including 2863 women and 2546 men aged 35-75 years (CoLaus study). Alcohol intake was assessed by the reported alcohol consumption of the last 7 days. Nineteen candidate genes known to influence HDL levels were studied. RESULTS: Alcohol consumption increased HDL cholesterol levels in both genders. After multivariate adjustment for gender, age, body mass index, smoking, hypolipidaemic drug treatment, physical activity and alcohol consumption, APOA5, CETP, LIPC and LPL gene polymorphisms were significantly (10(-5) threshold) related with HDL cholesterol levels, while no genexalcohol intake interaction was found for all SNPs studied. ABCA1 polymorphisms were related to HDL cholesterol levels on bivariate analysis but the relationship was no longer significant after multivariate analysis. CONCLUSION: Our data confirm the association of alcohol consumption and of APOA5, CETP, LIPC and LPL gene polymorphisms with HDL cholesterol levels. Conversely, no genexalcohol consumption interactions were found, suggesting that the effect of alcohol consumption on HDL cholesterol levels is not mediated via a modulation of HDL related genes.

Problèmes d'échantillonnage lors d'une enquête sur la plombémie d'enfants citadin [Sampling problems in a survey of blood lead levels in city children].

A study on lead pollution was carried out on a sample of ca. 300 city children. This paper presents the errors producing bias in the sample. It is emphasized that, in Switzerland, the difference between the Swiss and the migrant population (the latter being mainly Italian and Spanish) must be taken into account.

Benzodiazepine receptor ligand influences on learning: an endogenous modulatory mechanism mediated by benzodiazepines possibly of alimentary origin

In rats pre-but not post-training ip administration of either flumazenil, a central benzodiazepine (BSD) receptor antagonist, or of n-butyl-B-carboline-carboxylate (BCCB), an inverse agonist, enhanced retention of inhibitory avoidance learning. Flumazenil vlocked the enhancing effect of BCCB, and the inhibitory effect of the BZD agonists clonazepam and diazepam also given pre-training. Post-training administration of these drugs had no effects. The peripheral BZD receptor agonist/chloride channel blocker Ro5-4864 had no effect on the inhibitory avoidance task when given ip prior to training, buth it caused enhancement when given immediately post-training either ip or icv. This effect was blocked by PK11195, a competitive antagonist of Ro5-4864. These results suggest that ther is an endogenous mechanism mediated by BZD agonists, which is sensitive to inverse agonists and that normally down-regulates the formation of memories through a mechanism involving GABA-A receptors and the corresponding chloride channels. The most likely agonists for the endogenous mechanism suggested are the diazepam-like BZDs found in brain whose origin is possibly alimentary. Levels of these BZDs in the cortex were found to sharply decrease after inhibitory acoidance training or mere exposure to the training apparatus.

A vertebrate reproductive system involving three ploidy levels : hybrid origin of triploids in a contact zone of diploid and tetraploid green toads (Bufo viridis subgroup)

The rise and consequences of polyploidy in vertebrates, whose origin was associated with genome duplications, may be best studied in natural diploid and polyploid populations. In a diploid/tetraploid (2n/4n) geographic contact zone of Palearctic green toads in northern Kyrgyzstan, we examine 4ns and triploids (3n) of unknown genetic composition and origins. Using mitochondrial and nuclear sequence, and nuclear microsatellite markers in 84 individuals, we show that 4n (Bufo pewzowi) are allopolyploids, with a geographically proximate 2n species (B. turanensis) being their maternal ancestor and their paternal ancestor as yet unidentified. Local 3n forms arise through hybridization. Adult 3n mature males (B. turanensis mtDNA) have 2n mothers and 4n fathers, but seem distinguishable by nuclear profiles from partly aneuploid 3n tadpoles (with B. pewzowi mtDNA). These observations suggest multiple pathways to the formation of triploids in the contact zone, involving both reciprocal origins. To explain the phenomena in the system, we favor a hypothesis where 3n males (with B. turanensis mtDNA) backcross with 4n and 2n females. Together with previous studies of a separately evolved, sexually reproducing 3n lineage, these observations reveal complex reproductive interactions among toads of different ploidy levels and multiple pathways to the evolution of polyploid lineages.

Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress.

BACKGROUND: Depending on its magnitude, lower body negative pressure (LBNP) has been shown to induce a progressive activation of neurohormonal, renal tubular, and renal hemodynamic responses, thereby mimicking the renal responses observed in clinical conditions characterized by a low effective arterial volume such as congestive heart failure. Our objective was to evaluate the impact of angiotensin II receptor blockade with candesartan on the renal hemodynamic and urinary excretory responses to a progressive orthostatic stress in normal subjects. METHODS: Twenty healthy men were submitted to three levels of LBNP (0, -10, and -20 mbar or 0, -7.5, and -15 mm Hg) for 1 hour according to a crossover design with a minimum of 2 days between each level of LBNP. Ten subjects were randomly allocated to receive a placebo and ten others were treated with candesartan 16 mg orally for 10 days before and during the three levels of LBNP. Systemic and renal hemodynamics, renal sodium excretions, and the hormonal response were measured hourly before, during, and for 2 hours after LBNP. RESULTS: During placebo, LBNP induced no change in systemic and renal hemodynamics, but sodium excretion decreased dose dependently with higher levels of LBNP. At -20 mbar, cumulative 3-hour sodium balance was negative at -2.3 +/- 2.3 mmol (mean +/- SEM). With candesartan, mean blood pressure decreased (76 +/- 1 mm Hg vs. 83 +/- 3 mm Hg, candesartan vs. placebo, P < 0.05) and renal plasma flow increased (858 +/- 52 mL/min vs. 639 +/- 36 mL/min, candesartan vs. placebo, P < 0.05). Glomerular filtration rate (GFR) was not significantly higher with candesartan (127 +/- 7 mL/min in placebo vs. 144 +/- 12 mL/min in candesartan). No significant decrease in sodium and water excretion was found during LBNP in candesartan-treated subjects. At -20 mbar, the 3-hour cumulative sodium excretion was + 4.6 +/- 1.4 mmol in the candesartan group (P= 0.02 vs. placebo). CONCLUSION: Selective blockade of angiotensin II type 1 (AT1) receptors with candesartan increases renal blood flow and prevents the antinatriuresis during sustained lower body negative pressure despite a modest decrease in blood pressure. These results thus provide interesting insights into potential benefits of AT1 receptor blockade in sodium-retaining states such as congestive heart failure.

How to set up and apply reference levels in fluoroscopy at a national level.

A nationwide survey was launched to investigate the use of fluoroscopy and establish national reference levels (RL) for dose-intensive procedures. The 2-year investigation covered five radiology and nine cardiology departments in public hospitals and private clinics, and focused on 12 examination types: 6 diagnostic and 6 interventional. A total of 1,000 examinations was registered. Information including the fluoroscopy time (T), the number of frames (N) and the dose-area product (DAP) was provided. The data set was used to establish the distributions of T, N and the DAP and the associated RL values. The examinations were pooled to improve the statistics. A wide variation in dose and image quality in fixed geometry was observed. As an example, the skin dose rate for abdominal examinations varied in the range of 10 to 45 mGy/min for comparable image quality. A wide variability was found for several types of examinations, mainly complex ones. DAP RLs of 210, 125, 80, 240, 440 and 110 Gy cm2 were established for lower limb and iliac angiography, cerebral angiography, coronary angiography, biliary drainage and stenting, cerebral embolization and PTCA, respectively. The RL values established are compared to the data published in the literature.

Variable viral clearance despite adequate ganciclovir plasma levels during valganciclovir treatment for cytomegalovirus disease in D+/R- transplant recipients.

ABSTRACT: BACKGROUND: Valganciclovir, the oral prodrug of ganciclovir, has been demonstrated equivalent to iv ganciclovir for CMV disease treatment in solid organ transplant recipients. Variability in ganciclovir exposure achieved with valganciclovir could be implicated as a contributing factor for explaining variations in the therapeutic response. This prospective observational study aimed to correlate clinical and cytomegalovirus (CMV) viral load response (DNAemia) with ganciclovir plasma concentrations in patients treated with valganciclovir for CMV infection/disease. METHODS: Seven CMV D+/R- transplant recipients (4 kidney, 2 liver and 1 heart) were treated with valganciclovir (initial dose was 900-1800 mg/day for 3-6.5 weeks, followed by 450-900 mg/day for 2-9 weeks). DNAemia was monitored by real time quantitative PCR and ganciclovir plasma concentration was measured at trough (Ctrough) and 3 h after drug administration (C3h) by HPLC. RESULTS: Four patients presented with CMV syndrome, two had CMV tissue-invasive disease after prophylaxis discontinuation, and one liver recipient was treated pre-emptively for asymptomatic rising CMV viral load 5 weeks post-transplantation in the absence of prophylaxis. CMV DNAemia decreased during the first week of treatment in all recipients except in one patient (median decrease: -1.2 log copies/mL, range: -1.8 to 0) despite satisfactory ganciclovir exposure (AUC0-12 = 48 mg.h/L, range for the 7 patients: 40-118 mg.h/L). Viral clearance was obtained in five patients after a median of time of 34 days (range: 28-82 days). Two patients had recurrent CMV disease despite adequate ganciclovir exposure (65 mg.h/L, range: 44-118 mg.h/L). CONCLUSIONS: Valganciclovir treatment for CMV infection/disease in D+/R- transplant recipients can thus result in variable viral clearance despite adequate ganciclovir plasma concentrations, probably correlating inversely with anti-CMV immune responses after primary infection.

Collective victimisation and collective guilt in the former Yugoslavia : the interplay between individual, local and societal levels

The thesis examines the impact of collective war victimization on individuals' readiness to accept or assign collective guilt for past war atrocities. As a complement to previous studies, its aim is to articulate an integrated approach to collective victimization, which distinguishes between individual-, communal-, and societal-level consequences of warfare. Building on a social representation approach, it is guided by the assumption that individuals form beliefs about a conflict through their personal experiences of victimization, communal experiences of warfare that occur in their proximal surrounding, and the mass- mediatised narratives that circulate in a society's public sphere. Four empirical studies test the hypothesis that individuals' beliefs about the conflict depend on the level and type of war experiences to which they have been exposed, that is, on informative and normative micro and macro contexts in which they are embedded. The studies have been conducted in the context of the Yugoslav wars that attended the breakup of Yugoslavia, a series of wars fought between 1991 and 2001 during which numerous war atrocities were perpetrated causing a massive victimisation of population. To examine the content and impact of war experiences at each level of analysis, the empirical studies employed various methodological strategies, from quantitative analyses of a representative public opinion survey, to qualitative analyses of media content and political speeches. Study 1 examines the impact of individual- and communal- level war experiences on individuals' acceptance and assignment of collective guilt. It further examines the impact of the type of communal level victimization: exposure to symmetric (i.e., violence that similarly affects members of different ethnic groups, including adversaries) and asymmetric violence. The main goal of Study 2 is to examine the structural and political circumstances that enhance collective guilt assignment. While the previous studies emphasize the role of past victimisation, Study 2 tests the assumption that the political demobilisation strategy employed by elites facing public discontent in the collective system-threatening circumstances can fuel out-group blame. Studies 3 and 4 have been conducted predominantly in the context of Croatia and examine rhetoric construction of the dominant politicized narrative of war in a public sphere (Study 3) and its maintenance through public delegitimization of alternative (critical) representations (Study 4). Study 4 further examines the likelihood that highly identified group members adhere to publicly delegitimized critical stances on war. - Cette thèse étudie l'impact de la victimisation collective de guerre sur la capacité des individus à accepter ou à attribuer une culpabilité collective liée à des atrocités commises en temps de guerre. En compléments aux recherches existantes, le but de ce travail est de définir une approche intégrative de la victimisation collective, qui distingue les conséquences de la guerre aux niveaux individuel, régional et sociétal. En partant de l'approche des représentations sociales, cette thèse repose sur le postulat que les individus forment des croyances sur un conflit au travers de leurs expériences personnelles de victimisation, de leurs expériences de guerre lorsque celle-ci se déroule près d'eux, ainsi qu'au travers des récits relayés par les mass media. Quatre études testent l'hypothèse que les croyances des individus dépendent des niveaux et des types d'expériences de guerre auxquels ils ont été exposés, c'est-à-dire, des contextes informatifs et normatifs, micro et macro dans lesquels ils sont insérés. Ces études ont été réalisées dans le contexte des guerres qui, entre 1991 et 2001, ont suivi la dissolution de la Yougoslavie et durant lesquelles de nombreuses atrocités de guerre ont été commises, causant une victimisation massive de la population. Afin d'étudier le contenu et l'impact des expériences de guerre sur chaque niveau d'analyse, différentes stratégies méthodologiques ont été utilisées, des analyses quantitatives sur une enquête représentative d'opinion publique aux analyses qualitatives de contenu de médias et de discours politiques. L'étude 1 étudie l'impact des expériences de guerre individuelles et régionales sur l'acceptation et l'attribution de la culpabilité collective par les individus. Elle examine aussi l'impact du type de victimisation régionale : exposition à la violence symétrique (i.e., violence qui touche les membres de différents groupes ethniques, y compris les adversaires) et asymétrique. L'étude 2 se penche sur les circonstances structurelles et politiques qui augmentent l'attribution de culpabilité collective. Alors que les recherches précédentes ont mis l'accent sur le rôle de la victimisation passée, l'étude 2 teste l'hypothèse que la stratégie de démobilisation politique utilisée par les élites pour faire face à l'insatisfaction publique peut encourager l'attribution de la culpabilité à l'exogroupe. Les études 3 et 4 étudient, principalement dans le contexte croate, la construction rhétorique du récit de guerre politisé dominant (étude 3) et son entretien à travers la délégitimation publique des représentations alternatives (critiques] (étude 4). L'étude 4 examine aussi la probabilité qu'ont les membres de groupe fortement identifiés d'adhérer à des points de vue sur la guerre critiques et publiquement délégitimés.

Developmental critical period in gentic redox dysregulation: animal and human studies in schizophrenia

Converging evidence favors an abnormal susceptibility to oxidative stress in schizophrenia. Decreased levels of glutathione (GSH), the major cellular antioxidant and redox regulator, was observed in cerebrospinal-fluid and prefrontal cortex of patients. Importantly, abnormal GSH synthesis of genetic origin was observed: Two case-control studies showed an association with a GAG trinucleotide repeat (TNR) polymorphism in the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) catalytic subunit (GCLC) gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype 8/8 was three times more frequent in patients. The disease associated genotypes (35% of patients) correlated with decreased GCLC protein, GCL activity and GSH content. Similar GSH system anomalies were observed in early psychosis patients. Such redox dysregulation combined with environmental stressors at specific developmental stages could underlie structural and functional connectivity anomalies. In pharmacological and knock-out (KO) models, GSH deficit induces anomalies analogous to those reported in patients. (a) morphology: spine density and GABA-parvalbumine immunoreactivity (PV-I) were decreased in anterior cingulate cortex. KO mice showed delayed cortical PV-I at PD10. This effect is exacerbated in mice with increased DA from PD5-10. KO mice exhibit cortical impairment in myelin and perineuronal net known to modulate PV connectivity. (b) physiology: In cultured neurons, NMDA response are depressed by D2 activation. In hippocampus, NMDA-dependent synaptic plasticity is impaired and kainate induced g-oscillations are reduced in parallel to PV-I. (c) cognition: low GSH models show increased sensitivity to stress, hyperactivity, abnormal object recognition, olfactory integration and social behavior. In a clinical study, GSH precursor N-acetyl cysteine (NAC) as add on therapy, improves the negative symptoms and decreases the side effects of antipsychotics. In an auditory oddball paradigm, NAC improves the mismatched negativity, an evoked potential related to pre-attention and to NMDA receptors function. In summary, clinical and experimental evidence converge to demonstrate that a genetically induced dysregulation of GSH synthesis combined with environmental insults in early development represent a major risk factor contributing to the development of schizophrenia Conclusion Based on these data, we proposed a model for PSIP1 promoter activity involving a complex interplay between yet undefined regulatory elements to modulate gene expression.