Evaluation of a procedure to assess the adverse effects of illicit drugs.

The assessment procedure of new synthetic illicit drugs that are not documented in the UN treaty on psychotropic drugs was evaluated using a modified Electre model. Drugs were evaluated by an expert panel via the open Delphi approach, where the written score was discussed on 16 items, covering medical, health, legal, and criminalistic issues of the drugs. After this face-to-face discussion the drugs were scored again. Taking the assessment of ketamine as an example, it appeared that each expert used its own scale to score, and that policymakers do not score deviant from experts trained in the medical-biological field. Of the five drugs evaluated by the panel, p-methoxy-metamphetamine (PMMA), gamma-hydroxybutyric acid (GHB), and 4-methylthio-amphetamine (MTA) were assessed as more adverse than ketamine and psilocine and psilocybine-containing mushrooms. Whereas some experts slightly adjusted during the assessment procedure their opinion on ketamine and PMMA, the opinion on mushrooms was not affected by the discussion held between the two scoring rounds. All experts rank the five drugs in a similar way on the adverse effect scale i.e., concordance scale of the Electre model, indicating unanimity in the expert panel with respect to the risk classification of these abused drugs

Effects of Light-at-Night on the Rat Liver - A Role for the Autonomic Nervous System

Exposure to light at night (LAN) has been associated with serious pathologies, including obesity, diabetes and cancer. Recently we showed that 2 h of LAN impaired glucose tolerance in rats. Several studies have suggested that the autonomic nervous system (ANS) plays an important role in communicating these acute effects of LAN to the periphery. Here, we investigated the acute effects of LAN on the liver transcriptome of male Wistar rats. Expression levels of individual genes were not markedly affected by LAN, nevertheless pathway analysis revealed clustered changes in a number of endocrine pathways. Subsequently, we used selective hepatic denervations [sympathetic (Sx), parasympathetic (Px), total (Tx, i.e., Sx plus Px), sham] to investigate the involvement of the ANS in the effects observed. Surgical removal of the sympathetic or parasympathetic hepatic branches of the ANS resulted in many, but small changes in the liver transcriptome, including a pathway involved with circadian clock regulation, but it clearly separated the four denervation groups. On the other hand, analysis of the liver metabolome was not able to separate the denervation groups, and only 6 out of 78 metabolites were significantly up- or downregulated after denervations. Finally, removal of the sympathetic and parasympathetic hepatic nerves combined with LAN exposure clearly modulated the effects of LAN on the liver transcriptome, but left most endocrine pathways unaffected. Conclusion: One-hour light-at-night acutely affects the liver transcriptome. Part of this effect is mediated via the nervous innervation, as a hepatectomy modulated and reduced the effect of LAN on liver transcripts

Skin and liver diseases induced in flounder (Platichthys flesus) after long-term exposure to contaminated sediments in large-scale mesocosms.

Disease development in flounder (Platichthys flesus) was studied over a period of 3 years in three large mesocosms (40 m x 40 m x 3 m). Two of the mesocosms contained clean sand and the third, sharing a common water circulation with one of the clean-sand mesocosms, was stocked with contaminated dredged spoil. In this way, one of the clean-sand mesocosms was indirectly polluted via the water phase, and analysis of contaminant concentrations in sediments and flounder tissues showed that it had a status intermediate between the other two. Random samples of the flounder populations from the indirectly polluted and reference mesocosms were examined every 2 months for epidermal diseases (lymphocystis, skin ulcers, fin rot) and then released. In addition, every 6 months, random samples of fish from all three mesocosms were sacrificed for histological and chemical investigation. With regard to the development of epidermal disease, the results showed little difference between the reference mesocosm and the indirectly polluted mesocosm, with the exception that lymphocystis was significantly elevated in the indirectly polluted mesocosm. Although pollution may be a risk factor in the etiology of this disease, such a relationship would probably be obscured under field conditions due to variation arising from other factors. Histopathological analysis of the livers revealed in total four cases of hepatocellular adenoma (1.5% of sampled population) in fish from the polluted mesocosms, the first occurring after 2.5 years of exposure in fish from the indirectly polluted mesocosm. Furthermore, several other liver lesions, including foci of cellular alteration and hydropic vacuolated lesions, developed during the course of the experiment before tumor formation was apparent. Prevalences of these conditions were very much lower in the reference mesocosm than in the two polluted mesocosms. Densities of melanomacrophage centers in the liver showed a similar trend. The findings clearly indicate that long-term exposure to chemically contaminated dredged spoil can induce liver neoplasia and other liver lesions in flounder at contaminant levels comparable to those found in the natural environment

Effects of feeding time and light on energy metabolism in rats

Millions of people worldwide regularly work during the evening or at night. These shift workers run an increased risk to develop metabolic diseases, including obesity and diabetes type 2. It is thought that shift work conditions disturb the well-regulated biological clock within the body, which may lead to disease. The biological clock, which is located in a central area in the brain, regulates many rhythmic behaviors and functions in collaboration with molecular rhythms generated in each cell in the body. The first part of this thesis aimed to study in rats how the timing of food intake, often changed by shift work, affects these rhythms at multiple locations in the body. It was found that rhythms of clock genes and neuropeptides in the hypothalamus of the brain, and clock and metabolic genes in the liver and the muscle respond differently to the abnormal timing of food availability. This desynchronization of organ responses may play a role in the reduced metabolic health. The second part of this thesis, contains a series of rat studies investigating how another feature of shift work, light exposure at night, affects glucose metabolism. A single exposure of light immediately caused glucose intolerance, and this effect was dependent on the time-of-day, intensity, color and duration of the light exposure. In addition, changes in the liver transcriptome were found after one hour of light exposure. The studies in this thesis contribute to the understanding of the underlying pathology on how shift work affects health

Sugar and sweeteners may suppress the taste aversion against alcohol among youth and may enhance alcohol consumption

De zoete smaak van sommige zwak-alcoholhoudende dranken zorgt voor smaakherkenning en waarderingsreacties in de hersenen waardoor de aversie tegen alcohol onderdrukt kan worden.. De smaaksamenstelling van deze dranken verlaagt hierdoor de drempel om sneller en meer alcohol te gaan gebruiken op jonge leeftijd. Dit komt omdat de zoete smaak door jongeren gewaardeerd wordt. Jongeren moeten meestal aan bittere smaken wennen en dat geldt zeker voor de alcoholsmaak. Bovendien wordt in populaire zoete zwak-alcoholhoudende dranken meestal gebruik gemaakt van achtergrondsmaken van frisdranken en vruchtensappen die bij jongeren bekend zijn. De waardering van de zoete smaak en de bekendheid van de achtergrondsmaak maakt het gemakkelijk om over te stappen van alcoholvrije naar alcoholhoudende dranken.The taste of alcohol is generally not appreciated by children and young adolescents. Often it takes several years for young people to get used to drink alcohol, and this process is normally accompanied by increasing appreciation of the alcohol taste. Children like sweet taste starting at birth and after adolescence the preference of sweetness decreases slightly. The appreciation of bitter taste usually increases with age. Aversion to alcohol taste at young age seems to be suppressed when alcohol is consumed in combination with sweet and/or high caloric products such as milk. Complete masking of the alcohol taste does not occur, but it is difficult for inexperienced drinkers to estimate how much alcohol the drink contains. Sweet taste stimulates a reward response in the brain. As a result of adding sweeteners, such as sugars, to alcohol products, brain reward stimulation will be the result. It is likely that this sweet stimulus reward is the main reason for teenagers to consume sweetened low alcohol drinks, suppressing the aversion towards the taste of alcohol. Non-sweetened drinks with the same alcohol percentage are consumed less. In particular girls consume significantly less unsweetened alcohol drinks than sweetened drinks. 'Novely seeking" which often is stronger amongst boys than among girls, normally is an important driving force to start alcohol consumption. In addition 'nipping' is often the onset of alcohol consumption. Adding sweeteners to alcohol drinks may expand the 'nipping' process and may reduce the importance of novelty seeking. Alcopops and other sweetened low alcohol drinks have tastes which are recognized by children and young teenagers, thereby facilitating the consumption of alcohol. Furthermore it is shown in animal studies that the rewards for sweet and for alcohol in the brain may interact leading to easier adoption and more intense alcohol consumption . Although, to the best of our knowledge, no such information is available for humans, it may implicate that adding sweeteners to alcoholic drinks is more than only manipulating the taste of the drinks.VW