Abstract Bipolar disorder is a complex illness. It is a life long episodic disorder very disruptive for the patient and family. Repeated episodes lead to progressively deteriorating level of functioning and poor response to the treatment. Suicide attempts and completed suicide has been a frequent complication. The complexity and difficulties involved in treating this mental condition are well recognised .The pharmacological options include lithium, valproate, carbamazepine, lamotrigine, topiramate, benzodiazepines. The use of neuroleptics in bipolar disorder remain controversial because of the increased susceptibility of this group of patients to side effects of neuroleptics. Objectives: The aim of this research is to investigate in a population of patients with bipolar disorder who are having treatment with combination of a mood stabilizer and antipsychotics: 1) The number of prescriptions of antipsychotics, in bipolar patients in a community clinic 2) The rationale of such combination 3) Whether correlates exist between variables such as substance abuse and noncompliance and the prescription of antipsychotics Method: This retrospective, descriptive, analytic study was conducted at Voslooros Psychiatric Clinic, which is situated in the south of Johannesburg. The clinical records of all adult patients with an initial diagnosis of bipolar disorder as at December 2004 were examined Particular note was taken of demographic data, diagnosis, age of onset of psychiatric illness, V duration of illness, treatment prescribed, reasons for prescribing this medication, response to the treatment, social circumstances of each patient, substances use and compliance. Results: 74.1% of the patients were maintained on a combination of mood stabilizer with antipsychotic. Combination treatment was used in an attempt to improve the psychotic symptoms and dangerous behaviour in 48% of the patients, noncompliance in 38% of the cases and 14% patients were in transitional phase to stop antipsychotics. 80.65% of the patients were on treatment with antipsychotics for longer than 6 months. Use of atypical antipsychotics is associated with a better outcome than the conventional agents. In this study only a small percentage (10 %) of patients received atypical antipsychotics. 19.4 % patients reported side effects of the medication. The lower figures in our study can be due to underreporting and inadequate documentation. . 38.7% of the patients reported substance misuse. Our finding were much lower compared with the literature, probably due to underreporting. Alcohol was the most common substance. This study show that the need for more medication was increased 6.6 fold in patients with polysubstance abuse compared with the patients not abusing any substance. Noncompliance in the maintenance phase of the treatment is a important issue in the management of the patients with bipolar disorder. This study found that the majority of the patients (59.7%) were noncompliant with their treatment. Those findings were in line with studies done by Keck PE who reported rates of noncompliance from 51% to 64%. Our study show that 63% of the patients had a level of VI education less than matric and this may be a contributing factor to noncompliance. Conclusions: The results of the study suggest that a large number of bipolar patients are only partially responsive to mood stabilizers alone and the maintenance treatment with antipsychotics for longer than 6 months are needed because of persistence of the symptoms. More efficient strategies are necessary to educate the people, to improve the compliance and to decreased the use of substances.

O HCL-32 é um questionário de 32 itens, de auto-aplicação, onde os sintomas são avaliados através de respostas do tipo \"sim\" (presente ou típico) ou \"não\" (não está presente ou atípico). Além disso, o HCL-32 tem 8 seções para avaliar a gravidade e o impacto dos sintomas sobre os diferentes aspectos da vida do paciente. A pontuação é obtida pela soma das respostas positivas para os 32 itens sobre hipomania. A versão original do HCL-32 foi traduzido e adaptado para o português brasileiro. A primeira versão do HCL-32 foi traduzida por nós, revisados por especialistas em transtornos de humor, bem como por um professor de português brasileiro. Foi então retro-traduzida por um professor de inglês americano. Dos indivíduos inicialmente selecionados, foram excluídos 27, 11 devido à presença de comorbidades com abuso de substância, e 16 devido à incapacidade de preencher corretamente o questionário. Assim, nossa amostra final ficou composta por 81 pacientes com TB (37 TBI; 44TBII), 42 com TDM, e 362 sujeitos de uma população não clínica. A consistência interna foi elevada, com um alfa de Cronbach de 0,793 para todo o HCL-32 VB, indicando que os itens do questionário são suficientemente homogêneos. Indivíduos com TB tiveram a maior pontuação no HCL-32 VB. A média de respostas afirmativas foi significativamente diferente de acordo com o diagnóstico. Analisamos a capacidade em diferenciar os diagnósticos através da curva ROC. A área sob a curva foi de 0.702, indicando a boa capacidade da escala para distinguir entre diagnósticos. A melhor combinação de sensibilidade (0.75) e especificidade (0.58) ocorreu com uma pontuação acima de 18. Esta pontuação distinguiu entre pacientes com TB e TDM. Para comparar as propriedades discriminativas do HCL-32 VB e MDQ VB, foram calculadas a sensibilidade e especificidade de ambos os questionários. A HCL-32 VB teve uma sensibilidade de 0.75 e especificidade de 0.58. O MDQ teve sensibilidade de 0.70 e especificidade de 0.58. Assim, a HCL-32 BV apresentou maior sensibilidade, mas a mesma especificidade que o MDQ. A análise fatorial resultou em nove fatores com autovalores > 1, explicando 53,1% da variância total. De acordo com o teste Scree, foi preferida uma solução com três fatores. O primeiro fator, com autovalor de 4,90, explicou 15,3% da variância e foi composto por 10 itens. Essa subescala reflete questões relacionadas com ativação/elação. O segundo fator, com autovalor de 3,48 (10,88% da variância), composto por 11 itens e sua estrutura inclui questões relacionadas com \"irritabilidade / comportamento de risco\". O terceiro fator, com autovalor de 1,56 (4,87% da variância), ficou composto por cinco itens e sua estrutura reflete questões relacionadas com \"desinibição / ativação sexual. Os parâmetros psicométricos de HCL-32 VB sugerem que é um instrumento útil para a detecção de hipomania em pacientes com transtornos de humor. O HCL-32 VB é um questionário rápido de auto-aplicação e de fácil interpretação / The HCL-32 is a 32-item self-administered questionnaire where symptoms are assessed through yes (present or typical) or no (not present or untypical) answers. In addition, the HCL-32 has 8 other sections evaluating the severity and impact of the symptoms on different aspects of patient\'s life. The score is obtained by adding the positive responses to the 32 symptoms of hypomania. The original version of the HCL-32 was translated and adapted to Brazilian Portuguese .The first draft of the Brazilian version was translated by us, reviewed by experts in mood disorders, as well as by a Brazilian-Portuguese teacher. It was then back-translated by an English (American) teacher. Of the individuals initially enrolled, 27 individuals were excluded; 11 due to the presence of comorbidities with substance abuse, and 16 due to inability to properly fill the questionnaires. Accordingly, our final sample comprised of 81 patients with BP (37 BPI; 44 BPII), 42 with MDD, and 362 subjects from a nonclinical population. Internal consistency was high, with a Cronbach\'s alpha of 0.793 for the entire HCL-32 BV, indicating that the items of the questionnaire are sufficiently homogeneous. Individuals with BP had the highest HCL-32 BV scores. The mean number of affirmative responses to the list of symptoms was significantly different according to diagnosis. We analyzed the scale\'s discrimination for BP trough the ROC curve. The area under the curve was 0.702 indicating the good ability of this screening scale. The best combination of sensitivity (0.75) and specificity (0.58) happened with a score above 18. This score discriminates between BP patients and MDD. To compare the discriminative properties of HCL-32 BV and MDQ, we calculated the sensitivity and specificity of both questionnaires. The HCL-32 BV had a sensitivity of 0.75 and specificity of 0.58. The MDQ had sensitivity of 0.70 and specificity of 0.58. Hence, the HCL-32 BV showed higher sensitivity but the same specificity than the MDQ. The factor analysis resulted in 9 factors with eigenvalues > 1, explaining 53.1% of the total variance. According to the Scree test, a 3-factor solution was preferred. The first factor, with an Eigenvalue of 4.90, explained 15.3% of the variance and comprised 10 items . This subscales structure reflects questions related to active/elated symptoms. The second factor, with an Eigenvalue of 3.48 (10.88% of the variance), comprised 11 items and its structure includes questions associated with irritable/risk-taking items. The third factor, with an Eigenvalue of 1.56 (4.87% of variance), comprised 5 itens and its structure reflect questions related to disinhibition/activation sexual. The psychometric parameters of HCL-32 BV suggest it as a useful instrument for the detection of hypomania in patients with mood disorders. HCL-32 BV is a brief, self-administered questionnaire of easy application and interpretation

Evaluar el cumplimiento del tratamiento psicofarmacológico de pacientes con diagnóstico reciente de trastorno bipolar según a la Guía de Práctica Clínica Española (GPC) en el Hospital Nacional Almanzor Aguinaga Asenjo durante 2012 – 2015. Material y métodos: Estudio Descriptivo Transversal donde se escogieron todos los pacientes con diagnóstico reciente de trastorno bipolar, a través de la base de datos virtual del hospital, con el respectivo código CIE-10 durante 2012 – 2015. Resultados: Se obtuvieron 166 Historias clínicas de pacientes con diagnóstico reciente entre 2012 – 2015, se excluyeron 84 historias clínicas, quedando 82 historias. De éstas, 73 son de pacientes con reciente diagnóstico Trastorno bipolar con episodios maniaco, hipomaniacos o mixtos, 4 con episodios depresivos leves y 5 con episodios depresivos moderados/graves. El 46.3% fueron varones y el promedio de edad fue 51 ± 19 años. Se encontró 16 pacientes (19.5%) no tratados según la GPC. El psicofármaco más prescrito fue: Valproato (30 pacientes); Se utilizó monoterapia en el 21.5% (50% Litio y 50% Valproato). La prescripción de benzodiacepinas en pacientes con trastorno bipolar con episodios de manía, hipomanía o mixtos que cumplen la GPC, fue 59.4%. Conclusiones: La mayoría de los pacientes con diagnóstico reciente de trastorno bipolar fueron tratados según las recomendaciones de GPC, la mayor proporción pertenece a pacientes con trastornos bipolar con episodios maniacos, hipomaniacos y mixtos. El uso de monoterapia con los psicofármacos recomendados se dio en cerca de un quinto de los pacientes, además de una mayor prescripción de valproato. / Tesis

The research literature proposes that the concept of identity may be central to understanding responses to having severe and enduring mental health problems. Theorists hypothesise a relationship between identity and the individual's acceptance of having mental health problems mediated by societal pressures. Given the inconclusive findings from research carried out a decade ago, this study has attempted to explore whether the participants' identification as a community member or patient affected, or was affected by, their belief that they have mental health problems, need medication, need to see healthcare professionals and their awareness of disabilities. A quantitative methodology was employed to examine the main variables. Forty five individuals living in the community with a diagnosis of schizophrenia, bipolar affective disorder or schizoaffective disorder were interviewed. Both within-group and between-group analyses were employed. The relationship between the independent variables and their relationships with sociodemographic and diagnostic factors, self-esteem and health and social functioning were explored. Measures that had been either standardised or used in previous related research were employed. The three central measures were taken from previous research studies in this area. Socio-demographic information was obtained from clinical files. Neither beliefs about mental health problems nor awareness of disabilities were found to be associated with identity, as measured in this study. Health and social functioning and work-related variables appeared to contribute to an identification as a community member. It is suggested that defensive responses to disabilities existed to protect the individual's sense of self-worth. Furthermore, socially valued experiences prior to illness and level of ability may have contributed to the participants' identification as a community member. The clinical implications are discussed.

O transtorno bipolar (TB) tem sido associado a elevados índices de comorbidades médicas. Múltiplas vias biológicas aparentam estar envolvidas na conexão entre o transtorno bipolar e estas comorbidades, sendo que a inflamação vem ganhando destaque. Evidências sugerem que o lítio, o tratamento padrão ouro para esta doença, possui propriedades anti-inflamatórias. No entanto, até o momento, não consta na literatura um estudo investigando os efeitos do lítio em fatores inflamatórios e neurotróficos em resposta a um estímulo inflamatório em um modelo animal de mania. Desta forma, este estudo visou avaliar se um modelo animal de mania induzido por dimesilato de lisdexanfetamina (LDX) exibe um perfil inflamatório e analisar o efeito de uma ativação imune causada por lipopolissacarídeo (LPS) neste modelo. Adicionalmente, avaliamos a ação do lítio em fatores inflamatórios e neurotróficos. Ratos Wistar adultos machos foram submetidos ao modelo animal de mania e, após ser realizado o teste de comportamento, receberam LPS para causar uma ativação imune sistêmica. Posteriormente, foi coletado sangue dos animais para medir os níveis séricos de marcadores inflamatórios (TNF-α, IL-6, IL-1β, IL-10 e iNOS) e do fator neurotrófico derivado do cérebro (BDNF). LDX induziu hiperatividade nos animais e causou um aumento nos níveis de BDNF, porém não influenciou nos níveis de nenhum marcador inflamatório. O lítio não afetou os níveis de BDNF sérico, mas foi eficaz em prevenir o aumento nos níveis de iNOS nos ratos submetidos à ativação imune. Os resultados obtidos até o momento não permitem concluir acerca dos efeitos anti-inflamatórios do lítio neste modelo animal de mania, uma vez que o LDX não induziu inflamação. No entanto, o lítio possivelmente apresenta propriedade anti-inflamatória, visto que evitou o aumento de iNOS sérico em resposta à administração de LPS. A fim de investigar posteriormente os potenciais efeitos anti-inflamatórios do lítio também em nível central, foi realizada a padronização da técnica de imuno-histoquímica para a identificação de astrócitos e microglia, bem como para a classificação das células microgliais em fenótipo M1 (proinflamatório) ou M2 (anti-inflamatório). Para isso, foram utilizados os seguintes marcadores: GFAP para astrócitos; Iba1 para microglia; iNOS para o fenótipo M1; e arginase para o fenótipo M2. As condições apropriadas da técnica foram estabelecidas e, como perspectiva deste trabalho, a técnica padronizada será aplicada na avaliação destes tipos celulares neste modelo animal de mania. / Bipolar disorder has been associated with high rates of medical comorbidities. Multiple biological pathways appear to be involved in the connection between bipolar disorder and these comorbidities, and inflammation is gathering further importance. Evidences suggest that lithium, the gold standard treatment for this illness, has anti-inflammatory properties. However, no study investigated the effects of lithium on inflammatory and neurotrophic factors after an immune challenge in an animal model of mania. This study was designed to evaluate whether an animal model of mania induced by lisdexanfetamine dymesilate (LDX) exhibits an inflammatory profile and analyze the effect of a further immune activation caused by lipopolysaccharides (LPS) in this model. Moreover, we evaluated the action of lithium on inflammatory and neurotrophic factors. Adult male Wistar rats were submitted to the animal model of mania and after the open-field test were administered LPS to cause systemic immune activation. Subsequently, animals had their blood collected and serum levels of brain-derived neurotrophic factor (BDNF) and inflammatory markers (TNF-α, IL-6, IL-1β, IL-10 and iNOS) were measured. LDX induced hyperactivity in the animals, but did not increase any inflammatory marker, except BDNF levels. Lithium had no effect in BDNF serum levels, but prevented the increase in the iNOS levels in animals submitted to immune activation. Based on these results, we cannot conclude about lithium anti-inflammatory effects on this particular animal model of mania. Nonetheless, lithium prevented augmentation in the iNOS serum levels caused by LPS. In order to investigate potential anti-inflammatory effects of lithium in the SNC, standardization of the immunohistochemistry technique was performed to identify astrocytes and microglia, as well as classifying microglial cells in M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotype. For this purpose, the following markers were used: GFAP for astrocytes; Iba1 for microglia; iNOS for M1 phenotype; and arginase for M2 phenotype. Appropriate experimental technic parameters were established and, as a perspective to current findings would be the assessment of these cells centrally in this animal model of mania.

No description available.

Embora há muito tempo se considere que alterações neurobiológicas tenham um papel central no transtorno bipolar (TB), os mecanismos moleculares ligados à sua fisiopatologia permanecem desconhecidos. A hipótese atual sugere que alterações nos circuitos cerebrais associados à regulação do humor e alterações em sistemas de sinalização intracelular associados à plasticidade e sobrevivência neuronal estão envolvidas no TB. Modelos animais são ferramentas úteis que nos permitem testar essas hipóteses e a resposta aos agentes farmacológicos. Um dos mais bem estabelecidos modelos animais de mania é o de hiperatividade induzida por psicoestimulantes. Portanto, o nosso objetivo inicial foi testar no modelo animal de mania, induzido por anfetamina, o envolvimento do dano ao DNA e do estresse oxidativo, bem como verficar o efeito do lítio e do valproato sobre esse modelo. Ainda no modelo animal, testamos se o dano ao DNA estaria envolvido também com o tratamento crônico e agudo de ratos jovens e adultos com metilfenidato. Nos pacientes com TB também avaliamos o dano ao DNA e proteínas, bem como a atividade do sistema antioxidante glutationa. No modelo animal de mania, observamos que a anfetamina é capaz de aumentar a atividade das enzimas antioxidantes, peroxidação lipídica e dano ao DNA. O lítio forneceu proteção ao dano recente ao DNA induzido pela anfetamina e o valproato apenas foi capaz de modular a atividade das enzimas antioxidantes superoxido dismutase (SOD) e catalase. No tratamento com metilfenitado, tanto os ratos jovens como os adultos também apresentaram dano recente ao DNA. Nos resultados em pacientes com TB podemos verificar que o dano permanente ao DNA não está aumentado, porém os pacientes com TB apresentam um aumento da frequência de apoptose. Verificamos ainda que o dano oxidativo a proteínas ocorre por nitração da tirosina, avaliado pelo imunoconteúdo de 3-nitrotirosina, e que este pode ativar a enzima glutationa-S-transferase, aumentada nos pacientes bipolares com maior tempo de doença, indicando um mecanismo compensatório envolvido. Esses resultados apontam para um envolvimento do dano ao DNA na fisiopatologia do TB e que esse pode ser modulado por rotas ativadas pelo estresse oxidativo. / Although neurobiological changes have long been considered to have a central role in bipolar disorder (BD), the molecular mechanisms related to the pathophysiology of this condition remain unknown. The current hypothesis suggests that alterations in neurochemistry could be associated with mood regulation and intracellular signaling systems linked to neuronal plasticity and survival are involved in BD. Animal models are useful tools that allow testing hypotheses and response to pharmacological agents. One of the most well established models of mania is psychostimulant-induced hyperactivity. Therefore, our initial objective was assessing DNA damage and oxidative stress in an animal model of amphetamine-induced mania, in addition to verifying the effect of lithium and valproate in this same model. Still in this paradigm we tested if DNA damage is also associated with acute and chronic methylphenidate exposure in young and adult rats. In patients with BD we also assessed DNA and protein damage, as well as activity of the glutathione antioxidant system. In the animal model of mania we observed that amphetamine can increase the activity of antioxidant enzymes, lipid peroxidation and DNA damage. Lithium provided protection against recent amphetamine-induced DNA damage and valproate was only able to modulate the activity of SOD antioxidant enzymes and catalase. Both young and adult rats displayed DNA damage after amphetamine exposure. In patients with BD, we observed that permanent DNA damage is not increased, but they present a higher frequency of apoptosis. It was also verified that oxidative damage to proteins ensues via thyrosine nitration, assessed by 3- nitrotyrosine immunocontent. Possibly this damage activates the GST enzyme, which levels are raised in patients with bipolar disorder with a longer disease evolution, indicating that a compensatory mechanism is implicated. This results point to the importance of DNA damage in the pathophysiology of bipolar disorder, which is possibly mediated by routes activated by oxidative stress.

Evidências sugerem o envolvimento de mecanismos de resiliência celular, estresse e de alterações epigenéticas na patofisiologia dos transtornos de humor, como o transtorno bipolar (TB) e o transtorno depressivo maior. Os estudos apresentados nesta tese tiveram como objetivo explorar esses mecanismos de forma translacional, partindo da avaliação da morte e sobrevivência celular até a correlação dos achados com a resposta ao tratamento. O primeiro capítulo se propôs a revisar dados da literatura com relação à progressão do TB, os quais apontam para uma série de alterações biológicas envolvendo resiliência celular em pacientes com diferentes estágios do transtorno. O segundo capítulo teve como objetivo avaliar parâmetros de morte celular em pacientes com TB, onde um aumento na frequência de células em apoptose inicial foi detectado em comparação a controles. Em seguida, considerando os efeitos potenciais dos glicocorticóides na indução de apoptose, o terceiro capítulo avaliou a atividade do eixo hipotálamo-pituitária-adrenal (HPA) em pacientes com TB, seus irmãos e em controles saudáveis, além de mecanismos moleculares associados ao eixo. Nossos resultados sugerem uma disfunção do eixo HPA em pacientes associada a uma hiporresponsividade do receptor de glicocorticóide, maiores níveis da proteína ligante de FK506 de 51 kDa (FKBP51) e um aumento da metilação do gene FKBP5. Nós ainda observamos que os pacientes com maior número de episódios apresentaram uma disfunção do eixo mais pronunciada do que aqueles em estágio inicial. No quarto e último capítulo nós realizamos um estudo para verificar os mecanismos moleculares pelos quais o estresse pode induzir alterações epigenéticas envolvendo a metilação do DNA, onde descrevemos o efeito oposto das cochaperonas FKBP51 e FKBP52 sobre a fosforilação da enzima DNA metiltransferase 1 (DNMT1). Além disso, a redução da fosforilação da DNMT1 correlacionou-se com uma melhor resposta clínica ao tratamento em pacientes com transtorno depressivo maior. Em suma, os resultados desta tese sugerem que a resiliência celular, a resposta ao estresse e a metilação do DNA desempenham importantes papéis na patofisiologia, progressão e resposta ao tratamento de pacientes com transtornos de humor. Novos tratamentos com alvo em mecanismos epigenéticos, na modulação do receptor de glicocorticóide e no aumento da resiliência celular devem ser priorizados em estudos futuros. / Evidence suggests the involvement of cellular resilience mechanisms, stress, and of epigenetic alterations in the patophysiology of mood disorders, such as bipolar disorder (BD) and major depressive disorder. The studies presented in this thesis aimed at exploring these mechanisms in a translational fashion, going from the assessment of cellular death and survival to the correlation of findings with the response to treatment. The first chapter aimed at reviewing data from the literature regarding the progression of BD, which point to a series of biological alterations involving cellular resilience in patients at different stages of the disorder. The second chapter aimed at assessing cell death parameters in patients with BD, in which a higher frequency of cells in early apoptosis was detected when compared to controls. In addition, considering the potential effects of glucocorticoids in the induction of apoptosis, the third chapter assessed the activity of the hypothalamus-pituitary-adrenal (HPA) axis in patients with BD, their siblings, and in healthy controls, in addition to the molecular mechanisms associated with the axis. Our results suggest a dysfunction of the HPA axis in patients associated with a hyporesponsiveness of the glucocorticoid receptor, increased FK506-binding protein of 51 kDa (FKBP51) levels, and increased methylation levels at the FKBP5 gene. We also noted that patients with a greater number of previous episodes presented a more pronounced dysfunction of the axis when compared to early-stage patients. In the fourth and last chapter we performed a study to verify the molecular mechanisms by which stress can induce epigenetic alterations involving DNA methylation, where we describe opposing effects of the cochaperones FKBP51 and FKBP52 on DNA methyltransferase 1 (DNMT1) phosphorylation. In addition, the reduction of DNMT1 phophorylation was correlated with a better clinical response to treatment in patients with major depressive disorder. In summary, the results of this thesis suggest that cellular resilience, response to stress and DNA methylation play key roles in the pathophysiology, progression and response to treatment in patients with mood disorders. Novel treatments targeting epigenetic mechanisms, the modulation of the glucocorticoid receptor, and enhancing cellular resilience should be prioritized in future studies.

Durch Messung der Progranulinspiegel im Blutplasma mittels ELISA konnte in vorliegender Arbeit ein signifikanter Unterschied zwischen bipolaren Patienten und Kontrollen nachgewiesen werden. Dabei wies das Patientenkollektiv durchschnittlich niedrigere Konzentrationen auf. Befunde vorausgegangener Studien deuten darauf hin, dass ein peripherer Progranulinmangel auch mit zentralnervösen Veränderungen einhergehen kann und somit einen Anteil an der Pathophysiologie der bipolaren Störung haben könnte. Insbesondere eine immunologisch-entzündliche Dysregulation sowie fehlende neurotrophe Impulse könnten dabei eine wesentliche Rolle spielen. Überdies fiel bei der Auswertung der Daten eine hochsignifikante Korrelation zwischen Progranulinspiegel und Lebensalter der Probanden auf. Dabei nahm mit steigendem Alter auch die periphere Progranulinkonzentration zu, was im Zuge des physiologischen Alterungsprozesses oder aber auch als Folge von neurodegenerativen bzw. - inflammatorischen Vorgängen auftreten könnte. Bei der molekulargenetischen Untersuchung der Polymorphismen rs2879096, rs4792938 und rs5848 konnten keine signifikanten Unterschiede in der Genotypen- und Haplotypenverteilung zwischen Patienten und Kontrollen gefunden werden, was sich möglicherweise auf die relativ kleine Stichprobe von 181 Probanden zurückführen lässt. Zumindest existieren Hinweise auf eine Rolle der jeweiligen Polymorphismen bei verschiedenen neuropsychiatrischen Erkrankungen, möglicherweise auch bei der bipolaren Störung. Außerdem fand sich bei den im Progranulingen liegenden SNPs rs2879096 und rs4792938 keine Assoziation einer Risikogenvariante zu veränderten Progranulinspiegeln, das heißt keiner der beiden Polymorphismen scheint funktionelle Bedeutung zu haben. Somit ließe sich kein Effekt des Genotyps auf die periphere Progranulinkonzentration nachweisen, wobei wiederum die verhältnismäßig niedrigen Fallzahlen beachtet werden müssen. Der in der 3’UTR liegende SNP rs5848 scheint hingegen im Patientenkollektiv zu deutlich erniedrigten Proteinspiegeln zu führen. Dieser Befund steht auch im Einklang 47 mit einer Vielzahl von Studien, die rs5848 eine Bedeutung bei verschiedenen neuropsychiatrischen Erkrankungen beimessen und unterstreicht die Rolle niedriger Progranulinkonzentrationen in der bipolaren Störung. Zusammenfassend lässt sich feststellen, dass bei bipolaren Patienten signifikant niedrigere Progranulinkonzentrationen als in der Kontrollgruppe gemessen wurden. Weitere Studien, welche die zu Grunde liegenden biochemischen Vorgänge und Pathomechanismen erforschen, wären nun von Interesse, um ein besseres Verständnis der Erkrankung zu erlangen. Langfristig wäre die Nutzung des Progranulinspiegels als diagnostisches Werkzeug erstrebenswert, wobei sich dies auf Grund des großen Overlaps zwischen Patienten- und Kontrollgruppe wohl eher schwierig gestalten wird. Die relativ unkomplizierte Progranulinbestimmung im Blutplasma könnte möglicherweise im Rahmen einer Messung vieler verschiedener Parameter als Baustein eines diagnostischen Apparates zur Erkennung der bipolaren affektiven Störung dienen. Somit wären weiterführende Untersuchungen anhand größerer Fallzahlen und funktionelle Studien der pathomechanistischen Zusammenhänge des Progranulins ein interessantes Feld, um einige der zahlreichen ungeklärten Fragen rund um die bipolare Störung weiter aufzuklären. / Subject: Progranulin plasma levels and genotypes in bipolar disorder patients Methods: ELISA of progranulin and genotyping of 3 SNPs in patients and healthy controls Results: Progranulin plasma levels werde significantly reduced in bipolar patients. Progranulin levels were significantly higher with increased age in patients and healthy controls. Conclusions: Progranulin as an inflammatory biomarker could be involved in the pathogenesis of bipolar disorder, at least in a subgroup of patients

[Abstract]: This thesis investigates the feasibility of closing wounds in skin tissue by laser welding as a substitute for suturing. Such a process would provide advantages in some surgical procedures. The investigation revised available theory on the action of lasers on skin tissue as a basis for the experimental program. The results of experiments using rat skin are then reported. In addition a thorough investigation of the normal (uninjured) tensile strength of rat skin was undertaken to provide a base line comparison. Laser systems permit very high-energy radiation of a single wavelength to be focused on a tiny spot, and have found application in many areas of engineering. They are also currently used in many branches of medicine including ophthalmology, gynaecology, dermatology, otolaryngology, and gastroenterology. These medical applications employ argon, YAG, and carbon dioxide type lasers. In many cases, lasers have been found to be more effective than conventional treatment methods with advantages including reduced blood loss, more accurate removal of unwanted tissue, shorter operating times and less postoperative pain and care (Gibson and Kernohan, 1993). Tissue welding using laser energy represents a small but growing area of medical research and is largely focused on anastomosis. This thesis investigates, using a specific experimental program, the feasibility of the bipolar contact Nd:YAG laser to weld cutaneous tissue. No similar published research has been identified in this area. The available literature focuses on non-contact lasers of various types and settings and mainly in the area of anastomosis. The experimental methodology and the specific technique for the bipolar contact laser is developed, tested and evaluated as part of this project. The welding techniques developed in this project overcome the previous difficulties of tissue alignment. The use of the bipolar laser probes substantially improves the ability to align the tissue edges to be joined. The probes give tactile feedback to the user and the pressure effect of the probes may assist with the welding process. The developed technique was no faster or easier than suturing. Viable welds and a useable technique for welding skin on rats were developed and tested. The resultant healing was comparable with published literature and both sutured and welded wounds returned to full strength as compared with the baseline data collected. All wounds had returned to full strength within 91 days. At 75 days there was not significant difference between laser welded and sutured wounds and they had achieved approximately 90 percent of full strength. Time to half strength was approximately 42 days and there was a larger standard deviation for both laser welded and sutured wounds. The most significant increase in strength and therefore healing occurred in the first 42 days. Simhon et al, 2001 states that a tensile strength of 0.6 N plus/minus 0.4 N was sufficient to hold tissue together. By day 7 the strength of the wound (laser welded) was more than twice the strength needed to maintain closure. There may have been sufficient healing for this to occur earlier but there were insufficient animals to allow for testing of this theory. In conclusion this experimental program and investigation has reviewed the available literature on the current use of lasers in medicine and their specific laser-tissue interaction which leads to tissue welding. It has provided a large database of tensile strength measurements collected with a reproducible methodology and reported in a standardised format. The developed technique for laser tissue welding using a bipolar contact Nd:YAG laser has been established and verified. It produces viable welds comparable in strength and healing rates to sutures.