Melanoma é um tipo maligno de lesão de pele pigmentada, e atualmente está entre os tipos de câncer existentes mais perigosos. Entretanto, diferenciar casos malignos de benignos é uma tarefa difícil mesmo para experientes especialistas, e um sistema de diagnóstico auxiliado por computador pode ser uma ferramenta bastante útil. Normalmente, este sistema inicia por um pré-processamento da imagem, isto é, remoção de artefatos indesejados, como pelos, sardas ou efeitos de sombreamento. A seguir, o sistema executa uma etapa de segmentação, identificando as bordas da lesão. Por fim, baseando-se na área da imagem identificada como lesão, diversas feições são computadas e uma classificação é gerada. Neste tese, apresentada na forma de uma coleção de artigos publicados, nós apresentamos técnicas para automaticamente executar todos estes passos, resultando em um pré-diagnóstico para uma lesão de pele pigmentada baseado apenas em uma imagem convencional (uma simples fotografia). Nós testamos nossos métodos em bases de imagens públicas e atingimos melhores resultados de segmentação e classificação que os demais métodos presentes na literatura. / Melanoma is a type of malignant pigmented skin lesion, and currently is among the most dangerous existing cancers. However, differentiating malignant and benign cases is a hard task even for experienced specialists, and a computer-aided diagnosis system can be an useful tool. Usually, the system starts by pre-processing the image, i.e. removing undesired artifacts such as hair, freckles or shading effects. Next, the system performs a segmentation step to identify the lesion boundaries. Finally, based on the image area identified as lesion, several features are computed and a classification is provided. In this Thesis, presented as a collection of published papers, we detail approaches to automatically execute all these steps, resulting in a pre-diagnosis for a pigmented skin lesion based only in a standard camera image (i.e. a simple color photograph). We tested our methods on publicly available datasets and achieved better segmentation and classification results than methods previously proposed in the literature.

Neste trabalho, um novo método não-supervisionado para segmentação de lesões melanocíticas em imagens macroscópicas é proposto levando em consideração regiões suspeitas, e também uma nova abordagem para classificação de lesões que faz uso de evidências locais e de contexto para estimar um índice de probabilidade para malignidade em cada lesão. O método proposto realiza a segmentação das imagens em três tipos de regiões disjuntas: ‘pele saudável’, ‘região de incerteza’ e ‘lesão’. Regiões de incerteza são refinadas através da utilização de feições estocásticas também de forma não-supervisionada, resultando em uma máscara binária que discrimina a pele da lesão. As máscaras obtidas apresentam um erro XOR comparável aos métodos estado da arte. A imagem é segmentada utilizando um algoritmo de superpixels e as sub-regiões que intersectam a máscara obtida são categorizadas como evidências locais. Estas evidências são representadas por uma descrição especializada que explora as características como cor e textura. Estas sub-regiões são então associadas à evidências de contexto definidas pela borda da lesão de onde foram extraídas e classificadas de forma independente através de uma abordagem supervisionada. Com o resultado da classificação destas evidências é possível obter um indicador probabilístico para malignidade associado a cada lesão, e levando em consideração um valor de tolerância é possível identificar lesões malignas em potencial. Os resultados obtidos com o método proposto são promissores e apresentam maior acurácia do que os métodos existentes na literatura apesar do erro XOR da segmentação das lesões ser maior, o que tende a confirmar o potencial do método proposto para discriminar lesões melanocíticas benignas e malignas. / In this work, a novel unsupervised method for melanocytic macroscopic image segmentation is proposed considering suspicious regions, and also a novel approach for lesion classification using local and context evidence to estimate a probabilistic index of malignity or benignity in each lesion. The proposed method segment the macroscopic images in three types of disjoint regions: ‘healthy skin’, ‘suspicious region’ and ‘lesion’. Suspicious areas are refined using stochastic texture features also in an unsupervised approach, resulting in a binary mask discriminating skin and lesion. The resulting masks present an XOR error similar to other state-of-art methods. In the next step, the image is segmented using a superpixels algorithm and subregions that intersect the obtained mask categorized as local evidence. A specialized representation describes color and texture information present in the local evidence region. The border of the segmented skin lesion defines the context evidence and using a supervised approach, local and context evidence are combined and classified independently. With the evidence classification results is possible to obtain a probabilistic index of malignity and benignity associated to each lesion, and considering a tolerance value is possible to identify potential malignant lesions. The results achieved with the proposed method are promissing and present greater accuracy than other techniques in the literature, even with a greater XOR error in segmentation step, confirming the proposed method’s potential to discriminate benignant and malignant melanocytic lesions.

A compilação mais recente dos dados mundiais indica que anualmente 466.000 novos casos de câncer cervical são detectados em todo mundo. A infecção pelos tipos oncogênicos do papilomavírus humano (HPV), constitui importante fator de risco para o desenvolvimento do câncer do colo uterino. Em mulheres portadoras do vírus da imunodeficiência humana tipo 1 (HIV-1), tem sido demonstrado o aumento na prevalência e persistência da infecção por HPV oncogênicos, justificando o aumento da susceptibilidade destas mulheres para o desenvolvimento das lesões cervicais, lesões precursoras do câncer do colo uterino. Citocinas são importantes na defesa contra a infecção pelo HPV e o nível de sua produção é geneticamente determinado. A predominância de citocinas do padrão do tipo Th1, como o TNF-alfa, está associada com a regressão das lesões cervicais. Neste estudo foram analisados os fatores comportamentais, imunológicos e virais, possivelmente, associados ao desenvolvimento das lesões cervicais em 66 mulheres mexicanas, portadoras ou não da infecção pelo HIV-1, apresentando lesões cervicais. Assim, aspectos sócio-demográficos e hábitos sexuais, a identificação e a tipificação do HPV, e a detecção do polimorfismo da região promotora do TNF foram analisados. Ao avaliar os aspectos sócio-comportamentais, a maioria das mulheres estava casada legalmente ou em união consensual no momento da entrevista, com nível educacional fundamental e nível sócio-econômico baixo. Associado a isso, a maior porcentagem dos maridos eram migrantes dos Estados Unidos da América (EUA), em busca de emprego e melhores condições financeiras. O grupo de pacientes com HIV-1 que referiram utilizar a camisinha só algumas vezes ou nunca e que relataram possuir entre 2-3 parceiros sexuais foi maior do que o grupo de mulheres sem o HIV- 1. Adicionalmente, os parceiros sexuais de mulheres com o HIV-1 mantinham outras parcerias sexuais, sendo estas heterossexuais e/ou homossexuais. Todas as pacientes arroladas no presente estudo apresentavam infecção ativa por HPV e lesões cervicais de baixo grau. Os HPV oncogênicos, como os do tipo 16/18 e 35, foram significantemente mais freqüentes entre as HIV positivas em comparação às não portadoras dessa infecção. Relativo às comparações do polimorfismo do TNF, a freqüência do genótipo TNF-308 não mostrou diferenças significantes entre os grupos de pacientes. O gene da região promotora do TNF na posição -238 também foi avaliado e observamos que o alelo TNF-238G, associado à alta produção dessa citocina, apresentou significativo aumento de sua freqüência entre as pacientes com o HIV-1 em relação às pacientes sem o HIV-1. Estes resultados sugerem que as condições sócio-culturais e hábitos sexuais estão envolvidos com a vulnerabilidade para a aquisição do HIV e HPV em mulheres mexicanas. Embora as portadoras do HIV apresentem infecção ativa por HPV oncogênicos, a presença do alelo -238G, relacionado com a alta produção do TNFalfa, pode estar associado com a não progressão das lesões cervicais. Entretanto, esta interpretação deve ser realizada com cautela, pois algumas mulheres que apresentavam resultados de lesões cervicais de baixo grau morreram de câncer cérvico uterino. Este fato revela a fragilidade das análises e avaliações ginecológicas nos serviços de saúde referidos neste estudo e sugere que a alternativa de utilizar técnicas de biologia molecular para a identificação e tipificação dos tipos oncogênicos do HPV seja uma estratégia importante para os programas de prevenção do câncer do colo do útero. / The most recent compilation of global data indicates that, every year, 466,000 new cases of cervical cancer are detected around the world. Infection by oncogenic types of the human papillomavirus (HPV) constitutes an important risk factor for the development of colon cancer. In women with human immunodeficiency virus type 1 (HIV-1), an increased prevalence and persistence of infection by oncogenic HPV has been demonstrated, justifying these women\'s increased susceptibility to the development of cervical lesions, which precede colon cancer. Cytokines are important in the defense against infection by HPV and its production level is genetically determined. The predominance of th1 cytokines, such as TNF-alfa, is associated with the regression of cervical lesions. This study analyzed behavioral, immunological and viral factors that may be associated with the development of cervical lesions in 66 Mexican women, infected by HIV-1 or not and presenting cervical lesions. Sociodemographic aspects and sexual aspects, HPV identification and typification and the detection of polymorphism in the region that promotes TNF were analyzed. With respect to socio-behavioral aspects, most women were legally married or lived in consensual union at the time of the interview, with basic education and low socioeconomic level. Moreover, most husbands were migrants from the United States (USA) who were looking for a job and better financial conditions. The group of HIV-1 patients who mentioned using a condom sometimes or never had having 2-3 partners was larger than the group of women without HIV-1. In addition, the sexual partners of women with HIV-1 had other hetero and/or homosexual partners. All patients included in this research presented active infection by HPV and low-grade cervical lesions. Oncogenic HPV, such as types 16/18 and 35, were significantly more frequent among HIV-positive than among HIV-negative patients. As to the comparisons of TNF polymorphism, the frequency of the TNF-308 genotype did not show significant differences between the patient group. The gene of the TNF promoting region in position -238 was also assessed. It was found that the TNF 238G allele, associated with high production levels of the cytokine, presented a significant increase in frequency among patient with in comparison with those without HIV-1. These results suggest that sociocultural conditions and sexual habits are involved in Mexican women\'s vulnerability to infection by HIV and HPV. Although the HIV patients present active infection by oncogenic HPV, the presence of the -238G allele, related with the high production of TNF-alpha, can be associated with the non progression of the cervical lesions. However, this must be interpreted with caution, as some women with low-grade cervical lesion results died of colon cancer. This fact reveals the fragility of gynecological analyses and assessments at the health services mentioned in this research and suggest the alternative of using molecular biology techniques for the identification and typification of HPV as an important strategy for colon cancer prevention programs.

Orientador: Wellerson Rodrigo Scarano / Resumo: A capacidade de progressão do câncer de próstata para uma fase não-responsiva às terapias de privação androgênica traz à luz a importância do estudo de tratamentos adjuvantes. Pesquisas recentes apontam receptores estrogênicos como possíveis alvos terapêuticos em neoplasias, podendo ser modulados por fármacos como o Raloxifeno, atualmente utilizado na prevenção do câncer de mama e tratamento da osteoporose. Nesse contexto, o objetivo deste estudo foi avaliar os potenciais efeitos histoprotetores e antiproliferativos da terapia com Raloxifeno, durante a carcinogênese prostática. Para isso, 34 ratos Fisher 344 machos foram inoculados com o carcinógeno MNU (15 mg/kg) na cápsula dos lobos ventral e dorsolateral e receberam doses subcutâneas de cipionato de testosterona, duas vezes por semana, durante 220 dias, processo aqui denominado de Indução de Carcinogênese. Posteriormente, foram divididos em dois grupos experimentais para o período de Tratamento: grupo Raloxifeno, recebendo 10 mg/kg de peso corpóreo/dia de Raloxifeno diluído em 0,2 ml de óleo de milho durante 30 dias consecutivos; grupo Induzido, recebendo somente 0,2 ml de óleo de milho (veículo) durante 30 dias consecutivos. Outros 10 animais pertencentes ao grupo Controle receberam veículo duas vezes por semana por 220 dias para simular o processo de Indução e, posteriormente, durante 30 dias consecutivos para simular o período de Tratamento. Após a eutanásia, o sangue e as próstatas ventral e dorsolateral foram coletado... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Prostate cancer ability to progress to a non-responsive phase to androgen deprivation therapy emphasizes the importance of study on adjuvant treatments. Recent research suggests estrogen receptors as possible therapeutic targets in neoplasias and they can be modulated by drugs such as Raloxifene, currently used in the prevention of breast cancer and treatment of osteoporosis. In this context, this study aimed to evaluate the histoprotective and antiproliferative potential effects of Raloxifene therapy during prostatic carcinogenesis. Thereunto, 34 male Fisher 344 rats were inoculated with the MNU carcinogen (15 mg / kg) in the ventral and dorsolateral lobe capsule and received subcutaneous doses of testosterone cypionate twice a week for 220 days. Subsequently, they were divided into two experimental groups: Raloxifene group, receiving 10 mg/kg of body weight/day of Raloxifene diluted in 0.2 ml of corn oil for 30 consecutive days; Induced group, receiving only 0.2 ml corn oil (vehicle) for 30 consecutive days. Another 10 animals belonging to the Control group received vehicle twice a week for 220 days to simulate the induction process and subsequently for 30 consecutive days to simulate the treatment period. After euthanasia, blood and the ventral and dorsolateral prostate lobes were collected for hormonal dosage, histopathological analysis of the lesions, quantification of mast cells, picrosirius (collagen fibers) and immunostaining for AR (androgen receptor), α-actin and Ki... (Complete abstract click electronic access below) / Doutor

Onchocerca is a genus of roundworm most commonly associated with the human infection onchocerciasis, or river blindness. While typically a zoonotic infection of ungulate populations, canine cases (Onchocerca lupi) have been identified in the United States and Greece. In 2012, Los Angeles County, Veterinary Public Health Program identified 3 cases of Onchocerca spp. infections in domestic canines. Samples from the ensuing blackfly collections were sent to the Global Health Infectious Disease Research Unnasch Laboratory for parasite isolation and vector species identification. Species-specific primers were designed and optimized for O. lupi using a non- specific cytochrome oxidase (COI) gene target (689bp) previously utilized in Onchocerca identification as a base. A secondary, nested PCR primer set (115bp) was additionally designed to aid in the screening process. Extracted DNA samples from the collected blackflies were screened for the presence of the parasite and positive samples were further tested against the larger fragment for confirmation. The primers designed for the study were determined to be specific to O. lupi and not cross-reactive with other Onchocerca species or Dirofilaria immitis. Of the 213 blackflies screened, 6 samples tested positive for parasite presence. The blackfly species was identified as Simulium spp. The presence of the O. lupi parasite in the black fly population implicates that this is the likely vector in the LA County cases. While the blackfly identification was unable to be determined to the species level, the identification of Simulium spp. confirms the typically suspected vector in Onchocerca infections. Concerns of cross-species transmission make O. lupi an important parasite for public health study.

<p>Porphyrias are inherited metabolic disorders characterised by an impairment of heme biosynthesis. Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in Sweden. Acute attacks of AIP are characterised by neuro-psychiatric symptoms, including epileptic seizures. Environmental and acquired factors are related to the induction of symptoms. Acute attacks of AIP are treated with high doses of glucose and/or hematin infusions.</p><p>The pathogenesis of the neuro-psychiatric symptoms is not known. Reversible white-matter lesions, probably due to vasospasm, have been seen on brain MRI. Similarities between multiple sclerosis (MS) and AIP have previously been described, but to our knowledge no study has investigated whether AIP-gene carriers have white-matter lesions seen on brain MRI or oligoclonal bands (OB) in cerebrospinal fluid (CSF).</p><p>The percentage of AIP-gene carriers who have experienced epileptic seizures has been calculated at 10-20%, but previous investigations are derived from highly selected clinic-based studies. Studies were therefore undertaken to investigate the prevalence of epileptic seizures, the relationship of seizures to AIP, the type of seizures and the relationship of seizures to other factors such as melatonin.</p><p>A case report described the disappearance of porphyric attacks after the onset of diabetes mellitus (DM). In our study, we investigated the rate of attacks after the onset of DM. For many years, clinical issues relating to AIP have not been a focal area. We therefore carried out a study to update our knowledge of the clinical course of AIP in order to improve prevention, control and treatment. In our studies of AIP-gene carriers and epileptic seizures, we found that epileptic seizures are less common than has previously been described (3.7%) and they are not very different from what is expected in the general population, but the prevalence of 5.1% of seizures with manifest AIP is higher than in the general population. The seizures may be generalised or partial and the seizure frequency was generally low. The AIP-gene carriers who had had epileptic seizures had a lower melatonin excretion level in their urine compared with gender- and aged-matched AIP-gene carriers’ relatives without epileptic seizures, which may indicate that melatonin plays a possible anti-convulsive role.</p><p>In our study of AIP and DM, no subject had an attack of AIP after the onset of DM. White-matter lesions on brain MRI were seen in 25% of the AIP-gene carriers examined outside attacks. One carrier had elevated protein levels in the CSF, but no carrier had cells or OB in the CSF.</p><p>In our population-based study, 356 DNA-confirmed AIP-gene carriers from northern Sweden participated. Manifest AIP (MAIP) was identified in 42%, 65% of whom were women. Eight mutations were found. Women were more severely stricken by AIP attacks in terms of number and duration, hospital admission and early onset. Men (30%) reported most attacks > 40 years of age. The most commonly reported symptoms during attacks were severe abdominal pain (86%), fatigue (42%), constipation (41%), vomiting (36%), muscle pain (30%), psychiatric symptoms (29%), pareses (20%) and sensory impairment (10%). Chronic AIP symptoms were reported by 18%. Precipitating factors were often reported: menstruation (31%), psychological strain (30%), certain drugs and fasting (20%), infection and alcohol (14%), physical strain (12%) and pregnancy (5%). Smoking was more frequent in MAIP and was associated with the number of AIP attacks. Some 30% of MAIP carriers used drugs that were not considered safe (in 1999), mainly diuretics, calcium antagonists and ACE inhibitors. Twenty per cent of MAIP carriers reported that they were receiving a disability pension due to AIP. Elevated levels of ASAT, bile acids, creatinine, creatinine clearance, U-ALA and U-PBG were often found in MAIP-gene carriers. Hypertension, renal impairment and pain in the legs were associated with MAIP. Hepatoma was strikingly over-represented.To summarise; epileptic seizures are less common than has previously been described, melatonin may have an anti-convulsive effect and DM may have a beneficial effect on MAIP-gene carriers. White-matter lesions are seen on brain MRI. The lesions are unspecific but may relate to the patients’ porphyria. AIP is not a harmless disease. A large percentage of the AIP-gene carriers had frequent attacks, severe symptoms, long-lasting fatigue and chronic AIP and women were more severely stricken. Effects on the kidneys, blood pressure and the liver, including HCC, were evident. Measures should be taken to improve the quality of life and prognosis for AIP-gene carriers.</p>

Macrophages (monocytes/microglia) could play a critical role in central nervous system repair. We have previously found a synchronism between the regression of spontaneous axonal regeneration and the deactivation of macrophages 34 wk after a compression-injury of rat spinal cord. To explore whether reactivation of endogenous macrophages might be beneficial for spinal cord repair, we have studied the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in the same paraplegia model and in cell cultures. There is significant, though transient, improvement of locomotor recovery after a single delayed intraperitoneal injection of 2g GM-CSF. This improvement is associated with an increased expression of 5HT at the level of the CPG (T13-L2). At longer survival delays, axonal regeneration is significantly enhanced in GM-CSF-treated rats. We then studied the effects of GM-CSF on brain-derived neurotrophic factor (BDNF)secretion by macrophages/microglia, inflammatory reaction and phagocytosis by macrophages/microglia. In vivo, at short post-treatment delays, we found that GM-CSF increases significantly the expression of Cr3 and BDNF by macrophages at the lesion site. In vitro, BV2 microglial cells expressed higher levels of BDNF in the presence of GM-CSF and neurons cocultured with microglial cells activated by GM-CSF generated more neurites, an effect blocked by a BDNF antibody. In vivo, we showed that GM-CSF treatment (either immediate or delayed) does not increase IL-6 expression by macrophages/microglia or astrocytes. We showed that a delayed GM-CSF treatment down regulates IL-1 expression by astrocytes. In vivo, we showed that a delayed GM-CSF treatment can decrease MAG expression at the lesion site. These experiments suggest that GM-CSF could be an interesting treatment option for spinal cord injury and that its beneficial effects might be mediated by BDNF.

This dissertation presents results of a medical image analysis project leading towards development of a comprehensive set of methods and tools for computational image analysis of dynamic contrast-enhanced (DCE) breast magnetic resonance image (MRI), with the aim to aid the physician in interpreting DCE breast MRI examinations. Toward this goal, we developed image analysis methods that would be needed in a breast MRI computer aided diagnosis (CADx) system. A novel contribution of this dissertation is the performance evaluation for each of the major algorithm components developed in this dissertation project. This dissertation begins with reviewing breast imaging techniques, including routinely used modalities in current clinical practice and emerging techniques still in development. We discuss at length the principles of DCE breast MRI, a very sensitive breast imaging modality that has been increasingly used in clinical practice. Then we review the diagnostic guidelines for interpreting DCE breast MRI, and explain the needs and challenges that arise in developing computational image analysis system for breast MRI applications. In this dissertation project, both the morphological and kinetic features of the lesion are automatically extracted for diagnostic purpose. In order to extract morphological features from the segmented lesions, the lesion needs to be accurately segmented out from its surrounding tissues. We utilized a probabilistic method to obtain an optimal segmentation map based on several algorithmic segmentation outputs. In evaluating the performance of segmentation algorithms, we compared the algorithmic segmentation results against manually segmented lesions, and further assessed the segmentation impact on subsequent classification stage. In order to extract accurate kinetic information, the motion needs to be compensated across image volumes acquired sequentially. In this dissertation, we comparatively assessed the similarity metric in registering DCE breast MR images. The performance of cross correlation(CC) coefficient, and mutual information (MI) were studied in both rigid and non-rigid registration schemes. Numerical results and statistical properties were reported. The resultant image quality after registration is discussed both qualitatively and quantitatively. In this dissertation we implemented a classification system based upon quantitative morphological and kinetic features in improving the specificity of breast MRI. Morphological and kinetic features of the lesion were extracted automatically, and then the feature selection step was utilized to select the most relevant features to maximize the classifier performance. In our study, the area under the receiver operating curve (AUC) is used as the performance metric of the classifier, and our results are competitive with those of previous studies. The dissertation concludes by summarizing the contribution of this project and suggesting the future directions of quantitative and highly automated approaches to breast MR image analysis. / text

The philosophical and scientific studies of consciousness are two disciplines having much to learn from one another. On the one hand, a science of consciousness involves taking an objective approach to what is essentially a subjective phenomenon, giving rise to tricky conceptual and methodological issues, ones an analytic philosopher is perhaps best equipped to handle. On the other hand, a wealth of data now exists concerning the neural basis of consciousness. Such data, interpreted properly, can confirm or disconfirm philosophical views on consciousness, helping adjudicate debates thus far intractable. This dissertation explores some ways in which the philosophy and science of consciousness can be of mutual benefit to one another.

Porphyrias are inherited metabolic disorders characterised by an impairment of heme biosynthesis. Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in Sweden. Acute attacks of AIP are characterised by neuro-psychiatric symptoms, including epileptic seizures. Environmental and acquired factors are related to the induction of symptoms. Acute attacks of AIP are treated with high doses of glucose and/or hematin infusions. The pathogenesis of the neuro-psychiatric symptoms is not known. Reversible white-matter lesions, probably due to vasospasm, have been seen on brain MRI. Similarities between multiple sclerosis (MS) and AIP have previously been described, but to our knowledge no study has investigated whether AIP-gene carriers have white-matter lesions seen on brain MRI or oligoclonal bands (OB) in cerebrospinal fluid (CSF). The percentage of AIP-gene carriers who have experienced epileptic seizures has been calculated at 10-20%, but previous investigations are derived from highly selected clinic-based studies. Studies were therefore undertaken to investigate the prevalence of epileptic seizures, the relationship of seizures to AIP, the type of seizures and the relationship of seizures to other factors such as melatonin. A case report described the disappearance of porphyric attacks after the onset of diabetes mellitus (DM). In our study, we investigated the rate of attacks after the onset of DM. For many years, clinical issues relating to AIP have not been a focal area. We therefore carried out a study to update our knowledge of the clinical course of AIP in order to improve prevention, control and treatment. In our studies of AIP-gene carriers and epileptic seizures, we found that epileptic seizures are less common than has previously been described (3.7%) and they are not very different from what is expected in the general population, but the prevalence of 5.1% of seizures with manifest AIP is higher than in the general population. The seizures may be generalised or partial and the seizure frequency was generally low. The AIP-gene carriers who had had epileptic seizures had a lower melatonin excretion level in their urine compared with gender- and aged-matched AIP-gene carriers’ relatives without epileptic seizures, which may indicate that melatonin plays a possible anti-convulsive role. In our study of AIP and DM, no subject had an attack of AIP after the onset of DM. White-matter lesions on brain MRI were seen in 25% of the AIP-gene carriers examined outside attacks. One carrier had elevated protein levels in the CSF, but no carrier had cells or OB in the CSF. In our population-based study, 356 DNA-confirmed AIP-gene carriers from northern Sweden participated. Manifest AIP (MAIP) was identified in 42%, 65% of whom were women. Eight mutations were found. Women were more severely stricken by AIP attacks in terms of number and duration, hospital admission and early onset. Men (30%) reported most attacks &gt; 40 years of age. The most commonly reported symptoms during attacks were severe abdominal pain (86%), fatigue (42%), constipation (41%), vomiting (36%), muscle pain (30%), psychiatric symptoms (29%), pareses (20%) and sensory impairment (10%). Chronic AIP symptoms were reported by 18%. Precipitating factors were often reported: menstruation (31%), psychological strain (30%), certain drugs and fasting (20%), infection and alcohol (14%), physical strain (12%) and pregnancy (5%). Smoking was more frequent in MAIP and was associated with the number of AIP attacks. Some 30% of MAIP carriers used drugs that were not considered safe (in 1999), mainly diuretics, calcium antagonists and ACE inhibitors. Twenty per cent of MAIP carriers reported that they were receiving a disability pension due to AIP. Elevated levels of ASAT, bile acids, creatinine, creatinine clearance, U-ALA and U-PBG were often found in MAIP-gene carriers. Hypertension, renal impairment and pain in the legs were associated with MAIP. Hepatoma was strikingly over-represented.To summarise; epileptic seizures are less common than has previously been described, melatonin may have an anti-convulsive effect and DM may have a beneficial effect on MAIP-gene carriers. White-matter lesions are seen on brain MRI. The lesions are unspecific but may relate to the patients’ porphyria. AIP is not a harmless disease. A large percentage of the AIP-gene carriers had frequent attacks, severe symptoms, long-lasting fatigue and chronic AIP and women were more severely stricken. Effects on the kidneys, blood pressure and the liver, including HCC, were evident. Measures should be taken to improve the quality of life and prognosis for AIP-gene carriers.