Myelin and oligodendrocytes (OLGs) are the apparent targets of the immune-mediated injury that underlies the development of multiple sclerosis (M8). Recovery from M8 clinical relapses likely reflects remyelination attributed to recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), rather than to new process formation by previously myelinating OLGs. Newly emerging M8-directed immuno-modulatory therapies (statins and FTY720) can readily cross the blood-brain barrier and have been shown to impact signaling pathways implicated in cytoskeletal regulation, differentiation, migration, and survival; these are cellular events presumably important for myelin integrity and remyelination. / Statins inhibit the production of cholesterol (concentrated in the myelin membrane) and isoprenoids (post-translational attachments regulating the functions of proteins such as the Rho GTPases). We showed that treatment of human and rodent-derived OPCs with lipophilic statins induced an initial process extension associated with enhanced differentiation and impaired spontaneous migration, whereas prolonged treatment induced process retraction and cell death. Rodent and human mature OLGs demonstrated similar cytoskeletal and survival responses. Chronic simvastatin therapy of mice inhibited remyelination following demyelination induced by the OLG toxin, cuprizone, attributed to a block in OPC differentiation and consequent decrease in mature OLGs. Even fully myelinated animals treated with simvastatin over the long-term demonstrated a decrease in myelin in the brain by maintaining oligodendroglial cells in the pre-OLG state and preventing continual replacement of mature OLGs. / FTY720 is an agonist of G-protein-coupled receptors S1P1, 3, 4, and 5, that are associated with distinct receptor isotype-selective activation of Rho GTPases. In human OPCs, FTY720 could induce initial S1P3/5-dependent process retraction associated with an inhibition of differentiation, and subsequent S1P1-dependent process extension. Mature OLGs showed a dose-dependent cyclic modulation of process extension and retraction was observed over time. Both human OPCs and OLGs were rescued by FTY720 under death-promoting environments. Both cell types also demonstrated a cyclic and reciprocal modulation of S1P1 and S1P5 mRNA levels, reflected in the recurring receptor isotype-dependent functional responses over time. Studies using organotypic cerebellar slice cultures demonstrated that FTY720 did not impact myelin integrity under basal conditions, yet accelerated remyelination following lysolecithin-induced demyelination. Both treatment regimens were associated with an extension of OPC and mature OLG processes. / Our observations demonstrate that drug concentrations used to modulate immune function can have differential dose and time-dependent effects on OPCs, OLGs, as well as on myelin and remyelination processes. Our findings indicate the need to monitor the effects of putative immuno-modulatory therapies on myelin-related processes in MS patients.

This study has examined the effect of 3 doses of Methylphenidate (MPH) on the speed of motor and cognitive performance in children diagnosed with ADHD. Thirty children clinically diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD) aged 6-12 years were recruited through the ADHD Clinic and the Severe and Disruptive Behavior Disorders Program at the Douglas Mental Health University Institute. The three doses of MPH were administered according to a double blind randomized cross-over three day trial (0.3; 0.5 0.8 mg/kg/day in a bid schedule). An improvement across all three doses of MPH on motor, cognitive and behavioural measures was observed. The improvement is significant at low doses of MPH and an increase of dose up to 0.8 mg/kg/day does not lead to further improvement of the speed of simple motor task, but might be beneficial to specific cognitive tasks. No deterioration was observed in association with higher doses of MPH.

Vascular access-related bloodstream infection (BSI) is frequent among patients undergoing hemodialysis increasing significantly their morbidity and mortality. Studies assessing centre- and patient-predictors of BSI have had inadequate sample size and follow-up time. The aims of this project are: to describe the incidence rates; and to determine patient- and centre-level predictors of BSI in a cohort of incident hemodialysis patients treated in teaching or community hospitals, and in First Nation dialysis units. The rates of BSI in our population were lower than those observed in other settings. Central venous catheters were the most important risk factor for BSI and their use in our study was much higher than recommended. Some variability in BSI rates was found among centres, but no centre-related variable was found to be associated with the risk of BSI. Effort to reduce catheter use in hemodialysis patients may significantly reduce the risk of BSI in this patient population.

Os efeitos tóxicos decorrentes da exposição ambiental e ocupacional ao benzeno são amplamente descritos na literatura. Seus produtos de biotransformação fenólicos, entre os quais os compostos hidroxilados como FE e hidroquinona HQ, são indutores importantes de efeitos citotóxicos e genotóxicos responsáveis pela toxicidade ao sistema imune. No entanto, a contribuição de cada metabólito e os mecanismos envolvidos não estão completamente esclarecidos. Desta forma, o presente trabalho teve por objetivo estudar a capacidade da resposta inflamatória em ratos expostos à HQ, ao FE, ou a ambos simultaneamente (HQ+FE). Para tanto, ratos Wistar machos foram expostos aos agentes químicos por período de tempo prolongado (doses diárias de 5 ou 10mg/kg; i.p.; com 5 doses/semana no período de 17 ou 23 dias). Animais controles receberam o veículo pela mesma via. As respostas inflamatórias foram induzidas 24 horas após a última dose administrada. Foram avaliadas a resposta inflamatória inespecífica, decorrente da instilação intranasal de LPS de Salmonella abortus e a resposta inflamatória específica em animais previamente sensibilizados e desafiados pela OVA. Na resposta inflamatória inespecífica, as exposições à HQ e à HQ+FE provocaram redução acentuada no influxo de leucócitos para o pulmão inflamado, pelo menor número de leucócitos no LBA e pela atividade enzimática da MPO reduzida no tecido pulmonar. O efeito não é dependente de modificações no número de leucócitos circulantes nem de alterações nas expressões de moléculas de adesão nos leucócitos circulantes (L-selectina e β2 integrina) e no endotélio pulmonar (ICAM-1 , VCAM-1 e PECAM-1) envolvidas na interação leucócito-endotélio. Na vigência de resposta inflamatória específica, as exposições à HQ, FE ou HQ+FE reduziram significativamente a migração de leucócitos para o LBA e para o tecido pulmonar. Da mesma forma que a RI induzida pelo LPS, não foram detectados alterações nos número de leucócitos circulantes e na expressão de moléculas de adesão. No entanto, os resultados obtidos em ensaios de anafilaxia passiva cutânea e reação anafilática in vitro mostraram que o efeito é dependente, pelo menos em parte, da menor concentração de imunoglobulinas anafiláticas circulantes e, consequentemente, da menor habilidade de desgranulação mastocitária. Em conjunto, os dados obtidos demonstram que as exposições à HQ, ao FE ou à HQ+FE prejudicam a migração de leucócitos para o foco de lesão na vigência de respostas inflamatórias de origem inata ou adquirida. / The toxic effects of the ambiental and occupational exposures to benzene is widely described in the literature. Phenolic hydroxylated compounds obtainded from its biotransformation, such as phenol (PHE) and hydroquinone (HQ), induce important of cytotoxic and genotoxic effects responsible for the immunotoxicity. However, the role of each metabolite and mechanisms of toxicity are unknown. Then, the present work aimed to study the inflammatory response in rats exposed to HQ, PHE, ar both simultaneously (HQ+PHE). Male Wistar rats were exposed to they chemical agents for extended period of time (5 or 10mg/kg/day; ip.; during 17 or 23 days; 2 days intervals each 5 doses). Control animais received the vehicle. Inflammatory reactions were induced 24 hours after the last dose by they intranasal instillation of lipopolysaccharide of Salmonella aborlus (non-specific response) or by inhalation of ovalbumin in animals previously sensitized to the same antigen (specific response, produced by anaphylactic immunoglobulins). Animais exposed to HQ or HQ/PHE presented reduced n,3umbers of PMN and MN cells in the bronchoalveolar lavage fluid (BALF) and lesser myeloperoxidase (MPO) activity in the pulmonary tissue. The reduced influx of leukocytes is not dependent oh alterations on the numbers of circulating leukocytes either adhesion molecules expressions on leukocytes (L-selectin or β2 integrin) and on lung microvascular endothelium (ICAM-1, V CAM-1 or PECAM-1) responsible for leukocyte-endothelial interactions. On the other hand, rats exposed to ali schedules of exposures presented reduced numbers of leukocytes in the BALF and lesser MPO activity in the pulmonary tissue after an antigenic stimulus. As shown to inflammation induced by LPS, no alterations on circulating leukocyte numbers and adhesion molecules expressions were detected. However, the impaired leukocyte migration to the inflamed lung may be dependent, at last in part, on reduced levels of circulating anaphylactic antibodies, as detected by passive cutaneous anaphylaxis test, and by consequent reduced ability of mast cell desgranulation, evidenced by in vitro trachea contraction. Together, our data show that HQ and PHE exposure differently affect the specific and non-specific ínflammatory reactions.

Philosophiae Doctor - PhD / The income and employment multiplier effects of tourism- The case of Rwanda. A. NTIBANYURWA PhD Thesis, Department of Economics, University of the Western Cape. The growing popularity of developing countries as tourist destinations in recent years has stimulated a considerable body of research on the developmental benefits inherent in tourism. Developing countries have been attracting tourists mainly due to their natural resource endowments, considered a vital determinant in this newly-found source of their comparative advantage. After accounting for all the explicit and hidden costs linked to this natural resource-based tourism, the sustainable expansion of the tourism sector is claimed to be contributing substantially to economic growth. Studies to date have investigated the rising share of tourism in macroeconomic output, but have paid limited attention to the economic mechanisms through which tourism supposedly leads to broader development. This study seeks to contribute to filling this gap in our knowledge of the economic dynamics associated with tourism. More specifically, the goal is to shed light on the channels through which tourism contributes to economic growth and to derive tourism income and employment multipliers to estimate its developmental benefits for Rwanda. Our refined multipliers to capture the total effects of tourism to the economy confirm that through its powerful inter-sectoral linkages, tourism improves the economic wealth of many developing countries including Rwanda. Deeper analysis of the macroeconomic consequences of the expansion of the service sector however suggests that, under some conditions, this could exhibit “Dutch Disease” effects. Tourism generates substantial foreign earnings and its development is strongly correlated with the shrinkage of the traditional primary

Tourism is something that today is very common for most parts of the world. Tourism effects is a phenomenon that focuses on the effects of tourism which can affect destinations and residents in different ways. The most common are social, cultural, environmental and economic impacts. The purpose of this bachelor thesis has been to explore if there are any tourism effects and if so, what are they and in what ways can they affect a small rural area as a destination and the effect on the residents. For this purpose we have used an area called Glasriket in Sweden as an example. This study has used both qualitative and quantitative data with a deductive approach. After conducting our research, we then composed a questionnaire. The questionnaire was shared on our personal Facebook pages and also sent out through email to businesses, organizations and municipalities in Glasriket. In total, the empirical data was collected from 74 respondents. The results of the study showed that tourism is often perceived as positive. The positive effects of tourism outweigh the negative. It is clear that tourism has impacts on destinations in rural areas and not only on major cities or coastal areas. One conclusion is that yes, there are effects caused by tourism in Glasriket. There are several environmental, social, cultural and economic impacts in this area. It can also be concluded that tourism affects people and destinations in different ways and the ways the effects are perceived by residents might vary depending on factors such as cultural background, economic status and personal opinions.

Den psykiska ohälsan ökar stadigt i omvärlden, därav genomgår fler människor psykologiska behandlingar för att öka sitt välmående. Den tidigare forskningen har uppvisat att negativa effekter i samband med en psykologisk behandling existerar. Syftet med genomförandet av studien var att undersöka om det fanns negativa eller oönskade effekter hos personer som genomgått någon evidensbaserad psykologisk behandling samt att undersöka vilka de mest förekommande oönskade effekter var hos den rekryterade gruppen. Studien genomfördes genom en enkätstudie med totalt 63 deltagare (M = 33 år, SD = 8.4, åldersspann 20 - 57 år,67% kvinnor). Instrumentet som användes var The Negative Effects Questionnaire med 32 påståenden, vilka utgör en sex faktorsmodell (symptom, kvalitet, beroende, stigma, hopplöshet och misslyckande). Instrumentet mäter huruvida deltagarna upplevt att behandlingen lett till några negativa eller oönskade effekter. Resultatet på frågeställning A ”Vilka är de mestförekommande biverkningarna hos den rekryterade gruppen?” visar att den mest rapporterade negativa effekten var “känner du dig sorgsen”. Resultatet från frågeställningen B ”Finns det könsskillnader i medelvärden av faktorerna hos NEQ?” visar att kvinnor generellt rapporterat fler biverkningar jämfört med männen. Studien går i linje med tidigare forskning och svarar på samtliga frågeställningar. Studiens låga antal deltagare (N = 63), och dess bekvämlighetsurval gör att studien inte kan generalisera sitt resultat. Spridningen blir inte lika omfattande och representativ som den hade varit med en större urvalsgrupp. / Mental illness is steadily increasing in the world, because of which more people are undergoing psychological treatments to increase their well-being. Previous research has shown that negative effects in connection with a psychological treatment exist. The purpose of conducting the study was to investigate whether there were negative or unwanted effects inpeople who had undergone any evidence-based psychological treatment and to investigate what the most common unwanted effects were in the recruited group. The study was conducted through a questionnaire study with a total of 63 participants (M = 33 years, SD =8.4, age range 20 - 57 years, 67% women). The instrument used was The Negative Effects Questionnaire with 32 statements, which constitute a six-factor model (symptom, quality, dependence, stigma, hopelessness and failure). The instrument measures whether the participants experienced that the treatment led to some negative or unwanted effects. The result of question A shows that the most reported negative effect was "do you feel sad". The results from question B show that women generally reported more side effects compared to men. The study is in line with previous research and answers all questions. The study's low number of participants (N = 63), and its convenience selection means that the study can notgeneralize its results, the spread will not be as extensive and representative as it would have been with a larger sample group.

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: Methamphetamine-related deaths have been rising along with those involving synthetic opioids, mostly fentanyl and fentanyl analogs (FAs). However, the extent to which methamphetamine involvement in deaths differs from those changes occurring in synthetic opioid involvement is unknown.: To determine the patterns and temporal changes in methamphetamine-related deaths with and without other drug involvement.: Data from all methamphetamine-related deaths in West Virginia from 2013 to 2018 were analyzed. Quasi-Poisson regression analyses over time were conducted to compare the rates of change in death counts among methamphetamine and fentanyl//FA subgroups.: A total of 815 methamphetamine-related deaths were analyzed; 572 (70.2%) were male and 527 (64.7%) involved an opioid. The proportion of methamphetamine only deaths stayed relatively flat over time although the actual numbers of deaths increased. Combined fentanyl/FAs and methamphetamine were involved in 337 deaths (41.3%) and constituted the largest increase from 2013 to 2018. The modeling of monthly death counts in 2017-2018 found that the average number of deaths involving fentanyl without methamphetamine significantly declined (rate of change -0.025, < .001), while concomitant fentanyl with methamphetamine and methamphetamine only death counts increased significantly (rate of change 0.056 and 0.057, respectively, < .001).: Fentanyl and FAs played an increasingly significant role in methamphetamine-related deaths. The accelerating number of deaths involving fentanyl/FAs and methamphetamine indicates the importance of stimulants and opioids in unintentional deaths. Comprehensive surveillance efforts should continue to track substance use patterns to ensure that appropriate prevention programs are undertaken.