Alterações do Funcionamento da Glândula da Tiróide

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Xerostomia e hipofunção das glândulas salivares

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Medicina Dentária

Recent national trends in Salvia divinorum use and substance-use disorders among recent and former Salvia divinorum users compared with nonusers.

CONTEXT: Media and scientific reports have indicated an increase in recreational use of Salvia divinorum. Epidemiological data are lacking on the trends, prevalence, and correlates of S. divinorum use in large representative samples, as well as the extent of substance use and mental health problems among S. divinorum users. OBJECTIVE: To examine the national trend in prevalence of S. divinorum use and to identify sociodemographic, behavioral, mental health, and substance-use profiles of recent (past-year) and former users of S. divinorum. DESIGN: Analyses of public-use data files from the 2006-2008 United States National Surveys on Drug Use and Health (N = 166,453). SETTING: Noninstitutionalized individuals aged 12 years or older were interviewed in their places of residence. MAIN MEASURES: Substance use, S. divinorum, self-reported substance use disorders, criminality, depression, and mental health treatment were assessed by standardized survey questions administered by the audio computer-assisted self-interviewing method. RESULTS: Among survey respondents, lifetime prevalence of S. divinorum use had increased from 0.7% in 2006 to 1.3% in 2008 (an 83% increase). S. divinorum use was associated with ages 18-25 years, male gender, white or multiple race, residence of large metropolitan areas, arrests for criminal activities, and depression. S. divinorum use was particularly common among recent drug users, including users of lysergic acid diethylamide (53.7%), ecstasy (30.1%), heroin (24.2%), phencyclidine (22.4%), and cocaine (17.5%). Adjusted multinomial logistic analyses indicated polydrug use as the strongest determinant for recent and former S. divinorum use. An estimated 43.0% of past-year S. divinorum users and 28.9% of former S. divinorum users had an illicit or nonmedical drug-use disorder compared with 2.5% of nonusers. Adjusted logistic regression analyses showed that recent and former S. divinorum users had greater odds of having past-year depression and a substance-use disorder (alcohol or drugs) than past-year alcohol or drug users who did not use S. divinorum. CONCLUSION: S. divinorum use is prevalent among recent or active drug users who have used other hallucinogens or stimulants. The high prevalence of substance use disorders among recent S. divinorum users emphasizes the need to study health risks of drug interactions.

An operant determination of the behavioural mechanism of benzodiazepine enhancement of food intake

Rationale A recent review paper by Cooper (Appetite 44:133–150, 2005) has pointed out that a role for benzodiazepines as appetite stimulants has been largely overlooked. Cooper’s review cited several studies that suggested the putative mechanism of enhancement of food intake after benzodiazepine administration might involve increasing the perceived pleasantness of food (palatability). Objectives The present study examined the behavioral mechanism of increased food intake after benzodiazepine administration. Materials and methods The cyclic-ratio operant schedule has been proposed as a useful behavioral assay for differentiating palatability from regulatory effects on food intake (Ettinger and Staddon, Physiol Behav 29:455–458, 1982 and Behav Neurosci 97:639–653, 1983). The current study employed the cyclic-ratio schedule to determine whether the effects on food intake of chlordiazepoxide (CDP) (5.0 mg/kg), sodium pentobarbital (5.0 mg/kg), and picrotoxin (1.0 mg/kg) were mediated through palatability or regulatory processes. Results The results of this study show that both the benzodiazepine CDP and the barbiturate sodium pentobarbital increased food intake in a manner similar to increasing the palatability of the ingestant, and picrotoxin decreased food intake in a manner similar to decreasing the palatability of the ingestant. Conclusions These results suggest that the food intake enhancement properties of benzodiazepines are mediated through a mechanism affecting perceived palatability.

Spatial attentional bias as a marker of genetic risk, symptom severity, and stimulant response in ADHD

Attention-deficit hyperactivity disorder (ADHD) is a heritable childhood onset disorder that is marked by variability at multiple levels including clinical presentation, cognitive profile, and response to stimulant medications. It has been suggested that this variability may reflect etiological differences, particularly, at the level of underlying genetics. This study examined whether an attentional phenotype-spatial attentional bias could serve as a marker of symptom severity, genetic risk, and stimulant response in ADHD. A total of 96 children and adolescents with ADHD were assessed on the Landmark Task, which is a sensitive measure of spatial attentional bias. All children were genotyped for polymorphisms (30 untranslated (UTR) and intron 8 variable number of tandem repeats (VNTRs)) of the dopamine transporter gene (DAT1). Spatial attentional bias correlated with ADHD symptom levels and varied according to DAT1 genotype. Children who were homozygous for the 10-repeat allele of the DAT1 30-UTR VNTR displayed a rightward attentional bias and had higher symptom levels compared to those with the low-risk genotype. A total of 26 of these children who were medication naive performed the Landmark Task at baseline and then again after 6 weeks of stimulant medication. Left-sided inattention (rightward bias) at baseline was associated with an enhanced response to stimulants at 6 weeks. Moreover, changes in spatial bias with stimulant medications, varied as a function of DAT1 genotype. This study suggests an attentional phenotype that relates to symptom severity and genetic risk for ADHD, and may have utility in predicting stimulant response in ADHD.

Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma.

A radioiodinated ligand, [125I]SB-236636 [(S)-(-)3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]3-[125I]iodophenyl]2-ethoxy propanoic acid], which is specific for the ? isoform of the peroxisomal proliferator activated receptor (PPAR?), was developed. [125I]SB-236636 binds with high affinity to full-length human recombinant PPAR?1 and to a GST (glutathione S-transferase) fusion protein contg. the ligand binding domain of human PPAR?1 (KD = 70 nM). Using this ligand, the authors characterized binding sites in adipose-derived cells from rat, mouse and humans. In competition expts., rosiglitazone (BRL-49653), a potent antihyperglycemic agent, binds with high affinity to sites in intact adipocytes (IC50 = 12, 4 and 9 nM for rat, 3T3-L1 and human adipocytes, resp.). Binding affinities (IC50) of other thiazolidinediones for the ligand binding domain of PPAR?1 were comparable with those detd. in adipocytes and reflected the rank order of potencies of these agents as stimulants of glucose transport in 3T3-L1 adipocytes and antihyperglycemic agents in vivo: rosiglitazone > pioglitazone > troglitazone. Competition of [125I]SB-236636 binding was stereoselective in that the IC50 value of SB-219994, the (S)-enantiomer of an ?-trifluoroethoxy propanoic acid insulin sensitizer, was 770-fold lower than that of SB-219993 [(R)-enantiomer] at recombinant human PPAR?1. The higher binding affinity of SB-219994 also was evident in intact adipocytes and reflected its 100-fold greater potency as an antidiabetic agent. The results strongly suggest that the high-affinity binding site for [125I]SB-236636 in intact adipocytes is PPAR? and that the pharmacol. of insulin-sensitizer binding in rodent and human adipocytes is very similar and, moreover, predictive of antihyperglycemic activity in vivo.

Experiences with mephedrone pre- and post-legislative controls: Perceptions of safety and sources of supply

Background: Drug scenes within several countries have changed in recent years to incorporate a range of licit psychoactive products, collectively known as “legal highs.” Hundreds of different legal high products have been described in the literature. Many of these products contain synthetic stimulants that allegedly
“mirror” the effects of some illicit drugs. In 2009–2010, growing concern by the UK and Irish governments focused on mephedrone, a synthetic stimulant that had become embedded within several drug scenes in Britain and Ireland. In April 2010, mephedrone and related cathinone derivatives were banned under
the UK’s Misuse of Drugs Act 1971. Setting aside “worse case scenarios” that have been portrayed by UK and Irish media, little is known about mephedrone use from the consumer’s perspective. The purpose of this paper was to (1) explore respondents’ experiences with mephedrone, (2) examine users’ perceptions
about the safety of mephedrone, and primarily to (3) examine sources of mephedrone supply during the pre- and post-ban periods.
Methods: Semi-structured interviews were conducted with 23 adults who had used mephedrone during 2009–2010. Data collection occurred in May and June 2010, following the ban on mephedrone. A total of 20/23 respondents had used mephedrone during the post-ban period, and the vast majority had prior
experience with ecstasy or cocaine. Respondents’ ages ranged from 19 to 51, approximately half of the sample were female and the majority (19 of 23) were employed in full- or part-time work.
Results: Most respondents reported positive experiences with mephedrone, and for some, the substance emerged as a drug of choice. None of the respondents reported that the once-legal status of mephedrone implied that it was safe to use. Very few respondents reported purchasing mephedrone from street-based
or on-line headshops during the pre-ban period, and these decisions were guided in part by respondents’ attempts to avoid “drug user” identities. Most respondents purchased or obtained mephedrone from friends or dealers, and mephedrone was widely available during the 10-week period following the ban. Respondents reported a greater reliance on dealers and a change in mephedrone packaging following the criminalisation of mephedrone.
Conclusion: The findings are discussed in the context of what appears to be a rapidly changing mephedrone market. We discuss the possible implications of criminalising mephedrone, including the potential displacement effects and the development of an illicit market.

MODULATORY ACTION OF HELICOBACTER-PYLORI ON HISTAMINE-RELEASE FROM MAST-CELLS AND BASOPHILS IN-VITRO

Helicobacter pylori is important in the aetiology of peptic ulceration. Despite inducing an inflammatory response in the mucosa, the organism persists, suggesting that it has efficient protective mechanisms. Some bacterial and viral products modulate histamine secretion from inflammatory cells. Therefore, this study examined the modulatory effects of H. pylori preparations on histamine release from rat peritoneal mast cells and human basophils. Eleven clinical isolates of H. pylori were prepared in different ways: as whole washed bacteria, washed sonicated bacteria, and formalin-killed bacteria, and as outer-membrane and lipopolysaccharide (LPS) extracts. Histamine release from mast cells or basophils was not elicited by any of these bacterial preparations alone. However, when mixed with various secretory stimulants, the bacterial preparations caused inhibition of histamine release from rat mast cells (calcium ionophore A23187, compound 48/80, concanavalin A, anti-rat IgE) and human basophils (A23187, N-formyl Met-Leu-Phe). The degree of inhibition ranged from 48 % to 97 %. These results indicate that H. pylori exerts an inhibitory effect on cells of the immune system that contributes to its persistence within the gastric mucosa.

Primary airway epithelial cell culture and asthma in children-lessons learnt and yet to come

Until recently the airway epithelial cell (AEC) was considered a simple barrier that prevented entry of inhaled matter into the lung parenchyma. The AEC is now recognized as having an important role in the inflammatory response of the respiratory system to inhaled exposures, and abnormalities of these responses are thought to be important to asthma pathogenesis. This review first explores how the challenges of studying nasal and bronchial AECs in children have been addressed and then summarizes the results of studies of primary AEC function in children with and without asthma. There is good evidence that nasal AECs may be a suitable surrogate for the study of certain aspects of bronchial AEC function, although bronchial AECs remain the gold standard for asthma research. There are consistent differences between children with and without asthma for nasal and bronchial AEC mediator release following exposure to a range of pro-inflammatory stimulants including interleukins (IL)-1β, IL-4, and IL-13. However, there are inconsistencies between studies, e.g., release of IL-6, an important pro-inflammatory cytokine, is not increased in children with asthma relative to controls in all studies. Future work should expand current understanding of the "upstream" signalling pathways in AEC, study AEC from children before the onset of asthma symptoms and in vitro models should be developed that replicate the in vivo status more completely, e.g., co-culture with dendritic cells. AECs are difficult to obtain from children and collaboration between centers is expected to yield meaningful advances in asthma understanding and ultimately help deliver novel therapies. 

Regular medication reviews for children and young people with ADHD

The National Institute for Health and Care Excellence's (2008) guidelines for the diagnosis and management of attention deficit hyperactivity disorder (ADHD) recommend a full clinical and psychological assessment by an appropriately trained clinician; this should include a detailed developmental and psychiatric history. Stimulant medications, which are Schedule II controlled drugs, are the most commonly prescribed medicines in the UK and across the world for the management of ADHD. Children and young people with a diagnosis of ADHD receiving these stimulant medications are required to attend regular review appointments with a consultant child and adolescent psychiatrist or specialist nurse under shared care guidelines with general practices, and it has long been recognized that appropriately educated nurses can assist in the management of ADHD. Owing to the pharmacological action of the stimulant medication on neurotransmission, there is potential for misuse and dependence. A growing body of evidence suggests that adolescents with ADHD can become involved in drug diversion and that the topic should be explored during assessment. The level of misuse of prescribed stimulants is increasing, and adolescents and young people with ADHD may misuse to enhance cognitive function for academic purposes. The following scenario highlights some of the challenges and opportunities for independent nurse prescribers working in child and adolescent mental health services.

Situated regional university incubation: A multi-level stakeholder perspective

From a macro perspective, it is widely acknowledged that University incubation models within a region are important stimulants of economic development through innovation and job creation. With the emergence of quadruple helix innovation ecosystems, universities have had re-evaluate their University incubation activity and models to engage more fully with industry and end users. However, within a given region, the type of University may influence their ability to engage with quadruple helix stakeholders and consequently impact their incubation activity. To date there is a scarcity of research which explores this 'meso' environment and its subsequent impact on University incubation models. Therefore, the aim of this paper is to use a stakeholder lens to explore University Incubation models within unique regional and organisational characteristics and constraints. The research methodology employed was based on a comparative case analysis of incubation of two different Universities within a UK peripheral region. It was found that variances existed in relation to the two universities incubation models which were found to result from both regional (macro environment) and organisational (meso environment) influences (i.e. university type). This research contributes to both regional and national agendas by empirically illustrating the need for appropriate design and tailoring of university incubation models (via acknowledgement of quadruple helix stakeholder influence) to incorporate contextual influences rather than adopting a best practise approach.

During pregnancy, recreational drug-using women stop taking ecstasy (3,4-methylenedioxy-N-methylamphetamine) and reduce alcohol consumption but continue to smoke tobacco and cannabis

While recreational drug use in UK women is prevalent, to date there is little prospective data on patterns of drug use in recreational drug-using women immediately before and during pregnancy. A total of 121 participants from a wide range of backgrounds were recruited to take part in the longitudinal Development and Infancy Study (DAISY) study of prenatal drug use and outcomes. Eighty-six of the women were interviewed prospectively while pregnant and/or soon after their infant was born. Participants reported on use immediately before and during pregnancy and on use over their lifetime. Levels of lifetime drug use of the women recruited were high, with women reporting having used at least four different illegal drugs over their lifetime. Most users of cocaine, 3,4-methylenedioxy-N-methylamphetamine (MDMA) and other stimulants stopped using these by the second trimester and levels of use were low. However, in pregnancy, 64% of the sample continued to use alcohol, 46% tobacco and 48% cannabis. While the level of alcohol use reduced substantially, average tobacco and cannabis levels tended to be sustained at pre-pregnancy levels even into the third trimester (50 cigarettes and/or 11 joints per week). In sum, while the use of ‘party drugs’ and alcohol seems to reduce, levels of tobacco and cannabis use are likely to be sustained throughout pregnancy. The data provide polydrug profiles that can form the basis for the development of more realistic animal models.

Assessing the Activity of Agonistic Autoantibodies in Systemic Sclerosis and their Effects on Cultured Vascular Smooth Muscle Cells

La sclérose systémique (ScS) est une maladie auto-immune dévastatrice d'étiologie inconnue. Le dysfonctionnement immunitaire, la fibrose et la vasculopathie sont les trois principales caractéristiques de cette maladie. Une récente étude a révélé un nouveau lien entre l'auto-immunité et la fibrose, par la présence d'auto-anticorps stimulant le récepteur du facteur de croissance dérivé des plaquettes (PDGFR) des fibroblastes. Ces auto-anticorps sont capables de stimuler les espèces réactives de l'oxygène et d’activer la kinase régulée par un signal extracellulaire (ERK1/2). L’hypothèse que nous formulons est que les cellules musculaires lisses vasculaires (VSMCs) exprimant conjointement les PDGFR, répondront elles aussi aux autoanticorps anti-PDGF-R. Le travail présenté ici vise à valider la présence d'auto-anticorps PDGFR dans les sérums de patients ScS, et à caractériser ensuite la réponse de VSMCs exposées à de l'immunoglobuline G (IgG) de ces sérums, en mesurant l’activation des cascades de signalisation spécifiques, ainsi que l'induction des gènes impliqués dans la réponse fibrotique. Nos résultats démontrent la présence d'une fraction IgG stimulant une réponse phénotypique dans les cultures de VSMCs. Notamment, d’importantes régulations positive et négative des gènes pro-fibrotiques tgfb1 et tgfb2 respectivement, ont été observées dans les VSMCs exposées à des fractions de ScS-IgG. Les fractions de IgG positives pour l'activation de ERK étaient présentes dans la plupart, mais pas dans tous les échantillons de SSc (68%, 19/28), et moins présentes dans les contrôles 27% (11/3). Bien que, les fractions de SSc-IgG ont pu considérablement immunoprécipiter le PDGFR, l'utilisation d'un inhibiteur spécifique des récepteurs au PDGF (AG1296), n'a pas inhibé l'activation de ERK médiée par les fractions de SSc-IgG. Globalement, nos résultats indiquent la présence d'autoanticorps stimulants avec activité pro-fibrotique dans les sérums des patients ScS. Des travaux sont en cours pour identifier l'entité moléculaire responsable de la réponse d’IgG observée dans les cultures de VSMCs.

Les relations d’attachement et d’activation père-enfant : effet modérateur de l’engagement paternel pour prédire le développement socio-affectif des enfants

Tout autant que la mère, le père est une figure d’attachement importante pour l’enfant. Toutefois le lien d’attachement père-enfant se formerait différemment du lien d’attachement mère-enfant. Les pères sont souvent plus engagés que les mères dans des activités ludiques, moins dans des activités de soins. Les jeux faits avec le père sont souvent plus physiques aussi, plus stimulants. En incitant son enfant au jeu de façon sensible, le père devient un tremplin pour l’exploration de son enfant et le développement de sa confiance en soi et en l’autre. C’est en tant que figure d’ouverture sur le monde que le père aurait une plus grande influence sur le développement de son enfant. C’est ce que nous apprennent les études sur l’engagement paternel. Jusqu’à maintenant peu d’auteurs ont étudié l’engagement des pères en même temps que l’attachement père-enfant, mais plusieurs proposent déjà que cette fonction d’ouverture sur le monde expliquerait la formation du lien père-enfant. La relation d’attachement père-enfant serait basée sur une relation d’activation. L’objectif de la présente thèse est précisément de mieux comprendre la nature du lien d’attachement père-enfant. Deux articles composent cette thèse. Le premier article est théorique et fait une recension de la littérature sur l’attachement père-enfant et l’engagement paternel. Le deuxième article est empirique et propose justement de vérifier l’influence de l’engagement paternel sur la formation du lien d’attachement au père. En tout 53 dyades pères-enfants ont participé à cette étude. L’engagement des pères au niveau du réconfort, de la stimulation et de la discipline a été évalué lorsque les enfants avaient entre 12 et 18 mois. À cet âge, la qualité d’attachement et de la relation d’activation ont aussi été évaluées, respectivement avec la Situation étrangère et la Situation risquée. Les deux mises en situation ont ensuite été comparées pour voir laquelle prédit mieux le développement des enfants à l’âge préscolaire, au niveau des compétences sociales, des problèmes intériorisés et des problèmes extériorisés. Les résultats obtenus indiquent que la Situation risquée prédit mieux le développement socio-affectif des enfants (compétences sociales et problèmes intériorisés). Aucun lien n’a été trouvé avec la Situation étrangère, même en tenant compte de l’engagement du père au niveau du réconfort. Ces résultats valident la théorie de la relation d’activation et l’importance de la fonction paternelle d’ouverture sur le monde. Les limites de la présente étude, ainsi que ses implications théoriques et méthodologiques, seront abordées dans la discussion du deuxième article et en conclusion de la présente thèse.

Évaluation préliminaire de l’efficacité de la duloxétine dans le déficit de l’attention chez l’adulte : essai randomisé contrôlé

Le trouble du déficit de l’attention avec ou sans hyperactivité (TDAH) est de plus en plus reconnu chez l'adulte. Les psychostimulants représentent la première ligne de traitement, mais ceux-ci ne sont parfois pas tolérés, peuvent être contrindiqués ou ne pas être efficaces. Les médicaments non stimulants constituent une alternative mais ont été insuffisamment explorés. Cette thèse présente un essai clinique randomisé contrôlé de 30 sujets souffrant de TDAH qui ont reçu soit la duloxétine 60 mg par jour ou le placebo pendant une période de 6 semaines. Le Conners’ Adult ADHD Rating Scale (CAARS) et le Clinical Global Impression scale (CGI) ont été utilisés pour mesurer la sévérité des symptômes et l'amélioration clinique. Le Hamilton Anxiety Rating Scale (HARS) et le Hamilton Depression Rating Scale (HDRS) ont été choisis pour vérifier l'impact sur la symptomatologie anxio-dépressive. Les résultats démontrent que les sujets ayant reçu la duloxétine avait un score au CGI-Severity (CGI-S) inférieur au groupe contrôle à 6 semaines de traitement et une amélioration plus importante au CGI-Improvement (CGI-I). Ce groupe démontre également des diminutions supérieures des scores à plusieurs sous-échelles du CAARS. Aucun effet n'a été observé sur le HARS et le HDRS. Le taux de retrait du bras duloxetine remet par contre en question la dose initiale choisie dans ce protocole. La duloxétine semble donc une option prometteuse dans le traitement du TDAH chez l'adulte et la réplication des données cliniques serait la prochaine étape pour confirmer ces résultats.