Dissertations / Theses on the topic 'Dual pathology'

Active learning strategies are important for facilitating deep learning that may be carried throughout life, but which is still finding its way into the college setting. Educators are not often trained in effective learning practices, which reduces the cognitive and proficiency gains of their students. By providing such guidance in the formative years of a teacher’s training, we hypothesize that the learning environment will be greatly enriched and enhanced. On the opposite end of the spectrum of life and cognition, the plague of dementia also warrants examination. Alzheimer’s disease (AD), an incurable neurodegenerative disorder progressing from the medial temporal lobe, is the most common form of dementia diagnosed in people over age 65, afflicting 30-40% of those 85 years and older. Despite its prevalence, effective treatments are limited because the principal causes and triggers of AD are not entirely understood. Growing evidence demonstrates that oxidative stress (OS) is an important factor contributing to the initiation and progression of AD. A key player contributing to this OS is iron, an essential trace mineral which is required for proper neuronal function, but which generates reactive oxygen species during redox transitions. Intracellular labile iron pool (LIP) levels are strictly regulated by proteins such as transferrin (import), ferroportin (export), and ferritin (storage). However, when these proteins become dysregulated, excess iron associates with other proteins such as amyloid beta (Aβ) and tau, aggregations of which are hallmarks of AD. In our hypothetical model, under extensive or prolonged OS, as occurs in AD, much larger Aβ plaques form because the stress does not abate. Hyperphosphorylated tau is the last resort to protect the cell against free iron, and aggregates when the LIP is elevated because neither iron storage in ferritin nor iron export through ferroportin can relieve the neurons of the free iron.

El término patología dual describe la coexistencia de una o más enfermedades mentales y trastornos por el uso de sustancias, la cual es muy común y, a menudo, se asocia con una mayor gravedad psiquiátrica y peores condiciones médicas y sociales. Últimamente ha adquirido relevancia la investigación relacionada con el papel del sistema endocannabinoide (eCB) en las bases neurobiológicas de diversas afecciones neuropsiquiátricas, tales como la ansiedad, los trastornos del estado de ánimo o la esquizofrenia, así como los trastornos relacionados con el uso de sustancias. El propósito de este estudio es investigar la asociación entre varios polimorfismos de los genes que codifican algunas proteínas del sistema endocannabinoide (receptor de cannabinoides 1 [CNR1] y amida hidrolasa de ácido graso [FAAH]) de acuerdo con (1) la presencia o ausencia de uso de sustancias trastornos en toda la muestra y (2) según la presencia o ausencia de patología dual en el grupo de sujetos diagnosticados con un trastorno por uso de sustancias. Es un estudio de casos y controles con un tamaño muestral de 675 sujetos, de los cuales 362 son controles (C; individuos sin diagnóstico psiquiátrico) y 313 casos (Cs; individuos con un trastorno por uso de sustancias sin ningún trastorno neuropsiquiátrico comórbido [ TCS] así como individuos con un trastorno de uso de sustancias con una enfermedad neuropsiquiátrica comórbida [PD]). Se compararon los grupos C y Cs y los grupos TCS y PD en base a datos demográficos, antecedentes familiares y personales de trastornos psiquiátricos y trastornos por uso de sustancias (mediante la versión española validada de la Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV)) y los rasgos de personalidad (evaluada con la versión española del Cloninger’s Temperament and Character Inventory (TCI-R). Se genotiparon 768 polimorfismos de nucleótido único (SNP) que se utilizaron como marcadores genéticos en una aproximación de estudio de gen candidato. Se realizaron análisis estadísticos simples de polimorfismos, genes y haplotipos así como un posterior análisis multivariante. Finalmente se relacionaron los resultados del análisis genético con las características sociodemográficas y clínicas de la muestra. Los sujetos Cs mostraron una mayor prevalencia de antecedentes familiares de enfermedades mentales y trastornos por uso de sustancias, así como una puntuación más baja en dependencia de la recompensa, autodirección, cooperación y autotrascendencia respecto a los sujetos C. Asimismo, los sujetos PD tenían mayor prevalencia de trastornos por consumo de alcohol y cocaína, menor prevalencia de trastornos por consumos de cannabis y mayor prevalencia de antecedentes familiares de enfermedades mentales y trastornos por uso de sustancias frente a los sujetos TCS. Además, los sujetos con TCS obtuvieron puntuaciones más altas en evitación del daño y autotrascendencia, aunque el resultado en autodirección fue significativamente más bajo en los sujetos con PD. Se halló una prevalencia significativa de las variantes AA/AC de SNP rs324420 y TT de SNP rs11576941 (ambos SNP que pertenecen al mismo haplotipo del gen FAAH) en el grupo Cs en el estudio de asociación de CS vs. C. La prevalencia fue también significativa en el caso de la variante TT del SNP rs11576941 que pertenece al gen FAAH en el grupo TCS en el estudio de asociación de TCS frente a C. Además, se detectó un subgrupo de sujetos del grupo de DP con puntuaciones significativamente más bajas en la dimensión de la personalidad evitación del daño que se caracterizan por ser homocigotos GG para el SNP rs806380 del gen CNR1. Esta variación alélica se ha asociado con una mayor sensibilidad para los estímulos positivos y podría representar un marcador endofenotípico para aquellos sujetos con mayor inestabilidad emocional y, por lo tanto, con mayor gravedad clínica potencial.
The term dual pathology describes the coexistence of one or more mental illnesses and substance use disorders which is very common and is often associated with higher psychiatric severity, and worse medical conditions and social status. Likewise, there is now an important body of research on the important role that the endocannabinoid system (eCB) could play on the neurobiological bases of various neuropsychiatric conditions, such as anxiety, mood disorders or schizophrenia, in addition to several substance use disorders. The purpose of this study is to investigate the association between various polymorphisms of the genes encoding for some endocannabinoid system proteins (cannabinoid receptor 1 [CNR1] and fatty acid amide hydrolase [FAAH]) according to (1) the presence or absence of substance use disorders in the whole sample and (2) according to the presence or absence of dual pathology within the group of subjects diagnosed with a substance use disorder. This is a case-control study with a total sample size of 675 subjects, of whom 362 are controls (C; individuals without any psychiatric diagnosis) and 313 cases (Cs; individuals with a substance use disorder without any co-morbid neuropsychiatric condition [TCS] and those individuals with a substance use disorder with co-morbid neuropsychiatric condition [PD]). A comprehensive comparison including demographics, parental and personal background of psychiatric and substance use disorders (according to DSM-IV-R and performed by using the Spanish validated version of Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV)) and personality characteristics (evaluated using the Spanish version of the Cloninger’s Temperament and Character Inventory (TCI-R))was performed between both Cs and C groups and between TCS and PD groups. 768 single-nucleotide polymorphisms (SNPs) were genotyped wich were used as genetic markers in an approximation of candidate gene study. Simple statistical analysis of polymorphisms, genes and haplotypes and subsequent multivariate analysis were performed. We will relate the results of genetic analysis with sociodemographic and clinical characteristics. The phenotypical results of the comparison between both Cs and C groups showed that Cs subjects had greater prevalence of family background of mental illness and substance use disorders and a lower score on reward dependence, self-directness, cooperativeness and self-transcendence as regarding on personality traits. Likewise, TCS and PD groups contrast show that PD subjects had higher prevalence of alcohol and cocaine use disorders and lower prevalence of cannabis use disorder, as well as a higher prevalence of family background of mental illness and substance use disorders. In addition, TCS subjects had higher score on harm avoidance and self-transcendence but, interestingly, PD subjects score significantly lower on self-directness. We have found a significant prevalence of the AA/AC variants of SNP rs324420 and TT of SNP rs11576941 (both SNPs belonging to the same haplotype of the FAAH gene) in the Cs group in the association study of CS vs. C. The prevalence was significant in the case of the TT variant of the SNP rs11576941 belonging to the FAAH gene in the TCS group in the association study of TCS vs. C. Furthermore, a subgroup of subjects of the PD group with significantly lower scores in the personality dimension harm avoidance that are characterized by being homozygous GG for the SNP rs806380 of the CNR1 gene have been detected. This allelic variation has been associated with a greater sensitivity for positive stimuli and could represent an endophenotypic marker for those subjects with higher emotional instability and, therefore, with greater clinical potential severity.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in developed countries. Aggressive research is underway to elucidate putative molecular targets for therapy for both the atrophic and neovascular forms of this disease. Current pharmacotherapy is effective in some patients but not sufficient to halt disease progression or repair damage that has already occurred. Drug intervention and retinal cell replacement represent the two most promising potential treatment avenues. The purpose of this thesis was to investigate the role of a recently identified regulator of neural development, SIRT1, in retinogenesis and to further investigate whether pharmacological inhibition of this protein represents a possible treatment option in neovascular AMD. Via immunohistochemistry and immunocytochemistry we evaluated the expression and subcellular localization of SIRT1 and its innate inhibitor, DBC1, in mouse and human fetal and adult retinas. We further studied SIRT1 in mouse- and human-derived retinal progenitor cells, the former being using in small interfering RNA studies. We found SIRT1 to be widely expressed in developing and adult retinas and to be a regulator of key retinal development genes, namely PAX6, Nestin and CRX. Moreover, we found that photoreceptor precursor cells were among the smallest cells in the heterogeneous population of mouse retinal progenitors. Collectively, these results provide the foundation for manipulating SIRT1 expression in small retinal progenitors as a means of increasing the yield of photoreceptors for transplantation in models of retinal degeneration.We further found SIRT1 to be highly expressed in human-derived choroidal neovascular membranes and sought to pharmacologically inhibit its activity via the drug Nicotinamide. We found Nicotinamide to be a potent regulator of angiogenic and hypoxic signaling in a human retinal pigment epithelial cell line at both the protein level using angiogenesis arrays and at the RNA level using whole genome microarrays. These results point to the SIRT1 inhibitor, Nicotinamide, as a possible agent for treatment of neovascular AMD. Further studies of Nicotinamide are warranted in animal models of AMD. To the best of our knowledge, this is the first time that a detailed analysis of SIRT1 as a regulator of both retinal development and choroidal neovascularization has been reported.
La dégénérescence maculaire liée à l'âge (DMLA) est la principale cause de cécité chez les personnes âgées dans les pays développés. Une recherche dynamique est en cours pour élucider des cibles moléculaires potentiels pour le traitement de la dégénérescence à la fois pour la forme atrophique et la forme néovasculaire de cette maladie. L'actuelle pharmacothérapie est efficace chez certains patients mais pas suffisante pour arrêter la progression de la maladie ou la réparation des dommages qui ont déjà eu lieu. La decouverte de nouveaux medicaments et le remplacement de cellules rétiniennes représentent les deux avenues les plus prometteuses de traitements possibles. Le but de cette thèse est d'étudier le rôle d'un régulateur récemment identifié du développement neuronal, SIRT1, dans le developpement de la retine et de rechercher si l'inhibition pharmacologique de cette protéine représente une option de traitement possible dans la DMLA. Via l'immunohistochimie et l'immunocytochimie, nous avons évalué l'expression et la localisation subcellulaire de SIRT1 et de son inhibiteur inné, DBC1, chez la souris et les humains dans les retines fœtales et adultes. Nous avons également étudié SIRT1 dans les cellules souches de la rétine chez la souris et l'homme. Nous avons trouvé SIRT1 largement exprimé dans la rétine en développement et des adultes et à un régulateur de gènes clés du développement de la rétine, à savoir PAX6, Nestin et CRX. En outre, nous avons constaté que les cellules précurseurs des photorécepteurs ont été parmi les plus petites cellules dans la population hétérogène de cellules progénitrices. Collectivement, ces résultats fournissent la base pour la manipulation de l'expression SIRT1 dans les petits progéniteurs rétiniens comme un moyen d'augmenter le rendement des photorécepteurs à la transplantation dans les modèles de dégénérescence rétinienne. Nous avons en outre constaté que SIRT1 est fortement exprimé dans les membranes néovasculaires humaines et avons cherché à inhiber son activité pharmacologique par le nicotinamide. Nous avons trouvé que Nicotinamide est un puissant régulateur de l'hypoxie et de l'angiogenèse au niveau de la protéine et de l'ARN. Ces résultats indiquent que l'inhibiteur de SIRT1, Nicotinamide est un agent possible pour le traitement de la DMLA néovasculaire. D'autres études de la nicotinamide devraient être poursuivit dans des modèles animaux de la DMLA. Au meilleur de notre connaissance, c'est la première fois qu'une analyse détaillée de SIRT1 l'identifie comme un régulateur du développement tant de la rétine et de la néovascularisation choroïdienne.

Mestrado em Enfermagem, Área de especialização: Saúde Mental e Psiquiátrica
Este relatório tem como finalidade descrever o percurso realizado durante os estágios I e estágio final do 2º Mestrado em Enfermagem de Saúde Mental e Psiquiátrica (ESMP), tendo em conta o desenvolvimento e aquisição de competências de Enfermeiro Especialista e Mestre em Saúde Mental e Psiquiátrica. Para a elaboração deste relatório seguiu-se a metodologia de projeto e as suas etapas. A finalidade deste percurso de aprendizagem que foi desenvolvido numa Equipa Técnica Especializada de Tratamento (ETET) da margem sul do Tejo teve como objetivo compreender a importância das intervenções do Enfermeiro Especialista em Enfermagem Saúde Mental e Psi-quiátrica (EEESMP) no acompanhamento com a Pessoa Portadora de Patologia Dual (PPPD), e de adquirir contributos para a realização de um projeto de consulta de enfermagem especiali-zada em Saúde Mental e Psiquiatrica (SMP) para essas pessoas. Na elaboração do presente relatório foi utilizada metodologia científica e como instrumento a revisão Integrativa da literatura, a mesma servirá para uma integração do processo de teori-zação da prática através do recurso às etapas da prática baseada na evidência, respeitante à estrutura do ciclo de estudos conducente ao grau de mestre. As intervenções desenvolvidas basearam-se em competências relacionais e comunicacio-nais fundamentado na Teoria Tidal Model de Phil Barker. Foi desenhada uma proposta de con-sulta de Enfermagem de Saúde Mental e Psiquiatrica, fundamentada no Modelo Tidal. Esta es-trutura-se nas seguintes fases: 1) Avaliação Holística 2) Sessão individual ou Sessão “Um para Um” 3) Avaliação Monitorizada 4) Plano de Segurança Pessoal
This report aims to describe the journey performed during internships I and final stage of the second master`s degree in Mental Health Nursing and Psychiatry (an ESMP), taking into ac-count the development and acquisition of skills of Nurse Specialist and Master´s degree in Men-tal Health and Psychiatry. For the preparation of this report I followed the project methodology and its steps. The purpose of this journey of learning has been developed in a specialized technical Team of treatment (ETET) on the southern shore of Tagus aimed to understand the importance of the contributions of nurses and Mental health nurse specialist Psychiatry (EEESMP) in the follow-up with the person with Dual Pathology (PPPD), and to acquire contributions to the realization of a project of the nursing consultation specializing in Mental Health and Psychiatry (SMP) for these people. At this report we used scientific methodology: Integrative literature review as an instrument to obtain evidence-base outcomes. Serve to integrate the process of theorizing the practice through the use of evidence-based practice steps of Larrabee, concerning the structure of the course leading to the degree of master. The interventions developed were based on relational and communicational skills based on Phil Barker's Tidal Model. A proposal for a Mental Health and Psychiatric Nursing consultation was drawn up, based on this Model, and structured in the following phases: 1. Holistic Assessment 2. Individual Session or “One to One” Session 3. Monitored Evaluation 4. Personal Security Plan

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Background: Adolescence is evidenced as one of the age groups the incidence of drug users is high and growing, and this finding suggests the study and research on a variety of questions about the possible relationship between these two phenomena. Attempts to characterize adolescent drug users and the various aspects of its use are of particular importance to contribute to the understanding of substance abuse patterns among young people, as well as provide data for guidance and prevention in the field of problems relating to drugs. Aim: Describe the epidemiology, identify the factors associated with drug use and the presence of dual pathology in adolescents hospitalized in the Midwest of Brazil. Methods: Cross-sectional study of adolescent (10-18 years) drug users hospitalized in Children's Mental Health Association of Goiás between 2010 and 2015. Data were collected retrospectively by chart review. Only patients with chemical dependence on licit or illicit substances as the reason for hospitalization were selected for data collection. Sociodemographic variables and sample characterization, drug usage profile, environmental factors and dual pathologies were collected in a standardized form. Descriptive analysis and association of drug use profile for sex by Chi-square test or Fisher's exact with an alpha of 5% was performed. Results: Among the 214 adolescents studied, 70.2% were male. An early onset of drug use was detected, with a mean age of 13 ± 2 years. Approximately 50% of patients dropped out of school due to drugs and were involved in illegal acts to obtain drugs. The cannabis was the psychoactive substance responsible for most admissions in males, while in females was crack (p = 0.031). Cannabis was the first drug used in life for most individuals, followed by tobacco and alcohol. The main dual pathologies were disruptive behavior disorders (50.0%) and mood disorders (46.7%). Conclusion: This study found a high prevalence of dual disorders, high dropout rates from school due to drug use, involvement in illicit activities to obtain drugs and early onset of substance abuse.
Introdução: A adolescência evidencia-se como uma das faixas etárias cuja incidência de usuários de drogas é alta e crescente, e esta constatação sugere o estudo e pesquisa de uma variedade de questões sobre as possíveis relações entre estes dois fenômenos. Tentativas para caracterizar os adolescentes usuários de drogas bem como os diferentes aspectos relativos ao seu consumo são particularmente importantes para contribuir ao entendimento de padrões de dependência química entre os jovens, assim como também prover dados para a orientação e prevenção no campo dos problemas relativos às drogas Objetivo: Descrever o perfil epidemiológico, identificar os fatores associados ao uso de drogas e a presença de patologias duais em adolescentes hospitalizados no Centro-Oeste Brasileiro. Metodologia: Estudo transversal com adolescentes (10 a 18 anos) usuários de drogas hospitalizados na Associação de Saúde Mental Infantil de Goiás entre 2010 e 2015. Os dados foram obtidos retrospectivamente por meio de revisão de prontuário. Apenas os pacientes que apresentaram dependência química de substâncias lícitas ou ilícitas como motivo de internação foram selecionados para coleta de dados. Variáveis sociodemográficas e de caracterização da amostra, perfil de uso de drogas, fatores ambientais e patologias duais foram coletadas em formulário padronizado. Foi realizada análise descritiva dos dados e de associação do perfil de uso de drogas por sexo pelo teste Qui-quadrado de Pearson ou Exato de Fisher com alfa de 5%. Resultados: Dentre os 214 adolescentes avaliados, 70,2% eram do sexo masculino. Detectou-se início precoce do uso de drogas, com idade média de 13 ± 2 anos. Aproximadamente 50% dos indivíduos abandonaram os estudos devido às drogas e se envolveram com atos ilícitos para obtenção de drogas. A cannabis foi a substância psicoativa responsável pela maioria das internações principal no sexo masculino, enquanto no sexo feminino a principal foi o crack (p=0,031). A cannabis foi a primeira droga utilizada na vida pela maioria dos indivíduos, seguida por tabaco e álcool. As principais patologias duais foram transtornos disruptivos do comportamento (50,0%) e transtornos de humor (46,7%). Conclusão: O presente estudo encontrou alta prevalência de patologias duais, altas taxas de abandono dos estudos devido ao uso de drogas, envolvimento com atos ilícitos para obtenção de drogas e início precoce do abuso de substâncias químicas.

The development of Parkinson's disease (PD) in humans has been linked to genetic and environmental factors for many years. However, finding common single insults which can produce pathology in humans has proved difficult. Exposure to trichloroethylene (TCE) or traumatic brain injury (TBI) has been shown to be linked to PD and it has also been proposed that multiple insults may be needed for disease development. The present studies show that exposure to TCE prior to a TBI can result in pathology similar to early PD and that the interaction of both insults is required for impairment in behavioral function, and cell loss. Following exposure to TCE for 2 weeks there is a 75% impairment in mitochondrial function but it has yet to be shown if the addition of a TBI can make this worse. If the exposure to TCE is reduced to 1 week and combined with TBI a 50% reduction in mitochondrial function is observed following the dual injury which requires both insults. These studies provide further support for the hypothesis that PD may result from a multifactorial mechanism. It had been established that regional differences exist in mitochondrial function across brain regions. The present studies indicate that previous findings are not likely to be the result of differences in individual mitochondria isolated from the cortex, striatum, and hippocampus. Further analysis of the effect of mitochondrial inhibitors on enzyme activity and oxygen consumption reveal that the different regions of the brain are similarly affected by the inhibitors. These results suggest that findings from previous studies indicating regionally specific deficits following systemic toxin exposure, such as with TCE, are not the result of regional differences in the individual mitochondria. Given that TBI results in significant dysfunction, finding effective therapeutics for TBI will provide substantial benefits to individuals suffering an insult. Treatment with Pioglitazone following TBI reduced mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation. These findings provide initial evidence that treatment with Pioglitazone may be an effective intervention for TBI.

La coexistencia de esclerosis hipocampal con una lesión extrahipocampal potencialmente epileptógena, situación conocida como patología dual, traza un reto para planificar la cirugía resectiva de epilepsia farmacorresistente. Presentamos un caso de epilepsia focal farmacorresistente asociada a patología dual (esclerosis hipocampal izquierda y gliosis frontal izquierda), abordada con estimulación eléctrica cortical directa y electrocorticografía intraoperatoria, con buenos resultados a corto plazo.
The coexistence of hippocampal sclerosis with a potentially epileptogenic extra hippocampal injury is known as dual pathology, and presents a challenge to resection surgery strategies in cases of drug-resistant epilepsy. We present a case of drug-resistant focal epilepsy associated with dual pathology (left hippocampal sclerosis and left frontal gliosis), treated by means of direct cortical electrical stimulation and intraoperative electrocorticography with good short-term results.

Background: Inflammatory Bowel Disease (IBD) includes Crohn’s Disease, Ulcerative Colitis and Indeterminate Colitis, all characterised by chronic, gastrointestinal inflammation. Symptoms can be painful and embarrassing and treatment can result in invasive procedures, side effects and surgery. Qualitative studies suggest that body image may be affected by IBD. Aim: To review published quantitative papers with a measure of body image in children and adolescents with IBD. Method: Electronic databases (PsycInfo, Embase, Medline, Web of Science, CINAHL) were used to systematically review the literature, identifying 19 papers. These papers were reviewed using a critical appraisal tool. Results: The review discusses themes relating to body image including: type of IBD diagnosis; age at diagnosis; severity of symptoms; gender and treatment. Trends in body image are similar to healthy peers, particularly for those with mild or no symptoms. IBD can predispose the young person to risk factors, increasing their vulnerability to poor body image, including delayed growth, increase in severe physical symptoms and intrusive or demanding treatments. Conclusion: Routine assessment of psychosocial factors, including body image, for young people with IBD is recommended. This review highlights methodological limitations in the current body of evidence, calling for further research to improve understanding of this area. Background: The psychosocial issues and challenges for young people with a dual diagnosis of type 1 diabetes and coeliac disease and their parents have been explored and uncertainties within screening and diagnostic processes are documented. However, the experiences of healthcare professionals (HCPs) working with this group has to date remained unexplored. Method: Twelve HCPs (doctors, nurses, dieticians) working in this field from three paediatric teams were interviewed about their experiences. Transcripts were analysed using Interpretative Phenomenological Analysis. Results: Three superordinate themes emerged: ‘Connection and burden’; ‘Diagnoses together, but separate and uneven’; and ‘Sitting with certain uncertainty and complexity’. These represent participants‘ connection to the experience of patients and adding to their burden; a sense of disparity in managing the two conditions; uncertainty and complexity with the dual diagnosis, and a repertoire of coping strategies utilised. Positive aspects of the role (making a difference, improving health and reducing risk) along with coping strategies are likely to buffer the challenges of working with this client group. Conclusion: Recommendations include a dual review clinic and further support for staff. Additional research on medical and psychosocial aspects of this dual diagnosis is needed to develop services to support both patients and HCPs.

Vaken hjärnkirurgi med testning av tal- och språkfunktioner ger viktiga fördelar vid operation av lågmaligna gliom. Denna metod ökar möjligheten för radikal resektion av tumören samtidigt som viktiga funktioner som till exempel språk bevaras. Optimering av det intraoperativa språktestningsförfarandet ökar möjligheten för mer sensitiv språktestning. Det finns idag ingen konsensus, varken internationellt eller nationellt, kring hur man bör testa språkliga funktioner intraoperativt. Syftet med föreliggande arbete är att undersöka om det är möjligt att vidareutveckla de metoder som idag används för elicitering av spontantal och testning av läsning under vakenkirurgi av lågmaligna gliom på Akademiska sjukhuset i Uppsala. För att undersöka detta genomfördes en litteraturgenomgång vilken tillsammans med auskultationer vid operation och intervjuer med yrkesverksamma logopeder och neurokirurger har utmynnat i ett förslag på ett intraoperativt högläsningstest innehållande meningar med nonord, meningar utan nonord samt enskilda ord. Nivåindelningen av testmaterialet möjliggör för testledaren att individuellt anpassa språktestning utifrån patientens förmåga. I samband med färdigställandet av testet genomfördes en pilottestning av materialet. Det föreslagna lästestet förväntas vara mer heltäckande än det som används idag då det möjliggör testning av flera läsfunktioner så som de beskrivs i ”dual route-modellen”, en psykolingvistisk teori om läsning. Dessutom har ett förslag på riktlinjer kring intraoperativt elicitering av spontantal formulerats.
Awake surgery is the gold standard for treatment of low-grade gliomas nearby eloquent language areas in the brain. This method increases the possibility of radical resection while cognitive functions such as language are preserved, as the method allows for online testing of cognitive functions. Improvement of the intraoperative language tests could increase the possibility of more sensitive testing and thereby decrease the risk of postoperative language impairments. There is no international or national agreement on how intraoperative language testing should be performed. The aim of this study is to explore the possibility of developing the methods of language testing which are used today at Akademiska sjukhuset in Uppsala, focusing on reading and spontaneous speech. Therefore the authors have conducted a review of current literature. The literature review, observations of surgery and interviews with speech pathologists and neurosurgeons resulted in the development of an intraoperative reading aloud test with three tasks consisting of sentences with nonwords, sentences without nonwords and single words. The classification of the test material into different levels will allow clinicians to adapt the reading test based on each individual case. A pilot trial of the reading test was preformed. The proposed test is expected to be more comprehensive in comparison to the tests that are currently used, as it enables testing of the different reading routes described in the dual route model, a psycholinguistic reading model. Additionally, guidelines for eliciting spontaneous speech have been defined.

Le traitement des gliomes de haut grade constitue aujourd'hui encore un réel enjeu médical. Les techniques actuellement disponibles sont principalement palliatives et permettent d'augmenter la survie des patients de quelques mois seulement. Une technique innovante de radiothérapie consiste à renforcer la dose déposée dans la tumeur grâce à l'injection d'atomes lourds de manière spécifique dans celle-ci au préalable d'une irradiation de photons de basse énergie (50-100 keV). Cette technique a fait l'objet d'essais précliniques et maintenant d'essais cliniques de phases I et II sur la ligne médicale du synchrotron Européen dont le rayonnement monochromatique et intense est particulièrement adapté pour l'application. L'utilisation d'un agent de contraste (AC) iodé (Z=53) injecté par voie veineuse permet d'améliorer le bénéfice de la radiothérapie mais n'est cependant pas suffisante pour l'élimination complète de la tumeur. En effet, l'accumulation passive d'atomes lourds dans la tumeur n'est pas assez importante et le caractère extracellulaire d'un AC ne maximise pas l'efficacité biologique de l'irradiation. Les nanoparticules (NPs) métalliques apparaissent comme un moyen efficace pour repousser ces limites. Dans le cadre de cette thèse, des études ont été conduites sur la lignée cellulaire de gliome F98 afin de caractériser la toxicité et l'internalisation de trois types de nanoparticules différents : nanoparticules de gadolinium (GdNPs 3 nm), d'or (AuNPs 13 nm) et de platine (PtNPs 6 nm). La survie cellulaire a également été évaluée après différentes conditions d'irradiation de photons monochromatiques en présence de ces nano-objets. La dépendance de la réponse cellulaire à l'énergie du rayonnement incident ainsi qu'à la distribution subcellulaire des NPs a permis de mettre en évidence plusieurs mécanismes mis en jeu dans ce traitement. A concentration identique, les NPs diminuent la survie cellulaire de manière plus importante qu'un AC, validant ainsi l'intérêt microdosimétrique des NPs. L'effet est préférentiel à basse énergie (keV) indiquant que la photoactivation des atomes lourds est en partie responsable la réponse cellulaire. Par ailleurs, les GdNPs et les PtNPs se sont aussi montrées efficaces pour diminuer la survie cellulaire en combinaison à une irradiation à haute énergie (1.25 MeV) indiquant qu'un mécanisme de radiosensibilisation différent de la photoactivation intervient également. Les études précliniques, ont montré que le recouvrement complet de la tumeur par les NPs constitue un point clé pour garantir le bénéfice thérapeutique du traitement. Dans cette optique, une méthode de tomographie à deux énergies développée au synchrotron, a été caractérisée dans le cadre de ce travail. L'étude a permis d'imager de manière quantitative et simultanée la tumeur (mise en évidence par un AC iodé) et son recouvrement par des GdNPs (injectées par voie directe) chez le rongeur porteur d'un gliome. La correspondance entre la distribution de l'AC et la tumeur a également été étudiée à l'aide de techniques d'imagerie à haute résolution (IRM, tomographie X par contraste de phase et histologie).

Leishmania spp. undergo substantial adaptations from being promastigotes, found in sandflies, to being amastigotes, residing in parasitophorous vacuoles within mammalian macrophages. In the past, microarray studies have sought to elucidate these adaptations using axenic amastigote systems or amastigotes purified from host-cells, raising the question whether the observed transcriptomic signatures were a true reflection of intracellular amastigotes. Moreover, with ever-improving genome annotations being available, it is clear that these studies failed to address the transcriptomic behaviour of a considerable number of transcripts. In the work presented herein, I employed RNA-sequencing to obtain transcriptomic profiles of Leishmania mexicana axenic promastigotes (PRO), axenic amastigotes (AXA) and intracellular amastigotes (AMA) in murine bone-marrow derived macrophages. The intracellular amastigotes were not purified from host cells, but instead sequencing reads assigned to a hybrid L. mexicana - Mus musculus genome and the transcriptomes separated in silico. We were able to map pre-mRNA processing sites, thereby defining transcript boundaries, proposing 184 truncations and 1253 extensions of existing gene models as well as discovering 936 novel genes. Mass-spectrometric evidence was obtained for both proposed extended and novel proteins. Using this improved genome annotation, we generated gene expression profiles for AMA, AXA and PRO, identifying 3832 differentially expressed transcripts between PRO and AMA as well as 2176 between PRO and AXA and 1234 between AXA and AMA. Transcripts differentially expressed between AMA and PRO correlated well with previous reports, were enriched for novel transcripts identified in this study and contained an unprecedented wealth of yet uncharacterised transcripts. Guided by these data, I performed a GFP-tagging screen identifying two proteins which may play an important role in L. mexicana biology, LmxM.16.0500, a member of a small, divergent, amastin-derived gene family, which appears to be released from the cell body of PRO, and LmxM.09.1330 a specific marker of the amastigote flagellar pocket.

RESUMO A similaridade entre o tecido da mama e o da glândula salivar está bem estabelecida. A porção das estruturas acinares e ductais destes órgãos são basicamente semelhantes. Estes aspectos, associados ao fato de que uma coexistência de carcinomas da mama e de glândula salivar, têm sido relatados em uma incidência maior do que a esperada. Guiaram estudos tentando determinar a importância dos receptores de estrógeno e progesterona em adenomas pleomórficos (AP). A neoplasia é mais freqüente nas glândulas salivares e exibe uma predileção para o sexo feminino. Recentemente a presença do receptor de estrógeno (RE) e do receptor de progesterona (RP) tem sido investigada no AP, entre outras neoplasias de glândula salivar, questionando-se a possibilidade da existência da dependência hormonal. A expressão dos receptores hormonais nos carcinomas de mama é importante para determinar o prognóstico e a probabilidade de responder à manipulação hormonal. Neoplasias que apresentam positividade para ambos os receptores, estrógeno e progesterona, exibem maior probabilidade de resposta à terapia anti-estrogênica do que as neoplasias que são negativas para estes receptores. Baseando-se na literatura científica pertinente, o presente trabalho se propõe a investigar a presença da proteína RE e da proteína RP em APs humanos, relacionando-os com a proliferação de linhagens celulares sob a influência destes hormônios. A técnica utilizada foi a imuno-histoquímica para a pesquisa dos RE e RP em 10 APs emblocados em parafina pertencentes ao arquivo do Serviço de Patologia Cirúrgica da FOUSP, e de duas linhagens de APs estabelecidas no mesmo serviço: uma derivada de um paciente do sexo masculino e a outra de um paciente do sexo feminino. No meio de cultivo onde subculturas destas células proliferavam foram diluídos 17-b-estradiol e progesterona. Através de contagens destas células em períodos pré-determinados (24 horas, 48 horas e 72 horas), pretendeu-se verificar a influência dos respectivos hormônios na multiplicação celular. Como controle positivo utilizou-se uma linhagem denominada T-47D, que foi largamente estudada na literatura. A T-47D é derivada de um carcinoma metastático de mama, reconhecidamente hormônio dependente. E como controle negativo, utilizou-se de uma linhagem de carcinoma epidermóide, denominada HN30. Encontrou-se positividade para o RE em 7 de 10 APs estudados (4 em homens e 3 em mulheres) e positividade para o RP em 8 Aps estudados (4 em mulheres e 4 em homens). Pela análise estatística, constatou-se que existe uma diferença significativa no índice proliferativo entre o controle e as células submetidas à ação do 17-b-estradiol e da progesterona. Para a linhagem derivada do paciente do sexo masculino houve diferença entre o controle e as células expostas ao 17-b-estradiol e a progesterona somente nas últimas 72 horas. Para a linhagem derivada do sexo feminino constatou-se uma diferença significativa entre o controle e as células sob a influência da progesterona, a partir de 48 horas de proliferação celular. A diferença significativa entre o controle e as células sob a ação do 17-b-estradiol ocorreu somente a partir das 72 horas, sugerindo que o AP poderia ser uma neoplasia influenciada pela ação hormonal.
SUMARY It is well established the similarity between mammary and salivary glands especially between the acinic and ductile structures. These aspects, associated to the fact of coexistence of breast carcinomas and of salivary gland tumors been described, leaded studies in attempt to determine the importance of the ERs and Pr in pleomorphic adenomas (PA), the most frequent salivary gland tumor and with predilection for the females. Lately, the presence of ERs and of the PRs has been investigated in PA and other salivary gland tumors pointing out their hormonal dependency. The expression of hormone receptors in breast carcinomas is crucial to determine a presence for both receptors. These tumors exhibit better response to anti-estrogenic therapy than the negative ones. Basing on the pertinent scientific literature, the present study proposes to investigate the presence of the RE and of the RP in humans PA and connecting them with cellular proliferation in vitro, under the influence of these hormones. Immunohistochemistry technique was used for the detection of RE and RP in paraffin embedded 10 PAs from the files of the Department of Oral Pathology, School of Dentistry, University of São Paulo, and two PA cell lines one from a male patient and other female. The culture midia was supplied with, 17-b-estradiol and progesterone. A growth curve was performed (24 hours, 48 hours and 72 hours) to verify the influence of the respective hormones in the cellular proliferation. As a positive control T-47-D cells derived from a hormone dependent metastatic breast carcinoma were used, and as negative control HN30 cells, derived from a tongue squamous cell carcinoma. 7 of 10 PAs were positive (4 in men and 3 in women) for RP and 8 of 8 PAs (4 in women and 4 in men) for RE. The statistical analysis verified a significant difference in the proliferative index between the control cells and the ones submitted to the action of the 17-b-estradiol and of the progesterone: for male derived lineage a difference was only observed in the last 72 hours. In the other hand, for the female derived lineage a significant difference was verified starting from 48 hours, suggesting that PA can be influenced by hormonal action.

archives@tulane.edu
For decades, histopathology and cytology have provided the reference standard for cancer diagnosis, prognosis prediction and treatment decisions. However, they are limited to 2D slices, which are created via cutting and/or smearing, thus not faithfully representing the true 3D structures of the cellular or tissue material. Multiple imaging methods have been utilized for non-destructive histologic imaging of tissues, but are usually limited by varying combinations of low resolution, low penetration depth, or a relatively slow imaging speed, and all suffer from anisotropic resolution, which could distort 3D tissue architectural renderings and thus hinder new work to analyze and quantify 3D tissue microarchitecture. Therefore, there is a clear need for a non-destructive imaging tool that can accurately represent the 3D structures of the tissue or cellular architecture, with comparable qualities and features as traditional histopathology. In this work, dual-view inverted selective plane illumination microscopy (diSPIM) has been customized and optimized for fast, 3D imaging of large biospecimens. Imaging contrast of highly scattering samples has been further improved by adding confocal detection and/or structured illumination (SI) as additional optional imaging modes. A pipeline of dual-view imaging and processing has also been developed to achieve more isotropic 3D resolution, specifically on DRAQ5 and eosin (D&E) stained large (millimeter to centimeter size) biopsies. To determine the impact of 3D, high-resolution imaging on clinical diagnostic endpoints, multiple prostate cancer (PCa) biopsies have been collected, imaged with diSPIM, and evaluated by pathologists. It has been found that the pathologist is “equally” confident on the PCa diagnosis from viewing 3D volumes and 2D slices, and the diagnostic agreement between 3D volumes is significantly higher than 2D slices. The high-resolution and large-volume coverage of diSPIM may also help verify results from other lower-resolution modalities by serving as a 3D histology surrogate. Tissue correlations have been found between images acquired by diSPIM and photo-acoustic imaging, or by diSPIM and biodynamic imaging, proving diSPIM as a useful tool to aid in validation of lower-resolution imaging tools. The potential of diSPIM imaging has also been demonstrated in other applications, such as in the study of in-vitro neural models.
1
Bihe Hu

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
O consumo de drogas estimulantes do sistema nervoso central é um problema atual e a nível global, tendo consequências físicas, mentais e sociais graves para o consumidor. A psicose induzida por estimulantes é uma dessas consequências e carateriza-se pela manifestação de sintomas psicóticos mais intensos e duradouros do que seria expetável face ao consumo da substância. Os mecanismos pelo qual esta ocorre não são ainda claros, mas parecem existir alguns fatores de risco. No âmbito deste trabalho e após revisão bibliográfica sobre o tema, concluiu-se que consumos mais frequentes e de maiores doses, dependência de outras substâncias e a existência de outras comorbilidades psiquiátricas estão relacionados com a ocorrência de psicose induzida por cocaína ou anfetaminas. Uma idade precoce de instalação de dependência de cocaína e o consumo via endovenosa parecem também ser fator de risco para a psicose induzida por cocaína. Face a estes resultados recomenda-se que, durante o seguimento e tratamento de doentes com dependência de estimulantes, se tente identificar estes fatores de risco para que, quando presentes, se possa vigiar a existência de sintomas psicóticos de forma a que seja possível uma abordagem precoce .
The consumption of stimulant drugs is an actual and worldwide problem, which has severe physical, mental and social consequences for the user. Stimulant induced psychosis is one of those consequences and is defined by the presence of psychotic symptoms with an increased duration and intensity when compared to what would be expected from the intoxication of said substance. The mechanisms through which it occurs are still not clear, but there seem to be some risk factors. According to the reviewed studies on the matter, it was concluded that more frequent consumptions of bigger doses, other drugs dependence and comorbid psychiatric disorders are related to an increased chance of psychosis or amphetamines induced psychosis. An early onset of cocaine dependence and intravenous cocaine use also seem to be a risk factor for cocaine induced psychosis. It is recommended that these potential risk factors should be identified during the treatment and follow-up of patients with stimulant dependency, so a regular surveillance of psychotic symptoms can be done, allowing for an early detection and intervention .

Dissertação de Mestrado em Intervenção Social, Inovação e Empreendedorismo apresentada à Faculdade de Economia
This dissertation, Participatory construction of innovative social responses in the area of mental health, a requirement and a challenge. The "Deliciosas Diferenças" Cooperative takes as an object of analysis the problem of mental illness, and the need to construct innovative social responses in the area of the social economy.The study was guided by the need to respond to the process of deinstitutionalization of the seriously mentally ill patients, in Soure County, due to the absence of integrative and complementary responses to the process of psychosocial rehabilitation. In order to analyze the building process of the cooperative and the experiences of the Cooperators, a case study was chosen. We used a qualitative methodology of exploratory character, being the data collection done through interviews, participant observation and documentary analysis. The analysis of the collected data was based on the analysis of content, being the data subject to double hermeneutics.Through a comprehensive contextual analysis, it was realized that the cooperative's experience in the co-construction of the cooperative is not the end result of the social processes, but rather a phase of the personal and organizational construction by which the cooperative is constituted and, on a daily basis, updates. In this model, it is assumed that this mediation is done through its impact on the motivations, emotions and competencies, which are behavioral conditions. It is believed, then, that this response depends, essentially, on internal and egalitarian democracy, in order to create external autonomy.The results reveal the importance of each of us being an agent of the co-construction of innovative projects with social value in an attempt to build a better world.
A presente dissertação, Construção participativa de respostas sociais inovadoras na área da saúde mental , uma exigência e um desafio. A Cooperativa “Deliciosas Diferenças”, toma como objeto de análise a problemática da doença mental, e a necessidade de construção de respostas sociais inovadoras, na área da economia social.O estudo foi orientado pela necessidade de dar resposta ao processo de desinstitucionalização de doentes mentais graves, no Concelho de Soure, face à ausência no terreno de respostas integradoras e complementares ao processo de reabilitação terapêutica. Para analisar o processo de co-construção da cooperativa e as vivências dos cooperadores, optou-se por um estudo de caso. Utilizamos uma metodologia qualitativa de caráter exploratório, sendo a recolha de dados feita através de entrevistas, observação participante e análise documental. A análise dos dados recolhidos baseou-se na análise de conteúdo, sendo os dados sujeitos à dupla hermenêutica.Através de uma análise compreensiva contextualizada, percebeu-se que a experiência dos cooperadores na co-construção da Cooperativa não é o resultado final dos processos sociais, mas sim uma fase da construção pessoal e organizacional pelos quais a cooperativa se constitui e, diariamente, se atualiza. Neste modelo, assume-se que essa mediação é feita através do seu impacto nas motivações, emoções e competências, as quais são condições do comportamento. Crê-se, então, que esta resposta depende, essencialmente, da democracia interna e igualitária, de forma a criar autonomia externa.Os resultados dão conta da importância de cada um de nós ser agente da co-construção de projetos inovadores, com valor social na tentativa de construção de um mundo melhor.

O consumo de substâncias está relacionado com a deterioração das funções cognitivas, sendo que, a existência de uma patologia associada pode agravar essa mesma deterioração. O objetivo geral desta dissertação passa por identificar as alterações neuropsicológicas em indivíduos dependentes de substâncias com diagnóstico de perturbação de ansiedade e, como objetivo específico, verificar se existem diferenças no desempenho cognitivo entre os dependentes de substâncias com diagnóstico de perturbação de ansiedade e indivíduos dependentes de substâncias psicoativas sem diagnóstico de perturbação de ansiedade. A amostra foi constituída por 40 participantes, divididos em dois grupos: 20 homens com consumos de substâncias e 20 homens consumidores de substâncias com perturbação de ansiedade. Foi aplicada, individualmente, uma bateria de testes neuropsicológica para avaliar défices cognitivos, ao nível nível da atenção, memória, velocidade de processamento e funções executivas, em duas sessões com um iato temporal de uma semana. Os resultados demonstram a existência de diferenças estatisticamente significativas na memória verbal, memória de trabalho e estratégias de memória. Conclui-se então, que, os indivíduos com patologia dual são mais vulneráveis ao agravamento dos défices cognitivos do que os indivíduos substâncias sem patologia dual.
The consumption of substances is related to the deterioration of cognitive functions, and the existence of an associated pathology can aggravate this same deterioration. The general objective of this dissertation is to identify the neuropsychological changes in individuals dependent on substances with a diagnosis of anxiety disorder and, as a specific objective, to verify if there are differences in the cognitive performance between the addicts of substances with diagnosis of anxiety disorder and individuals dependent on psychoactive substances without diagnosis of anxiety disorder. The sample consisted of 40 participants, divided into two groups: 20 men with substance use and 20 men using substances with anxiety disorders. A battery of neuropsychological tests was applied individually to evaluate cognitive deficits, level of attention, memory, processing speed and executive functions, in two sessions with a temporal iat of one week. The results demonstrate the existence of statistically significant differences in verbal memory, working memory and memory strategies. We conclude that individuals with dual pathology are more vulnerable to worsening of cognitive deficits than individuals without dual pathology.

Dissertação de mestrado integrado em Psicologia (área de especialização em Psicologia Clínica e da Saúde)
O presente relatório de atividades profissionais tem como objetivo destacar a experiência e competências profissionais da autora no domínio da Psicologia Clínica e da Saúde. Pretende-se assim descrever as funções exercidas e papéis desempenhados pela autora na prática da Psicologia, bem como as competências teórico-práticas adquiridas e fortalecidas ao longo do seu percurso académico e profissional. Na generalidade, será abordado o trabalho desenvolvido no Serviço de Psiquiatria do Centro Hospitalar e Universitário de Coimbra – Hospital Sobral Cid, descrevendo, sobretudo, atividades clínico-assistenciais (avaliação e intervenção psicoterapêutica) e, igualmente, de formação e investigação. O presente trabalho incluirá ainda uma reflexão crítica acerca da pertinência e limitações dos modelos teóricos e interventivos no âmbito da Patologia Dual.
The present professional activities report has the objective of pointing out the author’s experience and professional competencies in the domain of Clinical and Health Psychology. It is aimed to describe the functions and roles performed by the author in the field of psychology practice as well as the theoretical and practical skills acquired and strengthened throughout her academic and professional career. In general, the work in the Psychiatric Service on the Coimbra Hospital and University Centre - Sobral Cid Hospital will be addressed, describing, mainly, the clinical-care activities (assessment and psychotherapeutic intervention) and, equally, the training and research activities. The present work will also include a critical reflection about the relevance and limitations of the theoretic and psychotherapeutic models on the Dual Pathology field.

A coexistência de perturbações psiquiátricas com abuso / dependência de substâncias ilícitas é um problema de saúde pública global. Devido a escassez de estudos acerca do Perfil Neuropsicológico em toxicodependentes, este estudo centra-se na investigação de uma das perturbações psiquiátricas mais devastadoras e incapacitantes da atualidade na patologia dual, a esquizofrenia. Estima-se que 75 a 85% dos doentes com esta patologia mental apresentem alterações das funções cognitivas. O objetivo primordial deste estudo é descrever o Perfil Neuropsicológico de indivíduos com esquizofrenia e dependentes de substâncias e simultaneamente comparar as diferenças no funcionamento cognitivo entre indivíduos policonsumidores com diagnóstico de esquizofrenia com indivíduos policonsumidores sem diagnóstico de patologia psiquiátrica. A amostra foi formada por 40 participantes, divididos em dois grupos: um grupo com 20 indivíduos do sexo masculino policonsumidores com diagnóstico de esquizofrenia e um grupo com 20 indivíduos do sexo masculino policonsumidores sem diagnóstico de patologia psiquiátrica. Os resultados demonstraram que os indivíduos com esquizofrenia e com policonsumos apresentam défices cognitivos estatisticamente significativos em várias funções cognitivas (atenção concentrada e velocidade de processamento, inibição de respostas automáticas, flexibilidade mental, memória de trabalho, capacidade de planificação e estratégia de ação e capacidade visuoconstrutiva) comparativamente aos indivíduos sem diagnóstico de patologia psiquiátrica e com policonsumos. Conclui-se, então que indivíduos com patologia dual são mais vulneráveis aos efeitos tóxicos das substâncias ilícitas.
The coexistence of psychiatric disorders with abuse / dependence on illicit substances is a global public health problem. Due to the lack of studies about the Neuropsychological Profile in drug addicts, this study focuses on the investigation of one of the most devastating and disabling psychiatric disorders of the present day in the dual pathology, schizophrenia. It is estimated that 75 to 85% of patients with this mental disorder show evidences of altered cognitive functions. The main objective of this study is to describe the Neuropsychological Profile of individuals with schizophrenia and dependence substance and also compare the differences in cognitive functioning between diagnosed with polydrug user with individuals without a diagnosis of psychiatric pathology. The sample consisted of 40 participants, divided into two groups: a group of 20 male polydrug user individuals diagnosed with schizophrenia and one group with 20 male polydrug user individuals without a diagnosis of psychiatric pathology. The results revealed that individuals with schizophrenia and polydrug show statistically significant cognitive deficits in various cognitive functions (concentrated attention, speed processing, inhibition of automatic responses, mental flexibility, working memory, planning capacity and action strategy and visuoconstructive capacity) compared to individuals without a diagnosis of psychiatric disorder and polydrug. We also conclude that individuals with dual pathology are more vulnerable to the toxic effects of substances.