Capacité en matière de prise de décisions chez des récidivistes de conduite avec capacités affaiblies par l’alcool

Thomas G. Brown, Ph.D., co-directeur de recherche

Nivel de escolaridad y consumo de alcohol etílico, cannabinoides y solventes en Colombia año 2014

Introducción: El consumo de sustancias psicoactivas como problema de salud pública, debe ser abordado desde diferentes perspectivas. En la literatura se evidencia factores involucrados como, edad de inicio de consumo, información de riesgo, círculo social y antecedentes personales. Igualmente se ha mostrado la asociación con el deterioro de las capacidades de aprendizaje y la farmacodependencia. En este estudio se determinó la asociación del consumo de inhalantes, cannabis y etanol y el nivel de escolaridad alcanzado. Metodología: Estudio observacional transversal, cross sectional, de los casos reportados al sistema único de indicadores de consumo de sustancias psicoactivas en Colombia en 2014. Muestra 6804 casos. Se realizó análisis univariado y bivariado con valores de p, para significancia estadística. Resultados y discusión: Se identificó comportamiento epidemiológico similar, en concordancia con otros estudios, evidenciándose población entre los 15 y 35 años de edad (76,7%), predominantemente hombres (83,9%) y consumo principal de cannabis (43,9%) y alcohol (23,1%). Se determina asociación estadísticamente significativa entre el consumo de inhalantes, etanol y marihuana y la finalización incompleta de estudios de secundaria (p<0,005), el cannabis con asocio a culminación incompleta de estudios universitarios (p<0,005). Hay plausibilidad biológica y epidemiológica con los hallazgos del estudio y otros trabajos desarrollados con anterioridad.

Thermodynamic analysis of the cogeneration system expansion in a sugar-alcohol factory

In this work it was performed energetic and exergetic analyses of three thermal plants to assessment a cogeneration system in expansion of a sugar-alcohol factory. The initial configuration considered is constituted by a low pressure steam generator, single stage steam turbines for electricity generation and crusher, shredder and mills with mechanical driving. In the intermediary configuration, the low pressure steam generator was substituted by another which generates steam at higher pressure and higher temperature, the steam turbines for electricity generation were substituted by a multiple stages extraction-condensation turbine and the other steam turbines were maintained. The final configuration consists in the substitution of these last turbines by electrical motors. Thermodynamic analyses were performed to evaluate the equipment and the overall plants efficiencies to permit a comparison among the plants. Besides of this, some important parameters of the sugar-alcohol factories were calculated.

The association between low alcohol use and traffic risk behaviors among Brazilian college students

Although there are a large number of studies focused on binge drinking and traffic risk behaviors (TRB), little is known regarding low levels of alcohol consumption and its association to TRB. The aim of this cross-sectional study is to examine the association of low to moderate alcohol intake pattern and TRB in college students in Brazil. 7037 students from a National representative sample were selected under rigorous inclusion criteria. All study participants voluntarily fulfilled a structured, anonymous, and self-questionnaire regarding alcohol and drug use, social-demographic data, and TRB. Alcohol was assessed according to the average number of alcoholic units consumed on standard occasions over the past 12 months. The associations between alcohol intake and TRB were summarized with odds ratio and their confidence interval obtained from logistic regression. Compared with abstainers students who consumed only one alcohol unit had the risk of being a passenger in a car driven by a drunk driver increased by almost four times, students who reported using five or more units were increased by almost five times the risk of being involved in a car crash. Compared with students who consumed one alcohol unit, the risk of driving under the influence of alcohol increased four times in students using three alcohol units. Age group, use of illicit drugs, employment status, gender, and marital status significantly influenced occurrence of TRB among college students. Our study highlights the potential detrimental effects of low and moderate pattern of alcohol consumption and its relation to riding with an intoxicated driver and other TRB. These data suggest that targeted interventions should be implemented in order to prevent negative consequences due to alcohol use in this population. (C) 2012 Elsevier Inc. All rights reserved,

SET overexpression decreases cell detoxification efficiency: ALDH2 and GSTP1 are downregulated, DDR is impaired and DNA damage accumulates

Alcohol and tobacco consumption are risk factors for head and neck squamous cell carcinoma (HNSCC). Aldehyde dehydrogenase 2 (ALDH2) and glutathione Stransferase pi 1 (GSTP1) are important enzymes for cellular detoxification and low efficiencies are implicated in cancer. We assessed the potential role of SET protein overexpression, a histone acetylation modulator accumulated in HNSCC, in gene regulation and protein activity of ALDH2 and GSTP1. SET was knocked down in HN13, HN12 and Cal27, and overexpressed in HEK293 cells; ethanol and cisplatin were the chemical agents. Cells with SET overexpression (HEK293/SET, HN13 and HN12) showed lower ALDH2 and GSTP1 mRNA levels and trichostatin A increased them (real-time PCR). Ethanol upregulated GSTP1 and ALDH2 mRNAs, whereas cisplatin upregulated GSTP1 in HEK293 cells. SET-chromatin binding revealed SET interaction with ALDH2 and GSTP1 promoters, specifically via SET NAP domain; ethanol and cisplatin abolished SET binding. ALDH2 and GSTP1 efficiency was assessed by enzymatic and comet assay. A lower ALDH2 activity was associated with greater DNA damage (tail intensity) in HEK293/SET compared with HEK293 cells, whereas HN13/siSET showed ALDH2 activity higher than HN13 cells. HN13/siSET cells showed increased tail intensity. Cisplatin-induced DNA damage response showed negative relationship between SET overexpression and BRCA2 recruitment. SET downregulated repair genes ATM, BRCA1 and CHEK2 and upregulated TP53. Cisplatin-induced cell-cycle arrest occurred in G0/G1 and S in HEK293 cells, whereas HEK293/SET showed G2/M stalling. Overall, cisplatin was more cytotoxic for HN13 than HN13/siSET cells. Our data suggest a role for SET in cellular detoxification, DNA damage response and genome integrity.

Mechanism of resistance to tyrosine kinase inhibitors in philadelphia-positive acute lymphblastic leukaemia (all): from genetic alterations to impaired RNA editing

The Ph chromosome is the most frequent cytogenetic aberration associated with adult ALL and it represents the single most significant adverse prognostic marker. Despite imatinib has led to significant improvements in the treatment of patients with Ph+ ALL, in the majority of cases resistance developed quickly and disease progressed. Some mechanisms of resistance have been widely described but the full knowledge of contributing factors, driving both the disease and resistance, remains to be defined. The observation of rapid development of lymphoblastic leukemia in mice expressing altered Ikaros (Ik) isoforms represented the background of this study. Ikaros is a zinc finger transcription factor required for normal hemopoietic differentiation and proliferation, particularly in the lymphoid lineages. By means of alternative splicing, Ikaros encodes several proteins that differ in their abilities to bind to a consensus DNA-binding site. Shorter, DNA nonbinding isoforms exert a dominant negative effect, inhibiting the ability of longer heterodimer partners to bind DNA. The differential expression pattern of Ik isoforms in Ph+ ALL patients was analyzed in order to determine if molecular abnormalities involving the Ik gene could associate with resistance to imatinib and dasatinib. Bone marrow and peripheral blood samples from 46 adult patients (median age 55 yrs, 18-76) with Ph+ ALL at diagnosis and during treatment with imatinib (16 pts) or dasatinib (30 pts) were collected. We set up a fast, high-throughput method based on capillary electrophoresis technology to detect and quantify splice variants. 41% Ph+ ALL patients expressed high levels of the non DNA-binding dominant negative Ik6 isoform lacking critical N-terminal zinc-fingers which display abnormal subcellular compartmentalization pattern. Nuclear extracts from patients expressed Ik6 failed to bind DNA in mobility shift assay using a DNA probe containing an Ikaros-specific DNA binding sequence. In 59% Ph+ ALL patients there was the coexistence in the same PCR sample and at the same time of many splice variants corresponded to Ik1, Ik2, Ik4, Ik4A, Ik5A, Ik6, Ik6 and Ik8 isoforms. In these patients aberrant full-length Ikaros isoforms in Ph+ ALL characterized by a 60-bp insertion immediately downstream of exon 3 and a recurring 30-bp in-frame deletion at the end of exon 7 involving most frequently the Ik2, Ik4 isoforms were also identified. Both the insertion and deletion were due to the selection of alternative splice donor and acceptor sites. The molecular monitoring of minimal residual disease showed for the first time in vivo that the Ik6 expression strongly correlated with the BCR-ABL transcript levels suggesting that this alteration could depend on the Bcr-Abl activity. Patient-derived leukaemia cells expressed dominant-negative Ik6 at diagnosis and at the time of relapse, but never during remission. In order to mechanistically demonstrated whether in vitro the overexpression of Ik6 impairs the response to tyrosine kinase inhibitors (TKIs) and contributes to resistance, an imatinib-sensitive Ik6-negative Ph+ ALL cell line (SUP-B15) was transfected with the complete Ik6 DNA coding sequence. The expression of Ik6 strongly increased proliferation and inhibited apoptosis in TKI sensitive cells establishing a previously unknown link between specific molecular defects that involve the Ikaros gene and the resistance to TKIs in Ph+ ALL patients. Amplification and genomic sequence analysis of the exon splice junction regions showed the presence of 2 single nucleotide polymorphisms (SNPs): rs10251980 [A/G] in the exon2/3 splice junction and of rs10262731 [A/G] in the exon 7/8 splice junction in 50% and 36% of patients, respectively. A variant of the rs11329346 [-/C], in 16% of patients was also found. Other two different single nucleotide substitutions not recognized as SNP were observed. Some mutations were predicted by computational analyses (RESCUE approach) to alter cis-splicing elements. In conclusion, these findings demonstrated that the post-transcriptional regulation of alternative splicing of Ikaros gene is defective in the majority of Ph+ ALL patients treated with TKIs. The overexpression of Ik6 blocking B-cell differentiation could contribute to resistance opening a time frame, during which leukaemia cells acquire secondary transforming events that confer definitive resistance to imatinib and dasatinib.

Cognition and driving in older persons

In Switzerland, approximately 350,000 people aged 70 years or older own a valid driving license. By law, these drivers are medically assessed every other year, most commonly by their general practitioner, to exclude that a medical condition is interfering with their driving skills. A prerequisite for driving is the integration of high-level cognitive functions with perception and motor function. Ageing, per se, does not necessarily impair driving or increase the crash risk. However, medical conditions, such as cognitive impairment and dementia, become more prevalent with advancing age and may contribute to poor driving and an increased crash risk. The extent to which driving skills are impaired depends on the cause of dementia, disease severity, other co-morbidities and individual compensation strategies. Dementia often remains undiagnosed and therefore general practitioners (GPs) can find themselves in the difficult situation to disclose a suspicion about cognitive impairment and queries about medical fitness to drive, at the same time. In addition, the literature suggests that cognitive screening tests, most commonly used by GPs, have a limited role in judging whether an older person remains fit to drive. Further specialist assessment, for example in a memory clinic or on the road testing (ORT), may be helpful when the diagnosis or its implication for driving remain unclear. Here, we review the literature about cognition and driving, for GPs who advise older drivers who wish to continue driving.

[Driving ability and daytime sleepiness]

Daytime sleepiness is a complaint of about 5-10% in a normal population. The consequences, such as impaired performance and accidents at the workplace and while driving, have major impact on the affected and on society. According to Swiss federal statistics only 1-3% of all motor vehicle accidents are due to excessive daytime sleepiness, which is in great contrast to a figure of 10 to 20% of all accidents derived from scientific studies. Due to the inadequate statistical representation of the problem, insufficient countermeasures have been realized, and the state of drivers breaching traffic regulations is not adequately investigated in this respect. The most prevalent cause of microsleep induced accidents is certainly lack of sleep due to social or professional reasons. A treating physician must also consider sedating drugs and various diseases. The typical characteristics of accidents due to falling asleep at the wheel and the risk factors involved are well established, so that informing the general public, taking prophylactic countermeasures and a targeted investigation in this respect of drivers who have breached the law are all feasible. Since symptoms of sleepiness can be recognized well before any impairment of performance occurs, the most important countermeasure is information of the drivers on the risk factors and on efficient countermeasures against sleepiness at the wheel. Besides correct diagnosis and treatment, the primary goal of physicians treating patients with pathological daytime sleepiness is to inform them at an early stage about the risks of sleepiness and the large responsibility they bear while driving. This information should be written down in the patients' records. Professional drivers suffering from daytime sleepiness, drivers who have already had an accident due to microsleep and unreasonable drivers should be referred to a centre of sleep disorders for objective measurements of sleepiness.

[Consensus recommendations for the assessment of fitness to drive in cognitively impaired patients]

Memory Clinics provide evidence based diagnosis and treatment of dementia. Whenever a diagnosis of dementia is made, it is important to inform the patients about the possible impact of dementia on driving. Patients and their next of kin require competent advice whenever this difficult question is addressed and the mobility desire and the risks related to driving need to be carefully weight up. The time of diagnosis does not necessarily equate to the time when a person with dementia becomes an unsafe driver. The cause and severity of dementia, comorbidities and the current medication need to be carefully taken into account for this decision. On behalf of the association of the Swiss Memory Clinics, a group of experts has developed recommendations to assess fitness to drive in cognitively impaired older adults.

Vision and night driving abilities of elderly drivers

OBJECTIVE: In this article, we review the impact of vision on older people's night driving abilities. Driving is the preferred and primary mode of transport for older people. It is a complex activity where intact vision is seminal for road safety. Night driving requires mesopic rather than scotopic vision, because there is always some light available when driving at night. Scotopic refers to night vision, photopic refers to vision under well-lit conditions, and mesopic vision is a combination of photopic and scotopic vision in low but not quite dark lighting situations. With increasing age, mesopic vision decreases and glare sensitivity increases, even in the absence of ocular diseases. Because of the increasing number of elderly drivers, more drivers are affected by night vision difficulties. Vision tests, which accurately predict night driving ability, are therefore of great interest. METHODS: We reviewed existing literature on age-related influences on vision and vision tests that correlate or predict night driving ability. RESULTS: We identified several studies that investigated the relationship between vision tests and night driving. These studies found correlations between impaired mesopic vision or increased glare sensitivity and impaired night driving, but no correlation was found among other tests; for example, useful field of view or visual field. The correlation between photopic visual acuity, the most commonly used test when assessing elderly drivers, and night driving ability has not yet been fully clarified. CONCLUSIONS: Photopic visual acuity alone is not a good predictor of night driving ability. Mesopic visual acuity and glare sensitivity seem relevant for night driving. Due to the small number of studies evaluating predictors for night driving ability, further research is needed.

Antibodies trap tissue migrating helminth larvae and prevent tissue damage by driving IL-4Rα-independent alternative differentiation of macrophages

Approximately one-third of the world's population suffers from chronic helminth infections with no effective vaccines currently available. Antibodies and alternatively activated macrophages (AAM) form crucial components of protective immunity against challenge infections with intestinal helminths. However, the mechanisms by which antibodies target these large multi-cellular parasites remain obscure. Alternative activation of macrophages during helminth infection has been linked to signaling through the IL-4 receptor alpha chain (IL-4Rα), but the potential effects of antibodies on macrophage differentiation have not been explored. We demonstrate that helminth-specific antibodies induce the rapid trapping of tissue migrating helminth larvae and prevent tissue necrosis following challenge infection with the natural murine parasite Heligmosomoides polygyrus bakeri (Hp). Mice lacking antibodies (JH (-/-)) or activating Fc receptors (FcRγ(-/-)) harbored highly motile larvae, developed extensive tissue damage and accumulated less Arginase-1 expressing macrophages around the larvae. Moreover, Hp-specific antibodies induced FcRγ- and complement-dependent adherence of macrophages to larvae in vitro, resulting in complete larval immobilization. Antibodies together with helminth larvae reprogrammed macrophages to express wound-healing associated genes, including Arginase-1, and the Arginase-1 product L-ornithine directly impaired larval motility. Antibody-induced expression of Arginase-1 in vitro and in vivo occurred independently of IL-4Rα signaling. In summary, we present a novel IL-4Rα-independent mechanism of alternative macrophage activation that is antibody-dependent and which both mediates anti-helminth immunity and prevents tissue disruption caused by migrating larvae.

Direct metabolites of Ethanol as biological markers of alcohol use: Basic aspects and applications

In addition to self reports and questionnaires, biomarkers are of relevance in the diagnosis of and therapy for alcohol use disorders. Traditional biomarkers such as gamma-glutamyl transpeptidase or mean corpuscular volume are indirect biomarkers and are subject to the influence of age, gender and non-alcohol related diseases, among others. Direct metabolites of ethanol such as Ethyl glucuronide (EtG), ethyl sulphate (EtS) and phosphatidylethanol (PEth) are direct metabolites of ethanol, that are positive after intake of ethyl alcohol. They represent useful diagnostic tools for identifying alcohol use even more accurately than traditional biomarkers. Each of these drinking indicators remains positive in serum and urine for a characteristic time spectrum after the cessation of ethanol intake - EtG and EtS in urine up to 7 days, EtG in hair for months after ethanol has left the body. Applications include clinical routine use, emergency room settings, proof of abstinence in alcohol rehabilitation programmes, driving under influence offenders, workplace testing, assessment of alcohol intake in the context of liver transplantation and foetal alcohol syndrome. Due to their properties, they open up new perspectives for prevention, interdisciplinary cooperation, diagnosis of and therapy for alcohol-related problems.

What Ethanol metabolites as biological markers tell us about alcohol use

Alcohol and tobacco related disorders are the two leading and most expensive causes of illness in central Europe. In addition to self reports and questionnaires, biomarkers are of relevance in diagnosis and therapy of alcohol use disorders.Traditional biomarkers such as gamma glutamyl transpeptidase or mean corpuscualr volume are indirect biomarkers and are subject to influence of age, gender and non alcohol related diseases, among others.Direct ethanol metabolites such as ethyl glucuronide (EtG), ethyl sulphate (EtS) and phosphatidylethanol (PEth) are direct metabolites of ethanol, that are positive after intake of ethyl alcohol. They represent useful diagnostic tools for identifying alcohol use even more accurately than traditional biomarkers. Each of these drinking indicators remains positive in serum and urine for a characteristic time spectrum after the cessation of ethanol intake-EtG and EtS in urine up to 7 days, EtG in hair for months after ethanol has left the body. Applications include clinical routine use, emergency room settings, proof of abstinence in alcohol rehabilitation programs, driving under influence offenders, workplace testing, assessment of alcohol intake in the context of liver transplantation and fetal alcohol syndrome.

A novel computer test to assess driving-relevant cognitive functions - a pilot study

BACKGROUND: The assessment of driving-relevant cognitive functions in older drivers is a difficult challenge as there is no clear-cut dividing line between normal cognition and impaired cognition and not all cognitive functions are equally important for driving. METHODS: To support decision makers, the Bern Cognitive Screening Test (BCST) for older drivers was designed. It is a computer-assisted test battery assessing visuo-spatial attention, executive functions, eye-hand coordination, distance judgment, and speed regulation. Here we compare the performance in BCST with the performance in paper and pencil cognitive screening tests and the performance in the driving simulator testing of 41 safe drivers (without crash history) and 14 unsafe drivers (with crash history). RESULTS: Safe drivers performed better than unsafe drivers in BCST (Mann-Whitney U test: U = 125.5; p = 0.001) and in the driving simulator (Student's t-test: t(44) = -2.64, p = 0.006). No clear group differences were found in paper and pencil screening tests (p > 0.05; ns). BCST was best at identifying older unsafe drivers (sensitivity 86%; specificity 61%) and was also better tolerated than the driving simulator test with fewer dropouts. CONCLUSIONS: BCST is more accurate than paper and pencil screening tests, and better tolerated than driving simulator testing when assessing driving-relevant cognition in older drivers.