Localized in vivo hyperpolarization transfer sequences.

In vivo localized and fully adiabatic homonuclear and heteronuclear polarization transfer experiments were designed and performed in the rat brain at 9.4 T after infusion of hyperpolarized sodium [1,2-(13)C(2)] and sodium [1-(13)C] acetate. The method presented herein leads to highly enhanced in vivo detection of short-T(1) (13)C as well as attached protons. This indirect detection scheme allows for probing additional molecular sites in hyperpolarized substrates and their metabolites and can thus lead to improved spectral resolution such as in the case of (13)C-acetate metabolism.

Defining substance use disorders: do we really need more than heavy use?

AIMS: The aim of the study was to explore whether the concept of heavy substance use over time can be used as definition of substance use disorder. METHODS: Narrative review. RESULTS: Heavy use over time clearly underlies the neurobiological changes associated with current thinking of substance use disorders. In addition, there is evidence that heavy use over time can explain the majority of social problems and of burden of disease (morbidity and mortality). A definition of substance use disorders via heavy use over time would avoid some of the problems of current conceptualizations, for instance the cultural specificity of concepts such as loss of control. Finally, stressing the continuum of use may avoid the high level of stigmatization currently associated with substance use disorders. CONCLUSION: 'Heavy substance use over time' seems to be a definition of substance use disorders in line with results of basic research and epidemiology. Additionally, it reduces stigmatization. This approach should thus be further explored.

Low prevalence of Chlamydia trachomatis infection in asymptomatic young Swiss men

BACKGROUND: Prevalence and risk factors for Chlamydia trachomatis infection among young men in Switzerland is still unknown. The objective of the present study was to assess prevalence and risk factors for C. trachomatis infection in young Swiss men. METHODS: 517 young Swiss men were enrolled in this cross-sectional study during their compulsory military recruitment. Participants completed a questionnaire and gave urine samples which were screened for C. trachomatis DNA by PCR. Genotyping of positive samples was done by amplification and sequencing the ompA gene. RESULTS: The prevalence of chlamydial infection among young Swiss male was 1.2% (95% confidence interval [95%CI], 0.4-2.5%). C. trachomatis infection was only identified among the 306 men having multiple sexual partner. Although frequent, neither unprotected sex (absence of condom use), nor alcohol and drug abuse were associated with chlamydial infection. Men living in cities were more frequently infected (2.9%, 95%CI 0.8-7.4%) than men living in rural areas (0.5%, 95%CI 0.1-1.9%, p = 0.046). Moreover, naturalised Swiss citizens were more often positive (4.9%, 95%CI 1.3-12.5%) than native-born Swiss men (0.5%, 95%CI 0.1-1.7%, p = 0.003). CONCLUSION: In comparison with other countries, the prevalence of chlamydial infection in men is extremely low in Switzerland, despite a significant prevalence of risky sexual behaviour. C. trachomatis infection was especially prevalent in men with multiple sexual partners. Further research is required (i) to define which subgroup of the general population should be routinely screened, and (ii) to test whether such a targeted screening strategy will be effective to reduce the prevalence of chlamydial infection among this population.

Impact d'une alcoolisation précoce sur le rat juvénile et conséquences sur la consommation d'alcool à l'âge adulte.

Contexte : l'adolescence est une période de transition au cours de laquelle l'enfant développe les capacités physiques et cognitives qui lui permettent de s'intégrer au monde adulte et qui se caractérise notamment par une prise de risque, une grande impulsivité et une constante recherche de sensations. Bien que des déterminants sociaux et familiaux entrent en jeu dans ce domaine, il y a également une composante neurobiologique importante. Les avancées techniques dans le domaine de l'imagerie ont permis de mettre en évidence plusieurs changements structurels à l'adolescence tels qu'un remodelage de la matière grise avec une perte de synapses plus ou moins importante selon la région observée et une augmentation de la myélinisation. En outre, le développement cérébral n'est pas uniforme dans le temps. En effet, la maturation du cortex préfrontal est ultérieure au développement du système limbique. Cet asynchronisme pourrait expliquer l'impulsivité des adolescents (consécutive à l'immaturité du cortex préfrontal) et leur comportement de recherche de sensation et/ou de prise de risque (consécutif au développement précoce du noyau accumbens notamment). Ces régions font également partie intégrante du système de récompense et modulent la motivation pour des récompenses naturelles et non-­‐naturelles, comme l'alcool et d'autres drogues. L'émergence d'une consommation d'alcool excessive est justement préoccupante chez les adolescents. En 2007, l'étude ESPAD (The European School Survey Project On Alcohol and Other Drugs) menée auprès de jeunes de 15 à 16 ans relève que 41% des jeunes questionnées ont régulièrement bu jusqu'à l'ivresse dans les 12 mois précédant l'entretien. Les conséquences neuropsychologiques à long terme de ce comportement de « binge-­‐drinking » commencent à alarmer le corps médical, mais l'interrogation demeure sur les risques de ce type de comportement vis-­‐à-­‐vis du développement d'un alcoolisme chronique à l'âge adulte. Objectifs du travail : en s'appuyant sur une revue de la littérature, ce travail a pour objectif d'expliquer les comportements qui émergent à l'adolescence à la lumière des modifications neurobiologiques qui s'opèrent durant cette période critique. Au niveau expérimental, nous proposons d'évaluer la propension de rats juvéniles exposés précocement à de l'alcool à développer un comportement d'abus de consommation d'alcool à l'âge adulte en comparaison avec un groupe contrôle. Dans un deuxième temps nous souhaitons déterminer la propension des rats exposés précocement à de l'alcool à montrer une préférence pour l'alcool par rapport à la saccharine, puis par rapport à de l'eau en comparaison au groupe contrôle. Méthode : nous comparons deux groupes de rongeurs adolescents (âgés de 32 jours à 67 jours). Le groupe test (groupe E, n=8), qui est exposé par un accès ad libitum à une solution d'éthanol 10 % contenant de la saccharine 0.2%, ceci afin de limiter l'aspect gustatif aversif de l'éthanol. Et le groupe témoin (groupe S, n=8), qui est exposé par un accès ad libitum à une solution de saccharine 0.2%. Ce conditionnement se fait sur 13 semaines. Une fois atteinte l'âge adulte, les animaux sont ensuite entraînés à appuyer sur un levier afin de recevoir de l'éthanol (0,1 ml d'une solution à 10%). Nous nous proposons d'évaluer la quantité d'alcool ainsi consommée, puis la motivation des animaux pour obtenir de l'éthanol et enfin leur capacité de résistance à un choc électrique non douloureux mais aversif, lorsque celui-­‐ci est associé à l'éthanol. Enfin, nous évaluerons, via un paradigme de choix à deux leviers, la propension des animaux à choisir de consommer volontairement de l'éthanol quand ils ont le choix entre de l'éthanol 10% et une solution de saccharine à différentes concentrations, puis entre de l'éthanol 10% et de l'eau. Résultats : la phase de tests de comportements à risque d'abus ne permet pas de mettre en évidence une différence significative entre les deux groupes. La phase de test de choix montre une diminution significative du pourcentage d'appuis sur le levier associé à la saccharine avec la diminution de la concentration de saccharine pour les deux groupes. Le groupe S a un pourcentage d'appuis sur le levier associé à l'éthanol significativement plus important que les rats du groupe E et a tendance à préférer l'éthanol pour une concentration de saccharine plus grande que le groupe E. Le groupe S montre également une préférence significative pour l'éthanol quand il n'a plus que le choix avec l'eau alors que le groupe E ne montre pas de préférence. Conclusions : chez des rats élevés dans les mêmes conditons, la consommation précoce d'éthanol n'est pas un facteur de risque de comportements d'abus de consommation d'alcool à l'âge adulte. Cependant un phénomène dit de « sensiblisation croisée » entre le goût sucrée et l'éthanol a été soulevé au cours de cette étude permettant de se questionner sur l'impact d'une consommation intermittente de substances au goût sucré à l'adolescence sur la consommation d'alcool à l'âge adulte.

Methamphetamine Abuse in Iowa, January 19, 2007

This second, and final, report is respectfully submitted to fully satisfy the following Senate File 169 requirement, as approved by the 2005 Iowa Legislature: “The Drug Policy Coordinator shall report, in a joint meeting, to the Committee on Judiciary of the Senate and the Committee on Public Safety of the House of Representatives in January 2006 and in January 2007, the effects of this Act on methamphetamine abuse and related criminal activity.” (*Please note that impact data contained in this document have been updated since the initial 2006 report, and are based on the most recent information available to the Governor’s Office of Drug Control Policy.)

Guidelines for Cleaning up Former Methamphetamine Labs, June 2009

Methamphetamine (meth) drug labs are not a new hazard to Iowa. In 2004, federal, state and local authorities seized more than 1,400 Iowa labs. These labs are discovered in houses, apartments, motel rooms, motor vehicles, and even an occasional combine. A dramatic decrease in the number of meth labs occurred in 2005 when a law restricting the purchase of pseudoephedrine was implemented. Although the number of meth labs has decreased, they continue to exist. Since there is currently no official federal guidance or regulations on how to clean up a former meth lab, the Iowa Department of Public Health, Division of Environmental Health, has created these basic guidelines to assist public health officials, property owners and the general public in cleaning up former meth lab properties.

Feasibility of in vivo 15N MRS detection of hyperpolarized 15N labeled choline in rats.

The increase of total choline in tumors has become an important biomarker in cancer diagnosis. Choline and choline metabolites can be measured in vivo and in vitro using multinuclear MRS. Recent in vivo(13)C MRS studies using labeled substrates enhanced via dynamic nuclear polarization demonstrated the tremendous potential of hyperpolarization for real-time metabolic studies. The present study demonstrates the feasibility of detecting hyperpolarized (15)N labeled choline in vivo in a rat head at 9.4 T. We furthermore report the in vitro (172 +/- 16 s) and in vivo (126 +/- 15 s) longitudinal relaxation times. We conclude that with appropriate infusion protocols it is feasible to detect hyperpolarized (15)N labeled choline in live animals.

Talking to kids about prescription drug abuse, 2010

As a parent you’re concerned about your children’s health and well-being. You teach them about crossing the street safely and about personal safety. You talk with them about the risks of using tobacco, alcohol and other illegal drugs. But did you know that one of the fastest growing threats to youth today is the abuse of prescription and over-the-counter (OTC) drugs? Did you know that nearly one in five teens (19 percent or 4.5 million) nationally report intentionally abusing prescription drugs to get high, and one in ten reports abusing cough medicine to get high.

Multicopy suppression of a gacA mutation by the infC operon in Pseudomonas fluorescens CHA0: competition with the global translational regulator RsmA.

The gacA gene of the biocontrol strain Pseudomonas fluorescens CHA0 codes for a response regulator which, together with the sensor kinase GacS (=LemA), is required for the production of exoenzymes and secondary metabolites involved in biocontrol, including hydrogen cyanide (HCN). A gacA multicopy suppressor was isolated from a cosmid library of strain CHA0 and identified as the infC-rpmI-rplT operon, which encodes the translation initiation factor IF3 and the ribosomal proteins L35 and L20. The efficiency of suppression was about 30%, as determined by the use of a GacA-controlled reporter construct, i.e. a translational hcnA'-'lacZ fusion. Overexpression of the rsmA gene (coding for a global translational repressor) reversed the suppressive effect of the amplified infC operon. This finding suggests that some product(s) of the infC operon can compete with RsmA at the level of translation in P. fluorescens CHA0 and that important biocontrol traits can be regulated at this level.

TRANSCRIPTION FACTORS INVOLVED IN PLANT DEFENCE AGAINST INSECT HERBIVORES IN ARABIDOPSIS THALIANA

Afin de pouvoir se défendre contre les insectes nuisibles, les plantes ont développé plusieurs stratégies leur permettant de maximiser leurs chances de survie et de reproduction. Parmi elles, les plantes sont souvent pourvues de barrières physiques telles que les poils urticants, les épines et la cuticule. En plus, les plantes sont capables de produire des protéines anti-digestives et des métabolites secondaires insecticides tels que la nicotine, les tannins ou les glucosinolates (GS). La mise en place de ces barrières physiques et chimiques comporte un coût énergétique au détriment de la croissance et de la reproduction. Par conséquent, en absence d'insectes, la plante investit la majeure partie de son énergie dans le développement et la croissance. A l'inverse, une blessure causée par un insecte provoquera une croissance ralentie, une augmentation de la densité de poils urticants ainsi que la synthèse de défenses chimiques. Au niveau moléculaire, cette défense inductible est régulée par l'hormone végétale acide jamsonique (AJ). En réponse à l'attaque d'un insecte, la plante produit cette hormone en grande quantité, ce qui se traduira par une forte expression de gènes de défense. Pendant ma thèse, j'ai essayé de découvrir quels étaient les facteurs de transcription (FT) responsables de l'expression des gènes de défense dans Arabidopsis thaliana. J'ai ainsi pu démontrer que des plantes mutées dans les FTs comme MYC2, MYC3, MYC4, ZAT10, ZAT12, AZF2, WRKY18, WRKY40, WRKY6, ANAC019, ANAC55, ERF13 et RRTF1 deviennent plus sensibles aux insects de l'espèce Spodoptera littoralis. Par la suite, j'ai également pu montrer que MYC2, MYC3 et MYC4 sont probablement la cible principale de la voie de signalisation du AJ et qu'ils sont nécessaires pour l'expression de la majorité des gènes de défense dont la plupart sont essentiels à la biosynthèse des GS. Une plante mutée simultanément dans ces trois protéines est par conséquent incapable de synthétiser des GS et devient hypersensible aux insectes. J'ai également pu démontrer que les GS sont uniquement efficaces contre les insectes généralistes tels S. littoralis et Heliothis virescens alors que les insectes spécialisés sur les Brassicaceae comme Pieris brassicae et Plutella xylostella se sont adaptés en développant des mécanismes de détoxification. - In response to herbivore insects, plants have evolved several defence strategies to maximize their survival and reproduction. For example, plants are often endowed with trichomes, spines and a thick cuticule. In addition, plants can produce anti-digestive proteins and toxic secondary metabolites like nicotine, tannins and glucosinolates (GS). These physical and chemical barriers have an energetic cost to the detriment of growth and reproduction. As a consequence, in absence of insects, plants allocate their energy to development and growth. On the contrary, an attack by herbivore insects will affect plant growth, increase trichome density and induce the production of anti-digestive proteins and secondary metabolites. At the molecular level, this inducible defence is regulated by the phytohormone jasmonic acid (JA). Thus, an attack by herbivores will be followed by a burst of JA that will induce the expression of defence genes. The aim of my thesis was to characterize which transcription factors (TF) regulate the expression of these defence genes in Arabidopsis thaliana. I could show that plants mutated in various TFs like MYC2, MYC3, MYC4, ZAT10, ZAT12, AZF2, WRKY18, WRKY40, WRKY6, ANAC019, ANAC55, ERF 13 and RRTFl were more susceptible to the herbivore Spodoptera littoralis. Furthermore, I could demonstrate that MYC2, MYC3 and MYC4 are probably the main target of the JA-signalling pathway and that they are necessary for the insect-mediated induction of most defence genes including genes involved in the biosynthesis of GS. A triple mutant myc2myc3myc4 is depleted of GS and consequently hypersensitive to insects. Moreover, I showed that GS are only efficient against generalist herbivores like S. littoralis and Heliothis virescens whereas specialized insects like Pieris brassicae and Plutella xylostella have evolved detoxification mechanisms against GS.

Routine therapeutic drug monitoring in patients treated with 10-360 mg/day citalopram

From data collected during routine TDM, plasma concentrations of citalopram (CIT) and its metabolites demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) were measured in 345 plasma samples collected in steady-state conditions. They were from 258 patients treated with usual doses (20-60 mg/d) and from patients medicated with 80-360 mg/d CIT. Most patients had one or several comedications, including other antidepressants, antipsychotics, lithium, anticonvulsants, psychostimulants and somatic medications. Dose-corrected CIT plasma concentrations (C/D ratio) were 2.51 +/- 2.25 ng mL-1 mg-1 (n = 258; mean +/- SD). Patients >65 years had significantly higher dose-corrected CIT plasma concentrations (n = 56; 3.08 +/- 1.35 ng mL-1 mg-1) than younger patients (n = 195; 2.35 +/- 2.46 ng mL-1 mg-1) (P = 0.03). CIT plasma concentrations in the generally recommended dose range were [mean +/- SD, (median)]: 57 +/- 64 (45) ng/mL (10-20 mg/d; n = 64), 117 +/- 95 (91) ng/mL (21-60 mg/d; n = 96). At higher than usual doses, the following concentrations of CIT were measured: 61-120 mg/d CIT, 211 +/- 103 (190) ng/mL (n = 93); 121-200 mg/d: 339 +/- 143 (322) ng/mL (n = 70); 201-280 mg/d: 700 +/- 408 (565) ng/mL (n = 18); 281-360 mg/d: 888 +/- 620 (616) ng/mL (n = 4). When only one sample per patient (at the highest daily dose if repeated dosages) is considered, there is a linear and significant correlation (n = 48, r = 0.730; P < 0.001) between daily dose (10-200 mg/d) and CIT plasma concentrations. In experiments with dogs, DDCIT was reported to affect the QT interval when present at concentrations >300 ng/mL. In this study, DDCIT concentration reached 100 ng/mL in a patient treated with 280 mg/d CIT. Twelve other patients treated with 140-320 mg/d CIT had plasma concentrations of DDCIT within the range 52-73 ng/mL. In a subgroup comprised of patients treated with > or =160 mg/d CIT and with CIT plasma concentrations < or =300 ng/mL, and patients treated with < or =200 mg/d CIT and CIT plasma concentrations > or = 600 ng/mL, the enantiomers of CIT and DCIT were also analyzed. The highest S-CIT concentration measured in this subgroup was 327 ng/mL in a patient treated with 140 mg/d CIT, but the highest S-CIT concentration (632 ng/mL) was measured in patient treated with 360 mg/d CIT. In conclusion, there is a highly linear correlation between CIT plasma concentrations and CIT doses, well above the usual dose range.

Exposition aux immunosuppresseurs in utero [Exposure in utero to immunosuppressives]

The number of pregnant women receiving immunosuppressive therapy is increasing. Use of immunosuppressants during pregnancy is indicated for anti-rejection therapy in transplantation patients and treatment of autoimmune diseases. Despite the maternal and fetal risks of these pregnancies, the proportion of surviving infants is improving and the possibility that a pregnancy could occur in these women during their childbearing years should be considered. All immunosuppressant drugs and their metabolites cross the placenta, raising questions about the long-term outcome of the children exposed to these agents in utera. There is no increased risk of congenital anomalies. However, there is an elevated incidence of prematurity, intrauterine growth retardation (IUGR) and therefore low birthweight, as well as maternal hypertension and preeclampsia. The most frequent neonatal complications are those associated with prematurity and IUGR, as well as adrenal insufficiency with corticosteroids, immunological disturbances with azathioprine and cyclosporin, and hyperkalemia with tacrolimus. The long-term follow-up of infants exposed to immunosuppressants in utero is still limited and experimental studies raise the question whether there could be an increased incidence at adult age of some pathologies including renal insufficiency, hypertension and diabetes. The follow-up of these infants should be carefully organized and multidisciplinary, taking the perinatal context into account.

Drug metabolism for the perplexed medicinal chemist.

Two related and significant issues may elicit perplexity in medicinal chemists and are discussed here. First, a broad presentation of the pharmacological and toxicological consequences of drug metabolism should justify the significance of drug metabolism and serve as an incentive to further study. When comparing the pharmacological activities of a drug and its metabolite(s), a continuum is found which ranges from soft drugs (no active metabolites) to prodrugs (inactive per se, as illustrated here with clopidogrel and prasugrel). Innumerable intermediate cases document drugs whose activity is shared by one or more metabolites, as exemplified with tamoxifen. The toxicological consequences of metabolism at the molecular, macromolecular, and macroscopic levels are manyfold. A brief overview is offered together with a summary of the reactions of toxification and detoxification of the antiepileptic valproic acid. The second issue discussed in the review is a comparison of the relative significance of cytochromes P450 and other oxidoreductases (EC 1), hydrolases (EC 3), and transferases (EC 2) in drug metabolism, based on a 'guesstimate' of the number of drug metabolites that are known to be produced by them. The conclusion is that oxidoreductases are the main enzymes responsible for the formation of toxic or active metabolites, whereas transferases play the major role in producing inactive and nontoxic metabolites.

Iowa Underage Drinking Plan, 2007

To better address the issue of underage drinking in the State of Iowa, a State Underage Drinking Task Force was formed to research the problem and develop a strategic plan of action. The Task Force was working on the development of goals and actions when the Surgeon General’s Call to Action to Prevent and Reduce Underage Drinking 2007 was released. Due to the similarity in the goals outlined in the Call to Action with those they had developed, the Task Force, along with the DPAC, is recommending that the document be used as the basis for the plan to curb underage drinking. The Call to Action is based on several overarching principles from which its goals and the means for achieving them were derived.