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This study reports the findings on the effect of Microcystin-LR (MCLR) on the gastrointestinal tract cells of mice and on two different cell lines, Caco2 and MCF-7. The cyanobacterium Microcystis aeruginosa produces the potent toxin, MCLR. This toxin has been implicated in a number of cases of ill-health. It was decided to investigate whether microcystin-LR induced apoptosis in the gastrointestinal tract of mice and also which possible mechanisms were involved in the induction in vitro. Balb/c mice were given a 75% LD50 intraperitoneal dose of pure microcystin -LR and sacrificed at 8, 16, 24 and 32 hours post-exposure. The small intestinal sections were stained with haematoxylin and eosin and examined for apoptotic cells. There was a time-dependent increase in the number of apoptotic cells with most in the duodenum and the jejunum. No change in glycogen content was evident at 24 hours post exposure when PAS-stained sections were examined. To determine that microcystin was the agent responsible for the changes, fluoroscein isothiocyanate (FITC) immunostaining for the toxin was done on the sections. Apoptosis in vitro was investigated in Caco2, a cell line that behaves like normal enterocytes when the cells are differentiated at confluency, and MCF-7, a breast cancer cell line deficient in pro-caspase-3, cells by 3-[dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays and by staining with DAPI and Rhodamine 123. MCLR exposure induced apoptosis, as seen in decreased cell viability and increased leakage of LDH, as well as mitochondrial damage shown by Rhodamine staining. The MCF-7 cells, deficient in pro-caspase-3, and Caco2 cells did not show cleavage of poly(ADP)ribose polymerase (PARP) after exposure to 50μM MCLR after 72 hours exposure. Both micro- and milli-calpain activity was however significantly increased in both cell lines exposed to the toxin. There was a significant increase in H2O2, one of the key reactive oxygen species, production during the first 30 minutes that the cells were exposed to 50 mM MCLR.

Mental disorders, like anxiety and depression, are a major health problem and can appear early in life. Developing new compounds for anxiety and other mental disorders is desirable and requires good animal models. Two widely used tests to evaluate fear and anxious behavior in rodents are the open field (OF) and elevated plus maze (EPM) tests. The models are simple and it has been argued that different environments give different behavior profiles and measure different kind of behavior. The multivariate concentric square fieldTM (MCSF) is a new test that gives the rodent opportunity to visit different environments and to evaluate more parameters in one test. Validation of the tests is mainly done with adult animals. The aim with this study is to study adolescent rat behavior in the OF, OF with start box, EPM and MCSF tests and to see if there is any difference in running trials in the morning or in the afternoon. A total of 48 adolescent male Wistar rats were divided into 12 rats per group. The groups were OF and MCSF, OF with start box and MCSF, EPM and MCSF, and repeated testing in MCSF. Each session was 20 minutes and there was one week between the two tests. Three rats where run in the morning and three in the afternoon. Statistical analysis did show significant difference in some parameters in the comparison between running trials in the morning or in the afternoon. Repeated testing in the MCSF yielded differences in trial two compared to trial one. No significant difference was found in the trend analysis. The results show individual differences and with larger groups results may have been more liable. In this study some differences were found between morning and afternoon groups. Lots of data have been generated and there are many opportunities to use the same data for additional analyses.

Even at very low concentrations in the environment, mercury (Hg) has the potential to biomagnify in food chains reaching levels of concern in apex predators such as fish-eating seabirds. The aim of this study was to determine the trophic structure and the transfer of total mercury (THg) and methylmercury (MeHg) in a Gulf of St. Lawrence food web using stable nitrogen (delta 15N) and carbon (delta13C) isotope analysis. Since food is the main exposure route to Hg in organisms, I wanted to characterize and compare the diet of top level predator seabirds using traditional and novel techniques. I found that body weight, trophic level and lipid content of organisms were the best predictors of THg and MeHg in this food web. Although the influence of habitat on the overall Hg distribution in the food web was low, I was able to demonstrate an effect within taxonomical groups which indicates that sediments are a source of THg and MeHg in this ecosystem. Several organisms at the base of the food chain were above the MeHg threshold level for the protection of wildlife suggesting a potential threat for upper trophic level predators. Diet composition of seabirds determined using traditional and novel techniques led to similar and complementary results illustrating that these methods can be combined for future studies to monitor prey availability and to predict the exposure of consumers to Hg.

Many blood cell mechanisms in the human body are working all the time to maintain haemostasis in the blood vessels. Once a wound arises platelets are alerted via different substances to cover the wound and prevent loss of blood. Most of the times these mechanisms do stop the blood, and further heal the wound. During other circumstances the platelet-covering continues to form a thrombus, preventing the blood to flow and instead causes myocardial infarction or stroke. There are several risk factors triggering development of circulatory diseases such as obesity, lack of exercise, smoking, infection and stress. This thesis describes the interaction between the two platelet thrombin receptors PAR1 and PAR4, together with the interaction of the oral pathogen Porphyromonas gingivalis (with thrombin-like gingipains), and the cross talk with the stress hormone epinephrine and its α2A adrenergic receptor. Until now PAR1 is thought to be the most important thrombin receptor due to its high affinity for thrombin. From a phylogenetical and patophysiological point of view there must be a reason why platelets express two different thrombin receptors. Today PAR4 is considered less important, but this thesis implies that PAR4 plays an important role in platelet signaling and haemostasis. The results show that bacteria pre-stimulated platelets, followed by epinephrine gives a strong and full aggregation and calcium mobilization, in both aspirinated and non-aspirinated human platelets. The amount of bacteria does not itself, or epinephrine alone give aggregation or calcium mobilization. This mechanism is dependent on both Rgp type gingipain released from P. gingivalis, and PARs in an interaction with the α2A adrenergic receptor. Further, results reveal that PAR4 interacts and cross talks with the platelet α2A-adrenergic receptor in aspirinated platelets. Neither of the two platelet purinergic P2Y-receptors (P2Y12 and P2Y1) contribute to this action, but the purinergic P2X1 does. In aggregation studies a low dose of PAR4 activating peptide (AP), but not PAR1-AP, followed by epinephrine results in a strong aggregation and in a calcium mobilization. ATP secretion measurements did reveal that ATP was released during epinephrine stimulation, which indicate that ATP and P2X1 have a key role in this event. By blocking P2X1 both aggregation and calcium mobilization were abolished, but not by blocking P2Y12 and P2Y1. Inhibition of PI3-kinase, both epinephrine-induced calcium mobilization and aggregation were significant reduced. In non-aspirinated platelets PAR1 synergizes with the α2A adrenergic receptor and P2X1. In conclusion, this thesis suggests that PAR4 plays an intriguing and important role in platelets with inactived cyclooxygenase 1.  The results described in this thesis contribute to an increased knowledge of the platelet thrombin receptors.

<p> Conventional cigarette smoking remains the leading cause of preventable death worldwide, yet one in five people continue to smoke. Recently, electronic cigarettes have become the most popular alternative tobacco product among adults and the most popular tobacco product of any kind among middle and high school students. However, the full health consequences of electronic cigarette use remain unclear, particularly with respect to the vascular system. The majority of tobacco product-related pathologies possess a vascular component, and it is imperative to determine whether electronic cigarettes pose the same vascular risk. This study examined the effects of electronic cigarette aerosol on vascular cell viability and function in primary human vascular cell lines. The parameters tested were cell viability, DNA damage, generation of reactive oxygen species and nitric oxide, the type of cell death induced, migration, proliferation, and vascular network formation and growth. The results indicate that commercial electronic cigarette aerosol reduces endothelial cell viability, causes DNA breaks, generates reactive oxygen species, and induces endothelial cell death through both apoptotic and non-apoptotic pathways. Further, the non-apoptotic pathway is dependent on oxidative stress and can be prevented with anti-oxidant therapy. An analysis of electronic cigarette components revealed that flavoring compounds, nicotine, and the vegetable glycerol/propylene glycol electronic cigarette liquid base are all capable of modulating vascular cell response. The flavoring compounds 2,3-butanedione and 2,3-pentanedione are capable of inducing cell death in both endothelial and smooth muscle cells in a cell type and compound dependent fashion. These two compounds were also shown to inhibit endothelial nitric oxide synthesis. Vegetable glycerol/propylene glycol electronic cigarette base with or without nicotine was shown to have a positive effect on endothelial cell viability, a negative effect on smooth muscle cell viability, and modulate endothelial cell proliferation and network formation. No formation of electronic cigarette aerosol was found to alter endothelial cell migration. Taken together, these results indicate that electronic cigarette aerosol may be safer than conventional cigarette smoke, but it is by no means safe. Additional research and careful regulatory controls are needed as these products are poised to become the leading tobacco product for future generations.</p><p>

The present study was carried out in Abu Dhabi to evaluate the levels of contamination of mother's milk with the 4-hydroxy metabolite of aflatoxin B1. More than 22 nationalities living in Abu Dhabi were chosen as donors for this study. These different nationalities have different food habits. Most of those donors with the exception of U.A.E. have come to U.A.E. at ages 18 - 35 years. Their previous food habits have been looked into in comparison with the present style of life in U.A.E. The present study revealed that mother's milk is showing an increase in the level of aflatoxin contamination. The level of AFM; in mother's milk was as high as 3 ng / ml and, from 445 mother donors, AFM1 was detected in 99.5% of mother's breast milk. Analysis of the data shows no significant correlation between nationalities and total fat content of mother's milk with the level of AFM1. However, a detailed analysis of the composition of the milk fat revealed that milk rich in saturated fatty acid may be associated with high level of aflatoxin M1. In contrast milk containing high AFM1 usually had low levels of linoleic acid. High concentration of Lactose, the sole carbohydrate in human milk, has no association with AFM1 levels. It was found that a high protein content in the diet may be associated with high AFM1, in the mother's milk. Clearly the interaction between dietary factors, the presence of AFB1 in the diet, and the physiology of milk production are complex.

Depression är den näst mest kostsamma sjukdomen för samhället efter hjärt-kärlsjukdom, främst på grund av långa sjukskrivningsperioder. Sjukdomen kan uppstå när som helst från sex månaders ålder, men prevalensen ökar med åldern. Det finns ett antal stressrelaterade faktorer som skulle kunna leda till depression, så som stor sorg, verbala eller fysiska övergrepp samt en svår barndom. Vad som orsakar sjukdomen är ännu inte helt känt, men det finns teorier att halterna av serotonin och noradrenalin är lägre hos deprimerade personer. Behandling som används är olika former av samtalsterapi, men även läkemedel så som selektiva serotoninåterupptagshämmare (SSRI). Det finns teorier som sammankopplar användandet av SSRI med självmord, framförallt hos personer ≤19 år. Syftet med detta litteraturarbete var att undersöka om SSRI preparat har någon effekt på depression hos barn och ungdomar och om de är säkra eller kan få allvarliga konsekvenser så som självmord. Sökningar i PubMed gjordes för att hitta relevanta artiklar. Fem av de åtta inkluderade studierna rapporterade olika effekter och säkerhet hos olika SSRI preparat bland barn och ungdomar, jämfört med placebo. Två andra studier undersökte förekomsten av suicidalitet till följd av läkemedlen. Den sista studien jämförde toxikologiska data från Rättsmedicinalverket med receptregistret på antidepressiva läkemedel från  Socialstyrelsen. Endast två av de fem studerade preparaten (fluoxetin och citalopram) hade en bättre effekt än placebo i hela populationen och ytterligare ett (sertralin) hade bättre effekt hos ungdomar. Det begicks inga självmord i studierna.    De studier som har granskats i detta arbete tyder på att olika SSRI preparat har olika bra effekt samt olika säkerhetsprofiler. Det sågs inget tydligt samband mellan behandlingen och självmord, men en något förhöjd risk för suicidalitet.

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