Дисертації з теми "Medicinal substances"

Mestrado em Controlo de Qualidade
MSc in Quality Control
Piper betle L., conhecida como bétele, é uma espécie que se desenvolve largamente nos países do Sudeste Asiático, onde as suas folhas são económica e medicinalmente importantes. Para determinar o maior número possível de compostos voláteis e semivoláteis, as folhas foram sujeitas as diferentes processos de extracção, nomeadamente headspace - microextracção em fase sólida (HS-SPME), hidrodestilação e extracção por Soxhlet, e posteriormente analisadas por GC/MS, o que permitiu identificar 50 compostos, distribuídos por várias classes químicas, 23 dos quais foram descritos pela primeira vez. As diferentes técnicas permitiram a extracção de compostos distintos, sendo a HS-SPME aquela com que se obteve o perfil mais completo e com que se determinou maior teor de compostos. Dentro deste processo os melhores resultados foram obtidos utilizando a fibra revestida com divinilbenzeno/polidimetilsiloxano (DVB/PDMS). Considerando que a espécie é vulgarmente mascada, o seu extracto aquoso também foi analisado, tendo sido caracterizados apenas sete compostos, sendo o eugenol o composto principal. A composição em ácidos orgânicos deste extracto foi determinada por HPLC/UV e os ácidos oxálico, aconítico, cítrico, pirúvico, málico, chiquímico, acético e fumárico foram descritos pela primeira vez. O extracto aquoso também revelou capacidade para inibir a acetilcolinesterase de modo dependente da concentração.
Piper betle L., popularly known as “Paan”, is a species widely growing in South East Asia, where its leaves are economically and medicinally important. In order to screen the highest possible number of volatile and semi-volatile components, the leaves were subjected to headspace solid-phase microextraction (HS-SPME), hydrodistillation and Soxhlet extraction, prior to their analysis by GC/MS, which allowed the identification of 50 compounds, distributed by several chemical classes, 23 of them described for the first time. The different techniques lead to distinct compounds' extraction, with HS-SPME extracting highest amounts and providing the most complete profile. Within this procedure, best results were obtaine using Divinylbenzene/Polydimethylsiloxane (DVB/PDMS) fibre. Considering the use of the species as masticator, an aqueous extract was also analysed, in which only seven compounds were characterize, being eugenol the main one. The organic acids composition of this extract was determine by HPLC/UV and oxalic, aconitic, citric, pyruvic, malic, shikimic, acetic and fumaric acids are reported for the first time in this species. The aqueous extract also displayed AChE inhibitory capacity, in a concentration-dependent way.

Mestrado em Controlo de Qualidade
MSc in Quality Control
Piper betle L., conhecida como bétele, é uma espécie que se desenvolve largamente nos países do Sudeste Asiático, onde as suas folhas são económica e medicinalmente importantes. Para determinar o maior número possível de compostos voláteis e semivoláteis, as folhas foram sujeitas as diferentes processos de extracção, nomeadamente headspace - microextracção em fase sólida (HS-SPME), hidrodestilação e extracção por Soxhlet, e posteriormente analisadas por GC/MS, o que permitiu identificar 50 compostos, distribuídos por várias classes químicas, 23 dos quais foram descritos pela primeira vez. As diferentes técnicas permitiram a extracção de compostos distintos, sendo a HS-SPME aquela com que se obteve o perfil mais completo e com que se determinou maior teor de compostos. Dentro deste processo os melhores resultados foram obtidos utilizando a fibra revestida com divinilbenzeno/polidimetilsiloxano (DVB/PDMS). Considerando que a espécie é vulgarmente mascada, o seu extracto aquoso também foi analisado, tendo sido caracterizados apenas sete compostos, sendo o eugenol o composto principal. A composição em ácidos orgânicos deste extracto foi determinada por HPLC/UV e os ácidos oxálico, aconítico, cítrico, pirúvico, málico, chiquímico, acético e fumárico foram descritos pela primeira vez. O extracto aquoso também revelou capacidade para inibir a acetilcolinesterase de modo dependente da concentração.
Piper betle L., popularly known as “Paan”, is a species widely growing in South East Asia, where its leaves are economically and medicinally important. In order to screen the highest possible number of volatile and semi-volatile components, the leaves were subjected to headspace solid-phase microextraction (HS-SPME), hydrodistillation and Soxhlet extraction, prior to their analysis by GC/MS, which allowed the identification of 50 compounds, distributed by several chemical classes, 23 of them described for the first time. The different techniques lead to distinct compounds' extraction, with HS-SPME extracting highest amounts and providing the most complete profile. Within this procedure, best results were obtaine using Divinylbenzene/Polydimethylsiloxane (DVB/PDMS) fibre. Considering the use of the species as masticator, an aqueous extract was also analysed, in which only seven compounds were characterize, being eugenol the main one. The organic acids composition of this extract was determine by HPLC/UV and oxalic, aconitic, citric, pyruvic, malic, shikimic, acetic and fumaric acids are reported for the first time in this species. The aqueous extract also displayed AChE inhibitory capacity, in a concentration-dependent way.

Magistro baigiamajame darbe yra nagrinėjamas dabartinis nanomedicinos teisinis reglamentavimas ES ir JAV. Ši tema Lietuvoje iki šiol dar nebuvo tyrinėjimų objektu. Pirmoji darbo dalis supažindina skaitytoją su nanomedicina bei su ja susijusių sąvokų problematiką. Antroji dalis atskleidžia nanomedicinos teisinio reglamentavimo prielaidas ES, o trečioji dalis – JAV. Be to, atsižvelgiant į gautus rezultatus, yra įvertinamos galimos nanomedicinos teisinio reglamentavimo perspektyvos ateityje. Darbe plačiai analizuojami atitinkami pasirinktų tarptautinės teisės subjektų teisės aktai bei specialioji teisinė literatūra (įvairių institucijų dokumentai, teisės mokslininkų darbai) bei tam tikra mokslinė-techninė literatūra (įvairių institucijų ir organizacijų ataskaitos ir tyrimai, mokslininkų tyrimai).
The master thesis researches the current regulation of nanomedicine in the EU and the US. Until now, this topic has not yet been researched in Lithuania. In the first part of the thesis nanomedicine and the problem of nanomedicine-related definitions are introduced to the reader. The second part reveals the basis of the regulation of nanomedicine in the EU, and the third part – in the US. Furthermore, considering the achieved results, the perspective of the future regulation of nanomedicine is assessed. The thesis extensively analyses the legal acts of the chosen subjects of international law and specific legal literature (documents of various institutions, works of law scholars) as well as some scientific-technical literature (reports and researches of various institutions and organizations, scientists’ researches).

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the monoamine transporters (MATs). Additionally, previous studies have found that the carbonyl oxygen atom can be replaced with a methoxy group, but this results in two chiral centers (i.e., four possible optical isomers for synthesis and evaluation). Here, the individual isomers of MCAT, their racemate, and achiral MCAT analogs were prepared where necessary, and examined in vitro and in silico at the MATs. All agents were active as substrates, with a rank order of potency suggesting that α-position chirality, in either configuration, is favored but not required, with the S(-) configuration slightly preferred. Either chiral center removal approach resulted in a reduction in potency, suggesting both favorable interactions with the α-methyl, and limited bulk tolerance. To further investigate this possibility, docking studies were conducted using homology models of the MATs. Common binding modes were identified that were similar to the binding mode of S(+)amphetamine co-crystallized at drosophila DAT. Taken together, these studies supported our conclusions, as steric hindrance was observed in the α-methyl region of the proposed binding site for the R(+)MCAT isomer. Inclusion of the original synthetic cathinones among Schedule I controlled substances has driven the clandestine development of a second generation of agents, resulting in an array of new synthetic cathinones diverse in structure and effect.Pyrrolidinophenones are a major constituent of second-generation bath salts. Little is known about their structure-activity relationships. Here, we have synthesized and examined a series of aryl-substituted pyrrolidinophenone analogs, as well as an achiral pyrrolidinophenone analog, utilizing novel synthetic chemistry and an innovative cell-based epifluorescence Ca2+ imaging technique. Herein, we evaluated the neurochemical properties of these novel compounds at the dopamine transporter (DAT), considered to exert a major role in actions of drugs of abuse. For future structure-activity relationship studies, additional analogs of synthetic cathinone-related agents were produced using novel synthetic approaches, including analogs and isomers of known amphetamine drugs of abuse. Finally, though much has been learned about the role of the dopamine and serotonin transporters in the mechanisms of action of synthetic cathinones, the role of the norepinephrine transporter is poorly understood. Homology models of the human norephinephrine transporter were built and docking studies conducted to inform the study of MAT ligand selectivity, activity, and binding. In conclusion, these studies represent progress towards the establishment of comprehensive structure-activity relationships for synthetic cathinones and related agents. Particular emphasis was placed on the SAR of the phenylalkylamine α-carbon in the synthetic cathinone context, and the role of the norepinephrine transporter in their activity.

O câncer é uma das doenças que mais acometem a população no mundo. Dessa forma, estudar suas terapêuticas é importante para o entendimento dos mecanismos e alvos biológicos por detrás da doença. Apesar dos tratamentos convencionais apresentarem uma boa eficácia, eles também provocam respostas indesejadas, como danos moleculares, resistência de células neoplásicas e efeitos colaterais fortes, colaborando para uma maior taxa de reincidência de neoplasias e mortalidade de pacientes. Sendo assim, a busca por alternativas é um importante desafio da Ciência Moderna para aprimorar e/ou substituir esses tratamentos. As plantas medicinais, como alternativa, são o foco de muitos estudos voltados ao câncer. O objetivo do presente trabalho foi avaliar o efeito citotóxico de 59 extratos em linhagens celulares humanas de câncer de mama (MDA-MB-231 e MCF7), próstata (PC-3 e DU 145) e fígado (HepG2). Foi realizada, inicialmente, uma triagem dos extratos por MTT em duas diluições 100x e 1000x para análise da viabilidade celular desses extratos. No total, 35 extratos obtiveram uma resposta para, pelo menos, uma das linhagens de câncer. A próxima etapa envolveu estudar os extratos pré-seletivos na triagem através de curvas-resposta quantificando a seletividade desses extratos para cada linhagem testada. Para essa etapa, foram selecionados 31 extratos. No câncer de mama, para a linhagem MDA-MB-231 nove extratos foram seletivos, e para MCF7 foram seis extratos. No câncer de próstata, para a linhagem PC-3, quinze extratos foram seletivos, e para DU 145 dezesseis extratos foram seletivos, mostrando uma maior sensibilidade do câncer de próstata comparado ao câncer de mama e fígado (HepG2 - sete extratos seletivos) em relação aos extratos testados. De todos os resultados apresentados, algodão de seda (Calotropis procera), camomila (Matricaria chamomilla), casca de anta (Drimys winteri), erva de São Caetano (Momordica charantia L.), estigmas de milho (Zea mays), graviola (Annona muricata), ipê roxo (Tabebuia sp.), malva - folhas (Malva sylvestris) e unha de gato (Uncaria tomentosa) foram os extratos mais amplamente significativos atingindo as linhagens celulares apresentando altos índices de seletividade. Com a realização desse trabalho podemos concluir que os extratos apresentam atividade antiproliferativa e seus fitoquímicos podem ser utilizados no estudo de novos fitoterápicos. O próximo passo é elucidar os mecanismos moleculares onde eles atuam.
Cancer is one of the most common diseases overworld. Studying the therapeutics of it is important to understand the biological mechanisms and targets behind this disease. Although conventional treatments show a good outcome against some types of cancer, they also currently cause undesired responses, such as molecular damage, neoplastic cell resistance and strong side effects, increasing recurrence of neoplasms, metastasis formation, and patient mortality. Therefore, the search for new alternatives is a challenge for Modern Science to improve or replace conventional treatments. In view of their antiproliferative effects medicinal plants have become the focus of many cancer studies as an alternative. The aim of the present study was to evaluate the cytotoxic and antiproliferative effect of 59 plant extracts in human cancer cell lines as breast cancer (MDA-MB-231 and MCF7), prostate cancer (PC-3 and DU 145) and liver cancer (HepG2). Initially, the extracts were screened in two different dilutions 100x and 1000x by MTT to analyze the cellular viability and cytotoxicity effects of them. To 59 extracts analyzed, 35 were effective against at least one of the tested lineages. The next step involved studying those pre-selective extracts through response curves to quantify the selectivity of these extracts for each cell lineage tested. For this stage, 31 extracts were selected. In breast cancer, for MDA-MB-231, nine extracts were selective and for MCF7 were six extracts. In prostate cancer, for PC-3, fifteen extracts were selective and for DU 145 were sixteen extracts. For liver cancer (HepG2) only seven extracts were selective. Comparing all the cancer lineages we can see a greater sensitivity of prostate cancer lineages compared to breast cancer and liver cancer in response of these tested extracts. Of all the results presented, silk cotton (Calotropis procera), chamomile (Matricaria chamomilla), winter\'s bark (Drimys winteri), bitter melon (Momordica charantia L.), corn silk (Zea mays), graviola (Annona muricata), purple trumpet tree (Tabebuia sp.), malva - folhas (Malva sylvestris) e unha de gato (Uncaria tomentosa) silk cotton (Calotropis procera), chamomile (Matricaria chamomilla), graviola (Annona muricata) and mallow-leaves (Malva sylvestris) were the most effective extracts reaching different cell types and present high selectivity indices. With the accomplishment of this work we can conclude that the natural extracts of plants presented antiproliferative activity in cancer lines and their phytochemicals can be used to study new herbal medicines. The next step, then, is to understand the molecular mechanisms where they act.

Diet has for many years been known to play a key role in the development of chronic diseases. There are clear associations between consumption of vegetables, fruits and berries, and risk of cardiovascular diseases, the number one cause of death in the world. To maintain homeostasis of the vascular wall the balance between angiotensin II, nitric oxide and reactive oxygen species is of great importance in order to affect the development of cardiovascular diseases. Angiotensin II, a potent vasoconstrictor causing cell growth and nitric oxide, a signalling molecule influencing the vascular system as a vasodilatator, inhibiting cell proliferation and reactive oxygen species, are linked together in the renin-angiotensin aldosteron system. Angiotensin-converting enzyme will as a key enzyme in the reninangiotensin aldosteron system convert angiotensin I to form angiotensin II and nitric oxide is known to inhibit angiotensin-converting enzyme and act as a scavenger of reactive oxygen species. Plant-derived substances as flavonoids, tocopherols and carotenoids are shown to have beneficial effects on the cardiovascular system due to their antioxidative effects. The aims of this study were to investigate beverages, dietary products, herbal medicinal plants, α-tocopherol, β-carotene, sterols and lipidowering drugs on angiotensin-converting enzyme activity and nitric oxide concentrations. This was done to investigate if the sole mechanism of plant-derived substances is their antioxidative properties and to investigate if there is any connection between effect and biosynthesis/structure of plant substances. The tested infusions and extracts containing high amounts of flavonoids, the flavonoids and β-carotene significantly inhibited angiotensin-converting enzyme activity in vitro. The other substances tested did not affect, or in some cases significantly increased, angiotensin-converting enzyme activity. The infusions and extracts containing high amounts of flavonoids, the flavonoids andβ-carotene showed an increase on nitric oxide concentrations in vitro. Oral intake of a single dose of Rooibos tea significantly inhibited angiotensin-converting enzyme activity. A significant inhibition of angiotensin-converting enzyme activity was seen with the green tea for the angiotensin-converting enzyme genotypes II and ID. A significant inhibition of angiotensin-converting enzyme activity was also seen with the Rooibos tea for the angiotensin-converting enzyme genotype II. Conclusion; flavonoids and β-carotene interact with the cardiovascular system in severalways, by reducing reactive oxygen species (as shown in several studies), increasing nitricoxide concentrations (as shown here and by others) and also by inhibiting angiotensinconvertingenzyme activity (as shown here). Infusions and extracts as tea containing highamounts of flavonoids function as angiotensin-converting enzyme inhibitors. Angiotensinconvertingenzyme contains two zink-dependent catalytic domains and angiotensinconvertingenzyme inhibitors are designed to bind to the Zn2+ at the active site. If theinhibitory mechanism of flavonoids on angiotensin-converting enzyme activity is due to theirability to bind to Zn2+ ions then it would be possible for the flavonoids to also inhibit otherzinc metallopeptidases, i.e. endothelin-converting enzyme, matrix metallopeptidases, neutralendopeptidase and maybe insulin-degrading enzyme, thereby exerting several additionalpositive effects on the cardiovascular system.
2009

L'objectif du travail effectué était la recherche de nouvelles substances actives d'origine végétale, présentant soit une activité antiplasmodiale soit une activité antifongique. Cette étude a été menée suivant deux stratégies différentes: l'étude de remèdes traditionnels antipaludiques identifiés suite à des enquêtes ethnopharmacologiques, et la mise en évidence des propriétés antifongiques d'huiles essentielles grâce à une stratégie bioinspirée. La première partie du travail a permis de mettre en évidence le rôle d'un quassinoïde connu, la simalikalactone D, dans l'activité antipaludique d'une tisane de jeunes feuilles fraîches de Quassia amara L. (Simaroubaceae). Dans le cas de la décoction de rameaux de Psidium acutangulum DC. (Myrtaceae), c'est cette fois un mélange de flavonoïdes glycosylés qui est responsable de l'activité du remède. Dans le cadre de la recherche de nouvelles substances antifongiques, le criblage effectué a permis d'identifier de nombreuses huiles essentielles présentant des activités intéressantes, validant ainsi la démarche bioinspirée retenue dans ce cas. L'huile essentielle d'Otacanthus azureus (Linden) Ronse a en particulier démontré une activité remarquable, à la fois seule et en combinaison avec des antifongiques azolés. Enfin, l'étude métabolomique de la composition des huiles essentielles a permis de mettre au point un outil pouvant orienter la sélection des huiles en fonction des données obtenues en GC/MS dans l'optique de la recherche de nouvelles substances antifongiques. Ce travail démontre donc la validité des stratégies retenues - ethnopharmacologie et bioinspiration - dans la recherche de nouvelles substances bioactives.

This thesis investigated the role of O\(_2\)-dependent substances in mediating the vasodilatation seen following exercise (post-exercise hyperaemia) and in fatigue development. Additionally we compared young and old subjects to investigate the effects of ageing in both of these phenomena. Breathing supplementary 40% O\(_2\) during handgrip exercise at 50% of maximum voluntary contraction had no effect of the magnitude of post-exercise hyperaemia compared to air breathing control. Furthermore, aspirin administration did not alter magnitude of post-exercise hyperaemia or the levels of prostaglandin E metabolites assayed from the forearm venous efflux. Similarly the magnitude of post-exercise hyperaemia was not affected by aminophylline administration. Collectively these suggest that prostaglandins and adenosine are not obligatory mediators of post-exercise hyperaemia. Supplementary O\(_2\) breathed during recovery had no effect on fatigue in a second bout of exercise or any of the substances proposed to mediate fatigue, in young subjects. We demonstrated that older subjects showed no changes in the magnitude of post-exercise hyperaemia, but they were more fatigue resistant. There was no O\(_2\)-dependence of either post-exercise hyperaemia or fatigue in older subjects. In conclusion, we have found no evidence of O\(_2\)-dependent mediators in either post-exercise hyperaemia or fatigue.

Le projet Plantinauv dans lequel s’inscrivent les travaux de ce mémoire de thèse, a pour but la valorisation du patrimoine botanique d’Auvergne en identifiant des plantes d’intérêts alimentaires et médicinales possédant des activités anti-inflammatoires, et de permettre leur commercialisation (ou celle de leurs bioactifs isolés) sous la forme de produits nutraceutiques, cosmétiques et/ou vétérinaires. Ce projet implique un consortium de partenaires académiques (UMR UNH) et industriels du pôle de compétitivité Vegepolys Valley (Greentech, Domes Pharma, AltoPhyto). Parmi les plantes de la flore auvergnate, seize ont été sélectionnées pour évaluer le potentiel anti-inflammatoire de leurs extraits (tests physico-chimiques et biologiques). Six d’entre elles, présentent sur différentes listes règlementaires (nutraceutique, cosmétique, vétérinaire), ont fait l’objet d’études phytochimiques. Le fractionnement chimio-et bio-guidé de L. sylvatica et D. fullonuma permis d’isoler de nouveaux métabolites secondaires d’intérêt. Quatre nouveaux phénanthrènes présentant des propriétés antiprolifératives prometteuses ont été isolés des parties aériennes de L. sylvatica. La mise en évidence des principaux marqueurs et le dosage de certains d’entre eux ont été réalisés pour les quatre autres plantes (P. erecta, T. angustifolia, H. Stoechas, K arvensis). Enfin, la préparation d’extraits industrialisable à partir de ces plantes a été mise au point dans le but de développer de nouveaux ingrédients commercialisables
The research work of this thesis, included in the Plantinauv project,aims to enhance the botanical heritage of Auvergne by identifying plants of medicinal and nutritional interest exhibiting anti-inflammatory activities, and to allow their merchandising (or that of their isolated bioactive agents) in the form of nutraceutical, cosmetic and / or veterinary products. This project involves a consortium of academic(UMR, UNH) and industrial partners from the cluster Vegepolys Valley (Greentech, Domes Pharma and Altophyto).Among the plants of the Auvergne flora, sixteen were selected to assess the anti-inflammatory potential of their extracts (chemical and biological tests). Six of them, present on different regulatory lists (nutraceutical, cosmetic, veterinary), have been the subject of phytochemical studies.The chemo-and bio-guided fractionation of L. sylvaticaand D. fullonumextracts allowed the isolation of new secondary metabolites. Four new phenanthrenes with promising anti-proliferative activities on cancer cells were isolated from L. sylvatica. The phytochemical profiles of the four other plants (P. erecta, T. angustifolia, H. stoechas, K arvensis) were also determined. Finally, the standardization of the different plant extracts was studied in order to develop new marketable ingredients

The interaction of recombinant TR with TRE-containing double-stranded DNA duplexes was monitored using the electrophoretic shift assay (EMSA). A protein titration allowed the calculation of the K& of TR for DNA. This quantitation of the affinity of TR for DNA was subsequently measured in the presence of known T3 analogues, thus providing the basis of a TR-DNA binding assay.

New psychoactive substances (NPSs) have appeared on the recreational drug market at an unprecedented rate in recent years. Many are not new drugs but failed products of the pharmaceutical industry. The speed and variety of drugs entering the market poses a new complex challenge for the forensic toxicology community. The detection of these substances in biological matrices can be difficult as the exact compounds of interest may not be known. Many NPS are sold under the same brand name and therefore users themselves may not know what substances they have ingested. The majority of analytical methods for the detection of NPSs tend to focus on a specific class of compounds rather than a wide variety. In response to this, a robust and sensitive method was developed for the analysis of various NPS by solid phase extraction (SPE) with gas chromatography mass spectrometry (GCMS). Sample preparation and derivatisation were optimised testing a range of SPE cartridges and derivatising agents, as well as derivatisation incubation time and temperature. The final gas chromatography mass spectrometry method was validated in accordance with SWGTOX 2013 guidelines over a wide concentration range for both blood and urine for 23 and 25 analytes respectively. This included the validation of 8 NBOMe compounds in blood and 10 NBOMe compounds in urine. This GC-MS method was then applied to 8 authentic samples with concentrations compared to those originally identified by NMS laboratories. The rapid influx of NPSs has resulted in the re-analysis of samples and thus, the stability of these substances is crucial information. The stability of mephedrone was investigated, examining the effect that storage temperatures and preservatives had on analyte stability daily for 1 week and then weekly for 10 weeks. Several laboratories identified NPSs use through the cross-reactivity of these substances with existing screening protocols such as ELISA. The application of Immunalysis ketamine, methamphetamine and amphetamine ELISA kits for the detection of NPS was evaluated. The aim of this work was to determine if any cross-reactivity from NPS substances was observed, and to determine whether these existing kits would identify NPS use within biological samples. The cross- reactivity of methoxetamine, 3-MeO-PCE and 3-MeO-PCP for different commercially point of care test (POCT) was also assessed for urine. One of the newest groups of compounds to appear on the NPS market is the NBOMe series. These drugs pose a serious threat to public health due to their high potency, with fatalities already reported in the literature. These compounds are falsely marketed as LSD which increases the chance of adverse effects due to the potency differences between these 2 substances. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was validated in accordance with SWGTOX 2013 guidelines for the detection for 25B, 25C and 25I-NBOMe in urine and hair. Long-Evans rats were administered 25B-, 25C- and 25I-NBOMe at doses ranging from 30-300 µg/kg over a period of 10 days. Tail flick tests were then carried out on the rats in order to determine whether any analgesic effects were observed as a result of dosing. Rats were also shaved prior to their first dose and reshaved after the 10-day period. Hair was separated by colour (black and white) and analysed using the validated LC-MS/MS method, assessing the impact hair colour has on the incorporation of these drugs. Urine was collected from the rats, analysed using the validated LC-MS/MS method and screened for potential metabolites using both LC-MS/MS and quadrupole time of flight (QToF) instrumentation.

The aim of the work described in this thesis was to develop a reliable method for retrospective assessment of occupational exposure, for individual workers, to substances hazardous to health. A review of existing methods for reconstructing exposure has shown a diverse range of approaches, partly dictated by the availability of measurement records and other documentation about work activities. These methods show little evidence of a coherent theoretical basis for exposure assessment. Progress has been made in defining a theory of exposure to hazardous substances and in elaborating this for substances where the main route of exposure is by inhalation. A new metric for exposure assessment, i.e. uptake, is proposed. For inhalation this corresponds to the cumulative amount of material inhaled during the exposure period, e.g. for a dust this would correspond to the time integral of the product of exposure level (i.e. concentration) and breathing rate. Analogous definitions are provided for dermal and ingestion uptake, and total uptake as the sum of these individual measures. It is argued that uptake should provide the best metric for reconstructing past exposure. For inhalation exposure several stages have been identified linking emission of hazardous substances from sources to inhalation of the substance by an individual worker. Emission from sources into the work environment has been divided into three parts (i.e. intrinsic emission, plus the effects of handling and local controls), which are assumed to be independent of each other. It is further assumed that the total emission from a source is determined by the product of these terms.

Objectives. To investigate experiences of substance use, bullying and psychological distress in adolescents. Differential patterns of substance use and levels of psychological distress were explored according to bullying status (bullies, victims, bully-victims and controls). There is little previous research exploring the relationship between bullying and substance use. Design. A between groups cross-sectional design was employed. Method. Students aged 13-16 years were recruited from several inner city schools. 263 students completed the Revised Olweus Bully/Victim Questionnaire, the Birlesen Depression Scale, the Spence Children's Anxiety Scale, the Rosenberg Self-esteem Scale and a measure of substance use designed by the researcher. Results. Victims and bully-victims were significantly more psychologically distressed, with higher levels of anxiety, depression and lower self-esteem, than bullies or controls. Those participants with higher levels of psychological distress used stimulants and hallucinogens more frequently than those with lower levels of psychological distress. There was no significant positive correlation between victim-hood and bully-victimhood with frequency of substance use. A negative correlation was found between victim-hood and use of hallucinogens and depressants. Being a bully was found to be positively correlated with use of depressants. Finally, reasons for substance use appear to vary according to bullying status. Bullies used substances to 'have a good time' and 'fit in with friends'. Victims used substances to 'block out bad things that had happened to them' and to 'block out negative feelings'. These results highlighted the unique identifiable patterns of substance use according to bully and victim status. However, bully-victims did not appear to have a unique pattern of substance use. Conclusion. Clinical implications of the results include the recognition of a complex association between substance use and bullying. Clinical services are encouraged to consider the differential patterns of substance use according to bullying status, and the subsequent requirement for different interventions and prevention strategies.

The comorbid presence of trauma and substance misuse is becoming increasingly recognized as a common occurrence that causes significant functional impairment in clients, and presents numerous challenges to clinicians. The first chapter in this thesis reviews recent empirical and theoretical literature regarding the nature of the relationship between trauma and substance misuse so as to highlight principal considerations applicable to the process of conceptualisation. In addition, Chapter two presents results of a principal component analysis of the Beliefs About Substance Use inventory (BASU) in order to facilitate the accurate measurement of beliefs in individuals who misuse substances. Findings indicated that in addition to its overall score reflecting the extent of dysfunctional be1iefs about substance use, the BASU is also able to evaluate important beliefs with regard to motivations for continued use, barriers to cessation and withdrawal, beliefs about dependence whilst also addressing contemplative state. With a view to further enhancing current conceptual knowledge, findings from the main empirical paper focussing on the role of beliefs in the relationship between trauma and alcohol abuse, are presented in chapter three. Associations between trauma exposure, trauma symptom severity, negative posttraumatic cognitions, beliefs about substance use and drinking expectations were examined. Following this preliminary investigation, results highlighted the significant contribution of trauma symptom severity and negative posttraumatic cognitions in relation to beliefs and expectancies about alcohol.

This research investigated expertise in hazardous substance risk assessment (HSRA). Competent pro-active risk assessment is needed to prevent occupational ill-health caused by hazardous substance exposure occurring in the future. In recent years there has been a strong demand for HSRA expertise and a shortage of expert practitioners. The discipline of Occupational Hygiene was identified as the key repository of knowledge and skills for HSRA and one objective of this research was to develop a method to elicit this expertise from experienced occupational hygienists. In the study of generic expertise, many methods of knowledge elicitation (KE) have been investigated, since this has been relevant to the development of 'expert systems' (thinking computers). Here, knowledge needed to be elicited from human experts, and this stage was often a bottleneck in system development, since experts could not explain the basis of their expertise. At an intermediate stage, information collected was used to structure a basic model of hazardous substance risk assessment activity (HSRA Model B) and this formed the basis of tape transcript analysis in the main study with derivation of a 'classification' and a 'performance matrix'. The study aimed to elicit the expertise of occupational hygienists and compare their performance with other health and safety professionals (occupational health physicians, occupational health nurses, health and safety practitioners and trainee health and safety inspectors), as evaluated using the matrix. As a group, the hygienists performed best in the exercise, and this group were particularly good at process elicitation and at recommending specific control measures, although the other groups also performed well in selected aspects of the matrix and the work provided useful findings and insights. From the research, two models of HSRA have been derived, an HSRA aid, together with a novel videotape KE technique and interesting research findings. The implications of this are discussed with respect to future training of HS professionals and wider application of the videotape KE method.

Background: Although there is a growing body of literature surrounding new psychoactive substances (NPS), and reasons for general use have been described, there is little understanding as to why certain NPS spread through user populations and become popular. This research used Rogers’ 1962 diffusion of innovations theory (DOI) to help better understand the NPS market and how it is shaped and characterised. Objective The aim of this research was to explore the diffusion of NPS in the UK and why different NPS diffuse and others fail to do so, to identify appropriate public health interventions to reduce harm. Methodology: A mixed methods approach was undertaken, which comprised four studies. The first study involved a critical analysis of the appropriateness of Rogers’ DOI to explain the diffusion of NPS. This study was followed by two sets of interviews. The first interview study was conducted with NPS online retailers based in the UK. The second interview study involved interviews with NPS professionals including law enforcement professionals, drug policy organisations and NPS early warning system representatives from the UK, wider Europe, America and Australasia. These findings were analysed using thematic analysis. The final study was an online questionnaire and choice-based conjoint analysis with UK pre-existing recreational drug users aged between 18 and 35. These findings were analysed using Latent Class Analysis. Results: The DOI was found to be applicable for the diffusion of an NPS product. However, the theory should be used in application to different individual NPS; NPS should not be classed as a homogenous group of substances and NPS users should not be classed as a homogenous group either. It was found that the theory should be updated in relation to NPS to include the influence of the internet. The key reason for the diffusion of an NPS was found to be the psychopharmacological effects of a product. However, there should also be an acknowledgment of the importance of friendship networks, and increasingly online forums. Even if a product had the desired psychopharmacological effects, if these are not communicated then it is unlikely to diffuse at a fast rate. Conversely, unless a product had the psychopharmacological effects desired by an individual, despite positive feedback from friends and online forums, it would be unlikely to diffuse. The emergence of NPS did not have a transformative effect for all drug-using groups; instead, it affected different user groups in different contexts. Similarly, it is likely that the introduction of the UK Psychoactive Substances Act will not have a transformative effect on the use of NPS by all drug-using groups. Nevertheless, the changes in health and social harms associated with individuals accessing NPS through the underground market or choosing to use traditional illegal drugs should be recognised. Finally, the need to conduct research with a range of stakeholders, to gain a greater understanding of motivations for drug use to assist with future public health interventions, was an important finding of the thesis.

Includes bibliographical references.
The systematic review undertaken for this MPH dissertation examines the existing evidence for youth violence interventions involving substance abuse intervention programs. Part A is the review protocol which outlines the background and process of the review. Search strategies combined related terms for youth, violence and a broad combination of terms for the intervention. Inclusion criteria were broad enough to include a wide range of study designs, given the large heterogeneity of outcomes and the paucity of randomised controlled trials (RCTs). Abstracts were screened by two reviewers, as were selected full texts articles. These were evaluated using the EPHPP questionnaire, a quantitative study assessment tool to identify methodological issues.

Glycosaminoglycans are heterogeneous polysaccharides that mediate important biological functions. There has been considerable interest in deciphering the precise GAG sequences that are responsible for protein interactions. In fact, several GAG oligosaccharides have been discovered to date as targeting proteins with higher level of specificity. Yet, it has been difficult to develop GAG oligosaccharides as drugs. One of the key reasons for this state of art is that GAG synthesis is extremely challenging and is highly structure-specific. Thus, much of the biology and pharmacology of GAG remains unknown and unexploited to date. An alternative approach is to prepare GAG oligosaccharides using enzymatic depolymerization of polymeric GAGs. GAG lyases, including heparinases and chondritinases represent powerful tools that can theoretically generate multiple oligosaccharides in parallel. However, it is difficult to implement such procedures with high consistency. Moreover, GAG lyases can digest GAGs down to disaccharides. A priori, non-polymeric GAGs, or alternatively GAG oligosaccharides containing 4 to 10 residues, would be expected to function better as therapeutic agents because they would be more homogeneous and less non-specific than their polymeric precursors. Thus, we reasoned that immobilization of these enzymes may engineer altered biopolymer processing, which may afford longer oligosaccharides in higher proportions and greater consistency. Heparinase-I and chondroitinase ABC were immobilized on CNBr-activated Sepharose and compared with the free form of the enzyme. Immobilized GAG lyases retained high efficiency of depolymerization over a wide range of pH, temperature and reusability. Most importantly, the immobilized enzyme was found to produce larger proportions of oligosaccharides longer than di- and tetra-saccharides as compared to lyases in the free form. A two dimensional separation involves size exclusion chromatography followed by reversed phase ion-pairing ultra performance liquid chromatography coupled to electrospray ionization mass spectrometry was employed to separate and characterize oligosaccharide structures. We have identified 40 heparin oligosaccharides, including regular and rare structures ranging from dp4 to dp10 and 39 chondroitin sulfate oligosaccharides in high homogeneity and significant yields. Overall, this technology is likely to offer a simple and cost effective route to preparation of larger amounts of sequences that can be expected to bind and modulate protein function.

The prenatal use of medicines and recreational substances is of significant importance because there is insufficient information on the effects of medicines and recreational substances on pregnancy outcomes. In addition, literatures on health beliefs of pregnant women about medicine and recreational substance use are lacking. The aim of this thesis was to investigate medicine and recreational substance use during pregnancy in an antenatal population of London. The study was approved by the ethics committee. The first part of the thesis was a prospective cohort study of medicine and substance use across all trimesters (using survey methods), and the pregnancy outcomes (using the medical records); the second part was a qualitative study of the health beliefs of pregnant women which employed semi-structured telephone interviews and the Health Belief Model as a framework for data collection and analysis. The results of the prospective study demonstrated that the prevalence of use of prescription, over-the-counter and complementary and alternative medicines during at least one trimester were 32.5%, 50.2% and 57.1% respectively. The prevalence of exposure to alcohol, cigarette and illicit substances were 16.0%, 3.5% and 0.9% respectively. However, due to limited sample size, the study could not demonstrate an association between the medicines and substances used and increased risk of congenital anomalies in the baby. The qualitative study indicated that pregnant women’s adherence to medicines could be explained by women’s perception of the severity of a medical condition, risks of non-adherence to the medicine as well as anxiety about the risks of the medicine on the foetus. In the case of substance use, a low risk perception could be used to explain women’s behaviour. Healthcare professionals have a responsibility to counsel pregnant women about the benefits or risks of medicines and substances, informed by the best evidence, and guided by the women’s perceptions.

Support groups are commonly found to be empowering and constructive of the mental health of those attending, not least within the arena of substance misuse. Shame on the other hand is an emotion that is detrimental to the social functioning and well-being ofmany participants of such groups. The conjunction of these contrasting foci, are explored in the following research portfolio.This is comprised of three sections. The first is a systematic literature review, collating literature in the field of support groups and shame or internalised stigma; a close relation.The literature is synthesised and presented in the form of themes arising from theinformation extracted, with reference to the quality of studies selected. The review concludes by delineating the overarching benefit of groups for those who may suffer shame or internalised stigma.Part two describes an empirical study in which the experiences of parents of illicit substance misusers are examined. This is done so qualitatively, with reference to parents’ understanding of the role that shame and stigma may play in their lives and experiences of the support group they attend. Outcomes of thematic analyses of interviews with participants are presented, and major themes are discussed. Benefits for parents of attending the support group is highlighted as one of the main themes.The final section of the portfolio consists of the appendices which support Sections One and Two, including a brief reflective summary of the research process from the author’s perspective.

Includes abstract.
Includes bibliograpical references.
Hospitals across South Africa are inundated with patients suffering from conditions associated with substance abuse. It is inevitable that contact with health services be made through an emergency centre (EC) at some point. This study aims to assess the exposure and attitudes of emergency physicians to substance abuse and addiction in major South African academic ECs. A prospective survey based on the Substance Abuse Attitude Survey (SAAS) was conducted in a convenience sample of eighty five emergency physician registrars and junior consultants in Cape Town, Gauteng, Limpopo and KwaZulu Natal. Respondents were targeted during academic meetings and by post.

It has been reported that an individual’s initial level of response to a drug might be predictive of his or her future risk of becoming dependent, thus basal gene expression profiles underlying those drug responses may be informative for both predicting addiction susceptibility and determining targets for intervention. This dissertation research aims to elucidate genetic risk factors underlying acute alcohol and nicotine dependence phenotypes using mouse genetic models of addiction. Phenotyping, brain region-specific mRNA expression profiling, and genetic mapping of a recombinant inbred panel of over 25 mouse strains were performed in order to identify quantitative trait loci (QTL) harboring candidate genes that may modulate these phenotypes. Previous BXD (B6 x D2) behavioral studies performed in our laboratory identified an ethanol-induced anxiolysis-like QTL (Etanq1) in the light dark box (LDB). We hypothesized that genetic variation within Nin (a gene within the Etanq1 support interval involved in microtubule-anchoring) may modulate anxiolytic-like responses to acute ethanol in the LDB as well as other preclinical models of anxiety, the elevated plus maze (EPM), and marble burying (MB) task. Molecular studies have allowed us to confirm cis regulation of Nin transcript levels in the NAc. To elucidate potential mechanisms mediating Etanq1, the pharmacological tools, diazepam and HZ166 (a benzodiazepine derivative) were utilized to interrogate whether GABAA receptor activation modulates ethanol’s anxiety-like behaviors in the LDB. We show that the LDB phenotype, percent time spent (PTS) in the light following a brief restraint stress, is not being modulated through direct activation of GABAA α2/α3 receptor subunits. To genetically dissect Etanq1 as well as parse the ethanol anxiolytic-like phenotype, we have assayed 8 inbred strains, selected based on genotypes at Nin, in various preclinical models of anxiety. Principal components analysis of these behavioral data suggests that the gene(s) modulating the ethanol anxiolytic-like component in the LDB do not overlap with similar phenotypes in the elevated plus maze (EPM), nor the MB phenotype. Furthermore, site-specific delivery of an sh-Nin lentivirus into the NAc of D2 mice revealed that Nin may modulate one LDB endophenotype, latency to enter the light side of the LDB, which loaded as a part of the “anxiolysis” principal component. These data strongly imply that basal neuronal Nin expression in the NAc is important for acute ethanol anxiolytic-like behavior, perhaps through a novel mechanism involving synaptic remodeling. In separate behavioral QTL mapping studies, we hypothesized that genetic variation regulating expression of Chrna7 modulates the reward-like phenotype, conditioned place preference (CPP), for nicotine. We provide evidence for genetic regulation of Chrna7 across the BXD panel of mice and through pharmacological and genetic behavioral studies, confirm Chrna7 as a quantitative trait gene modulating CPP for nicotine in mice. Microarrays, followed by network analyses, allowed us to identify a genetically co-regulated network within the nucleus accumbens (NAc), differentially expressed in mice null for Chrna7, which was similarly correlated in the BXD panel of mice. Our network and molecular analyses suggest a putative role for Chrna7 in regulating insulin signaling in the NAc, which together, may contribute to the enhanced sensitivity to nicotine observed in strains of mice that lack or have low mRNA levels of Chrna7 in the NAc. Overall, this research has elucidated and confirmed new genetic risk factors underlying alcohol and nicotine dependence phenotypes and has enabled a better understanding of the neurogenomic bases of alcohol and nicotine addiction. Future studies that further investigate the signaling pathways and/or gene interactions involving Nin and Chrna7 may lead the field to new candidates for pharmacotherapies that may be tailored for use in individuals with susceptible genotypes. Supported by NIAAA grants P20AA017828 and R01AA020634 to MFM, NIDA T32DA007027 to WLD, and NIDA R01DA032246 to MFM and MID.

To provide background information about previous findings about the prevalence of use, abuse and dependence of various substances (nicotine, alcohol, prescription and illicit drugs) findings of available epidemiological studies in Germany from the 1980s and 1990s are summarized and critically evaluated. Focusing on findings of substance use surveys in adolescents and young adults the review indicates: (a) a considerable number of large scale questionnaire surveys in general population samples documenting the frequency of use and patterns of use of most substances; (b) indications of increasing rates of drug use particularly in East Germany; (c) high rates of illicit drug use, mainly of cannabinoids, but also stimulants and hallucinogens, among young age groups. No data are available from substance use surveys or from clinical epidemiological studies allowing the determination of how frequent substance abuse and substance dependence diagnoses are in the general population or in adolescents and young adults. Priorities for future research to ameliorate this unsatisfactory situation are outlined with emphasis on research in adolescents and young adults.

Įvadas. Paskutinio dešimtmečio moksliniais duomenimis, Europoje ir visame pasaulyje didžiąją dalį sveikatos problemų sudaro psichikos ir elgesio sutrikimai. Tai tampa ekonomine našta valstybėms, o psichikos sveikatos apsauga – vienu iš didžiausių rūpesčių. Pastaraisiais metais atliekami psichologiniai ir socialiniai tyrimai bei studijos rodo, kad labiausiai pažeidžiama visuomenės dalis – jaunimas. Taigi šio tyrimo tikslas – nustatyti psichoaktyviųjų medžiagų vartojimo paplitimą tarp I – III kurso VU Medicinos fakulteto studentų ir jį įtakojančius veiksnius. Metodai. Anoniminė apklausa atlikta 2007 metais. 556 I – III kurso Vilniaus universiteto Medicinos fakulteto studentai užpildė Tarptautinio alkoholio ir kitų narkotikų tyrimo Europos mokyklose projekto (ESPAD) klausimyną, modifikuotą ir pritaikytą tiriamajam kontingentui. Duomenys apdoroti statistine programa SPSS 15.0. Rezultatai. 18,3 proc. Vilniaus universiteto Medicinos fakulteto I – III kurso studentų teigė, kad rūko. Didžioji jų dalis rūkė kasdien. Vaikinų statistiškai reikšmingai rūkė daugiau nei merginų (p<0,05). Alkoholį vartojo 77,3 proc. studentų. Dažniausiai vartojami alkoholiniai gėrimai buvo vynas ir alus. 68,7 proc. studentų teigė vartojantys kavą, pusė – energetinius gėrimus. Kofeino turinčios tabletės nebuvo paplitusios tarp studentų. 12,1 proc. studijuojančių buvo bandę narkotikų (vaikinų daugiau nei merginų (p<0,05)), narkotikus pastoviai vartojo apie 3 proc. studentų. Dažniausiai vartojama medžiaga buvo... [toliau žr. visą tekstą]
Background. According to the scientific material of the last decade major part of health problems in Europe and all around the World are due to psychical and behavioural disorders. It has become an economical burden for the countries whereas psychical health services have become one of the major concerns. The latest psychological and social researches and studies suggest that the most vulnerable part of the society is youth. So, the goal of this study is to determine the prevalence of using psychoactive substances amongst first-third year students of Vilnius University Medicine Faculty and factors influencing it. Methods. Anonymous inquiry was performed in the year 2007. A self-administered questionnaire of The European School Survey Project on Alcohol and Other Drugs (ESPAD), which was modified and applied for the exploratory crop, was completed by 556 first-third year students of Vilnius University Medicine Faculty. The data was analysed using the statistical programe SPSS 15.0. Results. In total 18,3% of Vilnius University Medicine Faculty first-third year students reported smoking. The majority of them smoked every day. Boys students reported significantly greater smoking then girls students (p < 0,05). 77,3% of students reported using alcohol. Most often used alcoholic drinks were wine and beer. 68,7% of students used coffee whereas half of them used energetic drinks as well. Caffeine containing tablets were not popular amongst the students. 12,1% of those who studied... [to full text]

Introduction: Substance use, including cigarette smoking, while pregnant can lead to a plethora of health concerns for both the mother and unborn child including premature birth, low birth weight, and stillbirth. Compared with women nationally, pregnant women in Tennessee are more than three times as likely to smoke during pregnancy. Preliminary findings suggest high levels of religious commitment may be reliable predictors of negative health behaviors. However, the association between religious commitment and substance use has not been thoroughly investigated in pregnant populations. Using a brief measure of religious commitment, it was hypothesized that pregnant women with higher levels of religious commitment would be significantly less likely to engage in cigarette smoking and other substance use. Methods: Participants included 654 pregnant women involved in the Tennessee Intervention for Pregnant Smokers program who completed multiple interviews during pregnancy. Of interest in the current investigation, participants’ religious commitment was measured using two items from the 12-item Surrender Scale, and a 1-item church attendance measure from the Brief Multidimensional Measure of Religiousness/Spirituality. Participants also completed a background information form assessing demographic characteristics, smoking habits, and drug use, with final substance use variables composites of both self-report and urine drug screen results. Results: Direct logistic regression was performed to assess associations between religious commitment and both smoking status (at conception and delivery) and other substance use. All models included level of education, age, marital status, and insurance status. The full direct model predicting smoking status at conception was statistically significant, χ2 (5, n = 654) = 178.76, p < .001, indicating the model could distinguish between participants who did and did not report smoking early in pregnancy. The model as a whole explained between 24% and 32% of the variance in smoking status, and correctly classified 71% of cases. All variables made statistically significant and unique contributions to the model, including religious commitment (OR=.857). A similar pattern was found in the model predicting smoking status at delivery χ2 = 157.01, p < .001. A third regression, using the same predictors, examining the impact of religious commitment on any illicit drug use prior to or during pregnancy, was also statistically significant, χ2 = 58.46, p < .001. Conclusions and Implications: In this sample, religious commitment predicted smoking status and other drug use during and prior to pregnancy. Inquiry into religious commitment as an additional gauge of health behaviors may be beneficial to healthcare professionals. Future research should investigate the possible mechanism of how religious commitment influences health behaviors in pregnancy.

Orientador : Paulo Mazzafera
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: O crescente interesse no estudo de espécies do gênero Hypericum, em decorrência das publicações sobre os efeitos farmacológicos de extratos de H. perforatum, fez com que surgissem nos últimos anos estudos fitoquímicos e farmacológicos com H. brasiliense, demonstrando que a espécie apresenta grande potencial farmacológico. Neste trabalho, a partir de análises fitoquímicas em raízes de H. brasiliense foram isoladas as substâncias acilfloroglucinol, xantona e ácido betulínico, que tiveram suas estruturas elucidadas através de técnicas de RMN de H1 e C13, EM, UV e IV. Tais substâncias, juntamente com quercetina e rutina, também identificadas nos extratos, foram quantificadas em diferentes partes das plantas (apical, mediana superior, mediana inferior e raiz), quando em diferentes estádios de desenvolvimento (vegetativo, florescimento e frutificação) e em plantas com 2 e 3 meses, após serem submetidas a estresse hídrico (hipoxia e déficit hídrico) e térmico (10, 30, 17 e 36°C sob baixa e alta intensidade luminosa). A variabilidade genética do material utilizado nos experimentos foi avaliada através da técnica de isozimas, utilizando dez sistemas enzimáticos. Também foi estudado o potencial morfogenético in vitro de gemas apicais provenientes de plantas em estádio de desenvolvimento juvenil e adulto. Completando o trabalho foi realizada a análise da composição do óleo essencial através de CG-EM, por co-injeção com hidrocarbonetos de cadeia longa e comparação do índice de Kovats, dos compostos identificados, com os da literatura. A maior produção de compostos fenólicos ocorreu quando as plantas encontravam-se em florescimento, mas o maior acúmulo de ácido betulínico ocorreu quando as plantas encontravam-se em frutificação. Verificou-se produção de metabólitos secundários em resposta às condições de estresse, havendo correlação inversa entre crescimento e a produção dos compostos analisados. Em condição de déficit hídrico houveram as maiores produções de compostos fenólicos totais e ácido betulínico, sendo que em temperatura noturna de 10°C e 36°C constante houve maior produção de compostos fenólicos totais. A produção de acilfloroglucinol intensificou-se sob déficit hídrico, mas a de xantona foi maior sob hipoxia. Também foi constatada produção de antocianinas em condições de elevada peroxidação lipídica. As análises isozimáticas revelaram que as enzimas eram monomórficas, com apenas 0,09% de variação de alelos, demonstrando que apesar da espécie não ser domesticada, praticamente não há variabilidade genética entre os indivíduos da população em estudo. As gemas, apicais provenientes de plantas juvenis proporcionaram desenvolvimento in vitro com dominância apical, sendo que as provenientes de plantas adultas, proporcionaram florescimento in vitro. Do óleo essencial, 20 compostos foram identificados (94,17% da composição total do óleo), sendo os principais representantes: ß-cariofileno, aromadendreno, a-humuleno, ledeno, ?-cadineno, ledol, óxido de cariofileno, epóxido de humuleno II, cubenol e a-muurolol
Abstract: The increasing interest in studying representatives of the genus Hypericum, mainly because the recent publications on the pharmacological effects of extracts of H. perforatum, has motivated Brazilian scientists to investigate the species H. brasiliense, demonstrating its phytochemical and pharmacological potential. In the present work, the substances acylfloroglucinol, xanthone and betulinic acid were isolated from rots of H. brasiliense and their structure identified by NMR-H1 and C13, mass spectrometry, UV and infrared spectra. These substances, together quercetin and rutin also identified in the extracts, were quantified in different parts of H. brasiliense plants (in the shoot - apical, middle and bottom of the canopy - and roots) , in different developmental stage (vegetative, flowering, frutification) and in plants (2 and 3 months old) subjected to water stress (hipoxy and deficit) and different temperature regimes (10, 30, 17 and 36°C under high and low light intensity). The genetic variability was also studied in the plant material used in the above experiments, using eleven isozyme systems. In addition, the in vitro morphogenetics potential of apical meristems in two developmental stages, named here juvenile and adult stages. Other phytochemical characterization was carried out with the essential oil fraction extracted from the whole plant which was analysed and identified by gas chromatography-mass spectrometry and co-injection with long chain hydrocarbons, and the data obtained compared with the Kovats index for substances already described in the literature. From the experiments of isolation and identification of substances with pharmacological potential, the phenolic substances (acylfloroglucinol, quercetina, rutin and xanthone) accumulated during the flowering. Betulinic acid was found in higher amounts at the fructification. It was observed increase of secondary metabolites in response to drought and a negative relationship between plant growth and the content of these compounds. Phenolic compounds and betulinic acid accumulated more under water stress. In addition, constant night temperatures (10°C and 36°C) induced the largest accumulation of phenolic compounds. There was an increase of acylfloroglucinol with water stress and xanthones increased under hipoxy. The stress was characterized by the increase in anthocyanins and membrane lipid peroxidation. Regarding the genetic variability, isozyme analyses showed that the enzymes used in the study were monomorphy showing only 0,09% allelic variation. This results means that despite of H. brasiliense is not domesticated genetic variability is almost absent in the population used in the present study. The apical meristem from juvenile plants proportionated plants displaying apical dominance while those from adults resulted in plants flowering in vitro. Twenty substances were isolated and identified in the analysis of the essential oil from of H. brasiliense amounting for 94.17% of the total fraction. The main substances were ß-caryophyllene, aromadendrene, a-humulene, ledene, ?-cadinene, ledol, caryophyllene oxide, humulen epoxide II, cubenol e a-muurolol
Doutorado
Doutor em Biologia Vegetal

Thesis (Ph.D.) -- University of Montana, 2008.
Title from author supplied metadata. Description based on contents viewed on June 15, 2009. ETD number: etd-03262009-133921. Author supplied keywords: Native Americans ; Medicine Wheel ; Alcohol misuse ; Substance Misuse ; Transtheoretical Model of Change. Includes bibliographical references.

Exercise training for clients at out-patient drug rehabilitation centers likely helps with coping skills. However, a better examination of the mechanisms producing changes may help identify effective interventions. PURPOSE: To test the effect of a vigorous exercise prescription on drug abstinence in voluntary rehabilitation patients. METHODS: 25 surveyed participants in a male drug treatment program underwent a 12-week minimum training program. The program included moderate-rigorous exercise and psychotherapy. Three days per week all subjects participated in EP for 90 minutes. Subjects also participated in ABIT 3 days per week where each session lasted 2 hours. Subjects also participated in ESM which ran for 90 minutes 5 days per week. Within each week, program participants also completed between 2-3 hours of psychotherapy (individual and/or group) per day, varying depending on level of care and phase of the treatment process. Exercise performance and adherence, sobriety and relapse rates, and emotional coping skills were collected. RESULTS: Subjects experienced frequent relapse (5±8 occurrences) prior to admission; however, 84% were currently sober on completion of the program, 8% relapsed during treatment, and 36% relapsed after treatment. The longest duration of sobriety a subject achieved was 273±111 days. Post-treatment survey results indicate 84% of subjects still exercised regularly, 68% continued to practice yoga or meditation, and 60% followed a diet that required disciplined awareness. Bench press max improved significantly throughout the program (39%; p<.001), as did squat (55% improvement; p<0.001) and deadlift (69.8%; p<0.001). On completion of the survey 91% of patients who exercised regularly were sober; 50% of patients who did not engage in regular exercise were sober on completion of the program (P=0.043). Owing to a small sample of patients who relapsed during treatment (N=2), the difference in exercisers who relapsed during treatment (5%) and non-exercisers who relapsed (25%) was not significant (P=0.171). Twenty-nine percent of exercisers relapsed after treatment; 75% of non-exercisers relapsed after treatment (P=0.076). The odds of managing adverse emotional states when they arose increased 20-fold among subjects who reported regular participation in exercise (Nagelkerke R2=0.333; P=0.036). Similarly, each additional day per week that a patient practiced yoga predicted a 20-day increase in duration of sobriety (R2=0.227; P=0.016). CONCLUSION: Exercise training exerts a statistically significant positive effect for sobriety and coping skills within a population that previously struggled with perpetual relapse.

Alors qu’un nombre non négligeable de produits contenant des nanomatériaux est déjà présent sur les marchés, nous manquons de recul tant en ce qui concerne les risques pour la santé et l’environnement que les bénéfices qu’ils peuvent apporter à la société sur le long terme. La présente thèse aborde la question suivante : quel régime règlementaire est en mesure de procurer le plus haut niveau de protection contre les risques avérés ou suspectés des nanotechnologies tout en soutenant simultanément la compétitivité et l'innovation ? Bien que l’Union européenne et les Etats-Unis se soient efforcés de trouver des solutions nuancées en fonction des besoins, des capacités, des enjeux inhérents à chaque secteur concerné et de leurs traditions juridiques respectives, l’on ne peut que constater l’émergence d’une réglementation des nanotechnologies à géométrie variable
While a significant number of products containing nanomaterials is already in widespread use, we have little understanding of risks and benefits they can bring to the society in the long term. The objective of this PhD thesis is to answer the following question: which regulatory framework can ensure a high level of protection against real or suspected risks of nanotechnologies while promoting competitiveness and innovation ? Although the European Union and the United States have attempted to find nuanced solutions according to the needs, capacities and challenges, which are proper to each sector concerned and their respective legal traditions, the emerging regulatory framework for nanotechnologies is characterised by a high degree of fragmentation

Connor O’Hara July 29, 2019 Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.1 The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.2 As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).3 The 5-year survival rate for metastasized CRC is <15%, and standard of care chemotherapy regimens utilizing combination treatments only marginally improve survival.3-5 Additionally, patients who have gone into remission from late-stage CRC have a high risk of recurrence despite advances in treatment.6-7 The Cancer Stem-like Cell (CSC) paradigm has grown over the last 20 years to become a unifying hypothesis to support the growth and relapse of tumors previously regressed from chemotherapy (Figure 1).8 The paradigm emphasizes the heterogeneity of a tumor and its microenvironment, proposing that a small subset of cells in the tumor are the source of tumorigenesis with features akin to normal stem cells.9 The CSCs normally in a quiescent state survive this chemotherapy and “seed” tumor redevelopment.10 First observed in acute myeloid lymphoma models, CSCs have since been identified in various other cancers (to include CRC) by their cell surface antigens and unique properties characterizing them from normal cancer cells.11-12 These include tumor initiation, limitless self-renewal capacity to generate clonal daughter cells, as well as phenotypically diverse, mature, and highly differentiated progeny.13-14 Previously our lab has identified a novel molecule called G2.2 (Figure 2) from a unique library of sulfated compounds showing selective and potent inhibition of colorectal CSCs in-vitro.15 G2.2 is a mimetic of glycosaminoglycans (GAGs) and belongs to a class of molecules called non-saccharide GAG mimetics (NSGMs). Using a novel dual-screening platform, comparisons were made on the potency of G2.2 in bulk monolayer cells, primary 3D tumor spheroids of the same cell line, and subsequent generations of tumor spheroids. This work has shown in-vitro the fold-enhancement of CSCs when culturing as 3D tumor spheroids. Spheroid culture serves as a more accurate model for the physiological conditions of a tumor, as well as the functional importance of upregulating CSCs. Evaluation of G2.2 and other NSGMs was performed in only a few cell lines, developing a need to better understand the ability of G2.2 to inhibit spheroids from a more diverse panel of cancer cells to better understand G2.2’s mechanism. The last few decades have seen the advancement in fundamental biological and biochemical knowledge of tumor cell biology and genetics.16 CRC, in particular, has served as a useful preclinical model in recapitulating patient tumor heterogeneity in-vitro.17 Recent work has characterized the molecular phenotypes of CRC cell lines in a multi-omics analysis, stratifying them into 4 clinically robust and relevant consensus molecular subtypes (CMS).18-19 Our work was directed to screen a panel of cells from each of the molecular subtypes and characterize the action of G2.2 and 2nd generation lipid-modified analogs, synthesized to improve the pharmacokinetic properties of the parent compound. Four NSGMs, namely G2.2, G2C, G5C, and G8C (Figure 2) were studied for their ability to inhibit the growth of primary spheroids across a phenotypically diverse panel. Compound HT-29 IC50 (μM) Panel Average IC50 (μM) G2.2 28 ± 1 185 ± 55 G2C 5 ± 2 16 ± 15 G5C 8 ± 2 63 ± 19 G8C 0.7 ± 0.2 6 ± 3 Primary spheroid inhibition assays were performed comparing the potency of new NSGMs to G2.2. Fifteen cell lines were evaluated in a panel of colorectal adenocarcinoma cell lines with several cell lines representing each CMS. Primary spheroid inhibition assays revealed 3 distinct response with regard to G2.2’s ability to inhibit spheroid growth. Cells from CMS 3 and 4, which display poor clinical prognosis, metabolic dysregulation, and enhanced activation of CSC pathways, showed the most sensitivity to G2.2 (mean IC50 = 89 ± 55 μM). Mesenchymal CMS 4 cell lines were over 3-fold more sensitive to treatment with G2.2 when compared to CMS 1 cell lines. Resistant cell lines were composed entirely of CMS 1 and 2 (mean IC50 = 267 ± 105 μM). In contrast, all lipid-modified analogs showed greater potency than the parent NSGM in almost every CRC cell line. Of the three analogs, G8C showed the greatest potency with a mean IC50 of less than 15 μM. Of the CRC spheroids studied, HT-29 (CMS 3) was most sensitive to G8C (IC50 = 0.73 μM). To evaluate the selectivity of NSGMs for CSC spheroid inhibition, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) cytotoxicity assays were performed on monolayer cell culture, and the fold-selectivity of NSGM for spheroids was analyzed. Data shows that NSGMs preferentially target CSC-rich spheroids compared with monolayer cellular growth, with G2.2 having over 7-fold selectivity for spheroid conditions. This fold selectivity was enhanced in CMS 3/4, supporting the idea that G2.2 targets a mesenchymal and stem-like phenotype. To further validate this selectivity, limiting dilution assays were performed across the panel to determine the tumor-initiating capacity of each cell line. Cell lines which showed a sensitive response to G2.2 were over 2-fold more likely to develop into spheroids, validating the previous hypothesis. Further characterization was performed analyzing the changes G2.2 induced on CSC markers, as well as the basal expression of a unique pair of cancer cells. Western blots showed a reduction in self-renewal marker across all CMS after treatment with G2.2, and that cell lines sensitive to G2.2-treatment overexpress mesenchymal and stem-like markers. G2.2-resistant cell lines show an epithelial phenotype, lacking this expression. The positive results observed in these studies enhance the understanding of G2.2 and analogs, and further evaluation with additional cell lines of various tissues would improve the knowledge thus far gained. However, all experiments described take valuable time to perform and analyze. Thus, there became a need to develop a high-throughput screening (HTS) platform for our assays that standardized analysis and enhanced productivity. Initial development of the method for this assay are underway, and recent evidence from these evaluations of breast cancer spheroids suggests that G2.2 and analogs may be tissue-specific compounds for the treatment of cancer. Future work entails refining the application of this method for evaluation of the NCI-60 (National Cancer Institute) tumor cell panel. Overall, these results make several suggestions concerning the NSGMs evaluated against the panel. First, G2.2 selectively targets CSCs with limited toxicity to monolayer cells of the same cell line. Further, G2.2 has the greatest potency with CMS 3/4, whose mesenchymal phenotypes are associated with poor clinical prognosis and enrichment of CSCs. Supporting evidence include that sensitive cell lines are highly tumorigenic and show enhanced expression of mesenchymal/CSC markers compared to resistant cell lines. Lipid-modification of G2.2 enhances in-vitro potency against spheroid growth, with nM potency reached in the most sensitive cell lines. Evidence in the development of a HTS platform also suggests these NSGMs show tissue specificity to cancers of the intestine. Further work characterizing the mechanism of NSGMs in a broader multi-tissue panel will enhance our understanding of the compounds as a potential therapy to dramatically improve patient survival through specific targeting of tumorigenesis. References 1. Colorectal Cancer Facts & Figures 2017-2019. American Cancer Society 2017. 2. Compton, C. C.; Byrd, D. R.; Garcia-Aguilar, J.; Kurtzman, S. H.; Olawaiye, A.; Washington, M. K. Colon and rectum. In AJCC Cancer Staging Atlas, 2nd ed.; Ed. Springer Science: New York, 2012; pp 185–201. 3. Van Cutsem, E.; Cervantes, A.; Adam, R.; Sobrero, A.; Van Krieken, J. H.; Aderka, D.; Aranda Aguilar, E.; Bardelli, A.; Benson, A.; Bodoky, G.; et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 2016, 27, 1386–422. 4. Siegel, R. L.; Miller, K. D.; Fedewa, S. A.; Ahnen, D. J.; Meester, R. G. S.; Barzi, A.; Jemal, A. Colorectal cancer statistics, 2017. CA Cancer J. Clin. 2017, 67, 177–193. 5. Moriarity, A.; O'Sullivan, J.; Kennedy, J.; Mehigan, B.; McCormick, P. Current targeted therapies in the treatment of advanced colorectal cancer: a review. Ther. Adv. Med. Oncol. 2016, 8, 276–293. 6. Seidel, J.; Farber, E.; Baumbach, R.; Cordruwisch, W.; Bohmler, U.; Feyerabend, B.; Faiss, S. Complication and local recurrence rate after endoscopic resection of large high-risk colorectal adenomas of >/=3 cm in size. Int. J. Colorectal Dis. 2016, 31, 603–611. 7. Pugh, S. A.; Shinkins, B.; Fuller, A.; Mellor, J.; Mant, D.; Primrose, J. N. Site and stage of colorectal cancer influence the likelihood and distribution of disease recurrence and postrecurrence survival: data from the FACS randomized controlled trial. Ann. Surg. 2016, 263, 1143–1147. 8. Batlle, E.; Clevers, H. Cancer stem cells revisited. Nat. Med. 2017, 23, 1124–1134. 9. Hanahan, D.; Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 2011, 144, 646–674. 10. Tirino, V.; Desiderio, V.; Paino, F.; De Rosa, A.; Papaccio, F.; La Noce, M.; Laino, L.; De Francesco, F.; Papaccio, G. Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization. FASEB J. 2013, 27, 13–24. 11. Bonnet, D.; Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 1997, 3, 730–737. 12. Desai, A.; Yan, Y.; Gerson, S. L. Concise reviews: cancer stem cell targeted therapies: toward clinical success. Stem Cells Transl. Med. 2019, 8, 75–81. 13. Munro, M. J.; Wickremesekera, S. K.; Peng, L.; Tan, S. T.; Itinteang, T. Cancer stem cells in colorectal cancer: a review. J. Clin. Pathol. 2018, 71, 110–116. 14. Zhou, Y.; Xia, L.; Wang, H.; Oyang, L.; Su, M.; Liu, Q.; Lin, J.; Tan, S.; Tian, Y.; Liao, Q.; Cao, D. Cancer stem cells in progression of colorectal cancer. Oncotarget 2018, 9, 33403–33415. 15. Patel, N. J.; Karuturi, R.; Al-Horani, R. A.; Baranwal, S.; Patel, J.; Desai, U. R.; Patel, B. B. Synthetic, non-saccharide, glycosaminoglycan mimetics selectively target colon cancer stem cells. ACS Chem. Biol. 2014, 9, 1826–1833. 16. Punt, C. J.; Koopman, M.; Vermeulen, L. From tumour heterogeneity to advances in precision treatment of colorectal cancer. Nat. Rev. Clin. Oncol. 2017, 14, 235–246. 17. Mouradov, D.; Sloggett, C.; Jorissen, R. N.; Love, C. G.; Li, S.; Burgess, A. W.; Arango, D.; Strausberg, R. L.; Buchanan, D.; Wormald, S.; et al. Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. Cancer Res. 2014, 74, 3238–3247. 18. Guinney, J.; Dienstmann, R.; Wang, X.; de Reynies, A.; Schlicker, A.; Soneson, C.; Marisa, L.; Roepman, P.; Nyamundanda, G.; Angelino, P.; et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015, 21, 1350–1356. 19. Berg, K. C. G.; Eide, P. W.; Eilertsen, I. A.; Johannessen, B.; Bruun, J.; Danielsen, S. A.; Bjornslett, M.; Meza-Zepeda, L. A.; Eknaes, M.; Lind, G. E.; et al. Multi-omics of 34 colorectal cancer cell lines - a resource for biomedical studies. Mol. Cancer 2017, 16, 116–132.

During the period of recovery from drug and alcohol misuse the individual starts to move gradually away from former habits and patterns of thinking whilst learning new skills, however returning to a normal diet can be challenging for many recovering substance misusers. Studies involving substance misuse have mainly focused on weight changes and eating behaviours during active substance addiction, whilst research on how substance misusers experience weight changes and how they describe the functions and meaning of food and eating behaviours in recovery from substance addiction is scarce. This is a qualitative study using a constructivist grounded theory approach which aimed to explicate the experiences of food, eating and weight changes from eight women in different stages of recovery (ranging from early, mid and late recovery) from drug and alcohol addiction. The areas identified from ‘the meaning of food’ included: substituting alcohol with food, structure and social benefits. The areas identified from ‘weight changes’ included: weight gain and weight loss, and the areas identified from ‘eating behaviours’ included: distorted eating and dieting. The findings lead to an emerging theory that indicated: ‘Food during recovery involved providing structure to the day, enjoyment of social eating and substituting alcohol with food, particularly sugar rich foods during early recovery to 1. Replace the substances by filling a void, 2. Satisfy the cravings and urges experienced from the substances and 3. Experience a change in mood. The excessive intake of sugar rich food caused weight gain and in turn resulted in dieting and distorted eating behaviours later in recovery’. The theory that emerged from this research should prove useful to substance misuse facilities in order to enhance and incorporate nutrition education into treatment programmes to address food, eating and weight issues faced by women in recovery from substance addiction.

The major part of this thesis is to obtain basic information in regard to changes of amino acids and middle molecular substances in fulminant hepatic failure (FHF) using a galactosamine induced rat model. The changes of these substances after hemoperfusion were also studied.
A generalized elevation of amino acid concentrations is demonstrated in the systemic blood plasma, portal plasma, CSF, cerebrum, liver, kidney and skeletal muscle tissues in GalN-FHF. The skeletal muscle is found to constitute the greatest source of accumulated amino acids in FHF. The other tissues also contribute to the increased amino acids in the body as a whole. The increase in aromatic amino acids (AAA) tyrosine, phenylalanine and free and total tryptophan were the most striking among all the amino acids, including branched chain amino acids (BCAA), in all the tissues studied. The molar ratio of BCAA/AAA was found significantly reduced in all the tissues studied. $ gamma$-amino butyric acid was found significantly increased in the cerebrum and the brain stem. Most of the increased tryptophan in plasma, and almost 100% of the increased tryptophan in the brain were in the free form (non-protein bound). The increase in tyrosine concentration in plasma was closely correlated with tyrosine in the brain. Hemoperfusion using collodion coated activated charcoal (CAC) significantly reduced a number of aromatic amino acids in the plasma. This was followed by a significant reduction of the AAA in CSF, but not in the brain, of GalN-FHF rats. Hemoperfusion using tyrosinase immobilized within artificial cells selectively reduced tyrosine in the plasma but did not influence the tyrosine level in the brain. Hemoperfusion procedures resulted in a high plasma clearance for the aromatic amino acids. The results also suggested the loss of the blood brain barrier for amino acids across the capillaries. However, transport mechanisms between brain cells themselves and interstitial fluid seems to be maintained.
The buildup of middle molecular metabolites (MW 500-2,000) was demonstrated as the elevation of middle molecule peak 7g in the plasma and brain extract samples from GalN-FHF rats using serial liquid chromatography. CAC hemoperfusion significantly reduced the levels of 7g fraction in both plasma and brain extract samples. The fraction of subpeak 7g was found to contain peptidic substances. SDS-polyacrylamide gel electrophoresis further revealed the peptide nature of some of the middle molecule substances. The estimated molecular weight of these peptides was in the range of 1,300 and 1,400. Radioimmunoassay study indicated the increase of substance P (MW 1,345) in the plasma of GalN-FHF rats.

Recognizing and understanding the potentially powerful roles that religiousness and spirituality (RS) may serve in the prevention and amelioration of disease, as well as symptom management and health related quality of life, significantly enhances research and clinical efforts across many areas of behavioral medicine. This article examines the knowledge established to date and suggests advances that remain to be made. We begin with a brief summary of the current knowledge regarding RS as related to three exemplary health conditions: (a) cardiovascular disease; (b) cancer; and, (c) substance abuse. We then focus on particular concerns for future investigations, emphasizing conceptual issues, possible mediators and moderators of relationships or effects, and methodology. Our discussion is framed by a conceptual model that may serve to guide and organize future investigations. This model highlights a number of important issues regarding the study of links between RS and health: (a) RS comprise many diverse constructs, (b) the mechanisms through which RS may influence health outcomes are quite diverse, and (c) a range of different types of health and health relevant outcomes may be influenced by RS. The multidimensional nature of RS and the complexity of related associations with different types of health relevant outcomes present formidable challenges to empirical study in behavioral medicine. These issues are referred to throughout our review and we suggest several solutions to the presented challenges in our summary. We end with a presentation of barriers to be overcome, along with strategies for doing so, and concluding thoughts.

Background: Parasites belonging to the Schistosoma genus exert an anti-haemostatic net effect upon infection of a definitive host, despite numerous mechanisms that should be pro-haemostatic. The anti-haemostatic mechanisms are thus highly interesting, as they may be leveraged for use as basis for novel anti-haemostatic therapeutics.Aim: The purpose of this systematic review is to provide an overview of research, conducted between 2010 and 2020, on Schistosoma-derived anti-haemostatic substances, as well as studies on Schistosoma-caused coagulation abnormalities, to derive a multifaceted assessment on the potential of Schistosoma-derived substances for use as basis for novel anti-haemostatic therapeutics.Method: Aggregation of publications was done through PubMed using a search string, accompanied by several exclusion criteria. The search string used was as follows: ((Schistosoma coagulation[Title/Abstract]) or (Schistosoma haemostatic[Title/Abstract])) AND ("2010/01/01"[Date - Publication] : "2020/06/01"[Date - Publication])Results: 10 original publications were aggregated: 3 patient studies, 1 murine study and 6 publications on Schistosoma-derived anti-haemostatic substances. Among these, 7 Schistosoma-derived anti-haemostatic substances were found, which were all discovered to be proteases. Conclusion: Out of the 7 proteases, 3 proteases from S. mansoni, namely SmCalp1, SmCalp2 and SmAP, were deemed to have high potential for use as basis for novel anti-haemostatic treatment development. However, research is sparse, so more research is required for a more conclusive assessment. Furthermore, high manufacturing costs of protease-based pharmaceuticals must be considered, by analyzing cost and competition. The other proteases, deemed less interesting, were found to have issues such as low specificity, conflicting pro-haemostatic effects or life-threatening effects if utilized systemically.

The use of anabolic androgenic steroids (AAS) has been associated with use of illegal or unprescribed prescription drugs, as well as different adverse psychiatric effects, such as ma-nia, psychosis and hostility. Further, there is an association between use of AAS and other different risk behaviours, including carrying guns and reckless driving. Taken together, these data suggest that there is a group of AAS users that are not elite athletes, but rather young men at risk for psychiatric illness and criminality, and who use AAS primarily for their aes-thetic effects and possibly for their psychoactive effects. The aim of this thesis is to investi-gate further the connection between use of AAS and use of other drugs, and to investigate whether the proposed side effects of AAS cause an increase in morbidity and mortality. The first study (Paper I) investigates morbidity and mortality in persons testing positive for AAS compared to persons testing negative for AAS at a doping laboratory. Paper II of this thesis studies the presence of psychoactive drugs in diseased men who tested positive for AAS upon autopsy and whether there is any difference between deceased users of AAS and deceased users of heroin or amphetamine (control group). The third article (Paper III) dis-cusses a surprising finding in paper I of increased seizures NOS in users of AAS. Paper IV and V are interview studies from an out-patient substance abuse clinic. The main findings in Paper I was that the majority of deceased users of AAS were also positive for other drugs and/or alcohol on autopsy, and that users of AAS more often than the control group had died from intentional death (suicide or homicide). The main finding of Paper II was that users of AAS were severely at risk for premature death compared to both the control group and the general population. Paper III concluded that the high prevalence of Convulsion NOS in users of AAS most likely was the result of concomitant substance abuse and withdrawal from such use. Paper IV concluded that twelve percent of the patients at the substance abuse clinic had used AAS for at least one cycle. Users of AAS had a higher risk of having been convicted of a violent offence, and users of AAS more often reported having been physically abused. In Paper V, long-terme users of AAS were found to have an increased risk for developing depression in connection with cessation of AAS use. AAS was also re-ported to be used in preparation for crime. In summary, this thesis concludes that there is a solid association between use of AAS and use of other psychotropic drugs in certain subpopulations, and that users of AAS are at risk for premature death due to unnatural causes that may be secondary to use of AAS.

The United Nations has, during many years, developed a model for a globally harmonized system for classification and labeling of chemicals, with the aim of it becoming a global standard. This system is implemented in the European Union through the CLP-regulation and is now working parallel to the existing directives until 1st of June 2015, when all the new classifications of substances and mixtures must be completed. The aim of this project was to adjust the laboratory to the new legislation, through inventory of stored chemicals, update the list of chemicals and perform self-classifications of mixtures. The work included handling of about 650 different chemicals with varying hazard classifications and search for information in corporate websites and chemical databases. This resulted in a new and complete list of chemicals stored and used in the laboratory and, in addition, an example of how to make a self classification of a mixture. Through this work using web based search for chemical classification according to the CLP-regulation, many difficulties were encountered and one of the conclusions is that due to the many noticed uncertainties and inconsistencies in self classification of mixtures the aim of keeping the globally harmonized system harmonized will be nearly impossible to fulfill.

Sexual minorities (lesbians, gays, and bisexuals) have a greater risk for substance abuse and mental illness than sexual majorities (heterosexuals). Associations between substance abuse and mental illness among sexual minority adults have not been widely studied. The purpose of this quantitative cross-sectional study was to use the 2015 National Survey on Drug Use and Health data from the Substance Abuse and Mental Health Administration to study the association of substance abuse (alcohol; hard drugs such as heroin, cocaine, methamphetamine; and hallucinogens), prescribed drugs (pain relievers, tranquilizers, sedatives, stimulants, psychotherapeutic, and inhalants, as well as marijuana) and mental illness (no past year, mild, moderate, and severe in the past year) among sexual minority adults ages 18 and older in the United States. Confounding factors that may influence these associations were controlled. The theoretical framework for this study was Meyer's minority stress model. The sample was 43,561 adults. Chi-square and logistic regression analyses were performed to estimate odds for mental illness by drug type. Findings showed that higher odds of mental illness were significantly associated with prescribed drugs and marijuana abuse (OR: 3.48, 95% CI:1.66, 7.29) among gays/lesbians, and with alcohol abuse among bisexuals (OR: 2.31, 95% CI: 1.62, 3.29). Positive social change resulting from this study may include increased knowledge of associations between substance abuse and mental illness among sexual minority adults and guidance for public health interventions to improve sexual minorities' access to early substance abuse and mental health prevention and treatment.

Dr. Robert Pack is Professor of Community and Behavioral Health, Associate Dean for Academic Affairs in the College of Public Health at East Tennessee State University, and Director of the new ETSU Center for Prescription Drug Abuse Prevention and Treatment. The Center grew out of a university and community collaborative that was started in 2012 to address the regional problem of prescription opioid abuse. At least five funded projects and dozens of other academic products have grown out of the Working Group. Dr. Pack is currently PI of the NIH/NIDA-funded Diversity Promoting Institutions Drug Abuse Research Program at ETSU, the research component of which is the five-year set of three studies titled Inter-professional Communication to Prevent Prescription Drug Abuse and Misuse. He was trained in health education/health promotion at the UAB Royals School of Public Health and is experienced in designing, running and disseminating theory-based intervention studies. In 2014, he was trained at the NIH-funded Training Institute for Dissemination and Implementation Research in Health (TIDIRH, Boston, 2014).

Background: Obesity remains a major public health problem and a risk factor for developing chronic diseases. Substance use such as e-cigarette, marijuana, and alcohol have been associated with the risk of being obese. However, the results from previous studies have been inconsistent. The purpose of this study is to determine the association between substance use and obesity among adults in the United States. Method: Data from the 2016 Behavioral Risk Factor Surveillance System (BRFSS), an annual cross-sectional survey administered to 446,687 adults in all 50 states to collect information about their health-related risk behaviors, chronic health conditions and the use of preventive services, was used in this study. Data was collected via a self-reported questionnaire validated by CDC. A multiple logistic regression model was conducted to determine the association between exposure variables (e-cigarette, marijuana, and alcohol abuse) and obesity. The model was adjusted for possible confounders such as demographics (age, sex and race) and behaviors such as tobacco smoking and physical activity. The data was analyzed using SAS v 9.4. Results: Individuals who used marijuana during the past 30 days were 32.4% less likely (adjusted odds ratio (aOR): 0.676, 95% CI: 0.631-0.723, P<0.001) to be obese compared to those who did not. The odds of being obese among heavy alcohol drinkers was 30% less (aOR: 0.70, 95% CI: 0.679-0.721, p<0.001) compared to those who were not heavy alcohol drinkers. Conclusion: The study findings demonstrate that marijuana and heavy alcohol drinking are significantly associated with reduced likelihood of obesity. However, e-cigarette use was not significantly associated with obesity. Further longitudinal studies to explore the relationship between these substances and obesity will be beneficial.