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No presente estudo, realizado em trÃs municÃpios do interior do Cearà com boa cobertura de serviÃos de AtenÃÃo PrimÃria à SaÃde (APS), foram investigados atravÃs de um instrumento epidemiolÃgico denominado AutÃpsia Verbal (AV), 215 Ãbitos de crianÃas menores de um ano de idade, representando 90% do total identificado num perÃodo de dois anos - 1993/1994. Foram averiguadas as caracterÃsticas sÃcio-econÃmicas, cuidados e higiene, estado nutricional, o processo de doenÃa-assistÃncia-morte, a causa bÃsica do Ãbito, o funcionamento do Sistema de InformaÃÃo sobre Mortalidade e do Sistema de InformaÃÃo dos Agentes de SaÃde (AS). Dentre os Ãbitos investigados, 39,1% tiveram como causa bÃsica diarrÃia, seguida da Prematuridade que representou 17,2% dos casos e InfecÃÃo RespiratÃria Aguda (IRA) - 10,2%. Quanto ao processo doenÃa-assistÃncia-morte, destaca-se que 49,5% das crianÃas morreram no domicÃlio, embora 79% das famÃlias tenham procurado os serviÃos de saÃde no decorrer da doenÃa fatal, sugerindo uma baixa efetividade na identificaÃÃo e no tratamento de lactentes com doenÃas graves. Em 84% dos casos, a famÃlia procurou a rezadeira. Os AS foram procurados em 29% dos casos, embora tenham notificado 78% dos Ãbitos investigados, chamando atenÃÃo para a necessidade destes profissionais serem melhor treinados para intervir nestes casos. A concordÃncia estatÃstica do diagnÃstico dos AS para causa bÃsica do Ãbito em relaÃÃo ao da AV foi boa para diarrÃia, regular para outras causas, e fraca para IRA. Na discussÃo sÃo relatadas iniciativas tomadas pelas equipes de saÃde dos trÃs municÃpios com base nas informaÃÃes obtidas pelas AV com o objetivo de evitar novas mortes. O Estudo conclui que a investigaÃÃo de Ãbitos com instrumento de AV pode ser incorporada à rotina dos serviÃos de APS do Estado, propiciando informaÃÃes valiosas para as equipes locais de saÃde e gerando uma consciÃncia crÃtica que favorece a reduÃÃo da mortalidade infantil. / This study, was done in three municipalities of Cearà with Primary Health services funcioning at least four years. It was investigated with an epidemiological instrument, the verbal autopsy (VA), 215 deaths of children less one year of age, 90% of total identificated deaths from january, 1993 to dezember 1994. It was investigated social and economicas caratheristics, care with the children, nutricional status, basic cause of death. It was investigated too, the funcioning of Mortality Information Sistem (SIM), the Information Sistem of Comunitary Health Workers (CHW) Sistem and the sickness-assistance and death process. The basic cause of the investigated deaths by the VA was diarrhoea (39,1%), prematurity (17,2%) and acute respiratory infection (ARI), 10,2%. About the sickness-assistance and death process, 49,5% of the children died at home, however 79% of the families have had search for health services during the children sickness. This indicates low efectivity in identification and treatment of sick infants. The families search for popular healers in 84% of cases. The CHW was searched for 29% families, however have had notificated 78% of investigated deaths, showing the necessity of better training. The statistical concordance between information of CHW and VA about basic cause of death was good to diarrhoea, regular to other cases, and low to ARI. In the discussion is related actions of health workers of three municipalities based on the information of VA to reduce infant mortality. The study concluded that the investigation of infant deaths with an instrument of VA can be incorporated to the routine of Health Primary Services of CearÃ.

INTRODUÇÃO: A literatura demonstra que tromboembolismo venoso permanece como uma doença subdiagnosticada entre os pacientes hospitalizados, com aproximadamente 25% dos casos associados à internação. OBJETIVOS: Avaliar as doenças associadas ao desenvolvimento de tromboembolismo pulmonar (TEP) diagnosticado em autópsias, e demonstrar a frequência de TEP como causa do óbito ou fator contributivo. MÉTODOS: Estudo caso-controle retrospectivo, realizado no Instituto Central do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de 1995 a 2004. Revisamos os relatórios diagnósticos das autópsias, identificando TEP fatal, quando TEP foi a causa de morte, e TEP não fatal, quando TEP foi doença associada. RESULTADOS: 1.506 pacientes (502 casos e 1.004 controles), 18.359 óbitos no período, média 2.040; 71,2% desses submetidos a autópsias. Observou-se importante declínio nas taxas de autópsias. De 1995-1999 (87,2%) e 2000-2004 (54,4%); p = 0,016. Dos 502 casos (3,8%), em 328 (2,5%) TEP foi causa de morte e 174 (1,3%), causa contributiva. Gênero: 51,6% homens e 48,4% mulheres. Idade: TEP fatal (328) vs controles (1.004), diferença estatisticamente significativa (p = 0,013). Condições prevalentes: câncer grupo, 31,4%, pós-operatório grupo, 17,2%, infecção grupo, 11,7%, e AVC grupo, 11%. Câncer de pulmão, 3,5%, câncer de cérebro e linfoma, 2,8%. Tempo de internação foi utilizado como indicador de imobilização. Outras doenças: AVCH (7,7%), pós-operatório de abdome (6,7%), pneumonia (5,9%), AVCI (3,1%) e pós-operatório vascular (4%) foram frequentes no grupo controle. Em contrapartida, aterosclerose (1,4%), ITU (1,2%), pós-operatório de ginecologia (0,8%), pós-operatório de obstetrícia (0,6%) e doença falciforme (0,6%) foram frequentes no grupo TEP. Cirrose, média de 14,9 dias de internação dos controles vs TEP com 4,4 dias (p < 0,001). Análise multivariada incluiu as condições com p 0,20 da univariada, idade e tempo de internação. Fator protetor para TEP: aneurisma de aorta (OR 0,02, IC 95% 0,46-0,56; p = 0,004), cirrose (OR 0,16, IC 95% 0,08-0,34; p < 0,001) e SIDA (OR 0,44, IC 95% 0,23-0,84; p = 0,013). Entretanto, AVCI (OR 1,82, IC 95% 1,04-3,19; p = 0,035), câncer de cérebro (OR 2,47, IC 95% 1,28-4,78; p = 0,007), câncer indeterminado (OR 3,12, IC 95% 1,01-9,68; p = 0,049), DPOC (OR 2,83, IC 95% 1,47-5,43; p = 0,002), ICC (OR 1,71, IC 95% 1,11-2,62; p = 0,015) e ITU (OR 4,34, IC 95% 1,05-17,82; p = 0,042) mostraram associação positiva com TEP. Idade vs TEP (OR 1,10, IC 95% 1,04-1,16; p = 0,001). Tempo de internação vs TEP (OR 1,19, IC 95% 1,05-1,36; p = 0,008). DISCUSSÃO: A porcentagem dos pacientes com TEP permanece inalterada, ocorrência de 4,1% e 3,4% no primero e no segundo períodos, com uma média de 3,8%. Em 50,4% dos pacientes não foi realizado o diagnóstico clínico de TEP. CONCLUSÃO: Constatou-se AVCI, câncer de cérebro indeterminado, DPOC, ICC e ITU com significância estatística e associação com TEP. Algumas fraquezas do presente estudo devem ser apuradas, e talvez explicarão as discordâncias com a literatura para algumas doenças. A identificação de fatores associados a TEP auxiliarão no diagnóstico precoce / INTRODUCTION: Literature shows that venous thromboembolism (VTE) remains as a sub-diagnostic disease among hospitalized patients, approximately 25% of all cases are associated to hospitalization. PURPOSE: Evaluate diseases associated to pulmonary thromboembolism (PE) development diagnosed in autopsies, and demonstrate the frequency of PE as cause of death or as a contributive factor. METHOD: The reports performed from 1995 to 2004 in a Brazilian tertiary referral medical school we reviewed for a retrospective study the autopsies diagnosis, identified as fatal PE, when PE was the cause of death and nonfatal PE, when PE was an associated disease. RESULTS: 1,506 patients (502 cases and 1004 controls), 18,359 deaths during the period, average 2,040; 71.2% of these were submitted to autopsies. It was observed an important decline in the autopsies rates. From 1995-1999 (87.2%) and 2000-2004 (54.4%) p = 0.016. From 502 cases (3.8%), 328 (2.5%) PE was the cause of death and 174 (1.3%) PE was contributive cause. Gender: 51.6% males and 48.4% females. AGE: fatal PE (328) vs controls (1,004) significant statistic difference (p = 0.013). Prevalent Conditions: cancer group, 31.4%, postsurgical group, 17.2%, infectious group, 11.7%, and CVA group, 11%. Pulmonary Cancer, 3.5%, Brain cancer and Lymphoma, 2.8%. Hospitalization period was taken as immobilization indicator. Other diseases: HCVA (7.7%), abdomen postsurgical (6.7%), pneumonia (5.9%), ICVA (3.1%) and vascular postsurgical (4%) were frequent in the control group. On the other hand, atherosclerosis (1.4%), UTI (Urinary Tract Infection) (1.2%), gynecology postsurgical (0.8%), obstetrics postsurgical (0.6%) and sickle cell anemia (0.6%) were frequent in the PE group. Cirrhosis, average of 14.9 hospitalization days of the controls vs PE with 4.4 days (p < 0.001). Logistic regression analysis includes the in univariated analysis with p 0.20, age and the hospitalization period. Protector factor for PE: Aortic aneurysm (OR 0.02, 95% CI 0.46-0.56; p = 0.004), cirrhosis (OR 0.16, 95% CI 0.08-0.34; p < 0.001) and SIDA (OR 0.44, 95% CI 0.23-0.84; p = 0.013). However, ICVA (OR 1.82, 95% CI 1.04-3.19; p = 0.035); brain cancer (OR 2.47, 95% CI 1.28-4.78; p = 0.007); undetermined cancer (OR 3.12, 95% CI 1.01-9.68, p= 0.049), COPD (OR 2.83, 95% CI 1.47-5.43; p = 0.002), CHF (OR 1.71, 95% CI 1.11-2.62; p = 0.015) and UTI (OR 4.34, 95% CI 1.05-17.82; p = 0.042), showed positive association with PE. Age vs PE (OR 1.10, 95% CI 1.04-1.16; p = 0.001). Hospitalization Period vs PE (OR 1.19, 95% CI 1.05-1.36; p = 0.008). DISCUSSION: The percentage of patients with PE remains unchanged, occurrence of 4.1% and 3.4% in the first and second periods, with an average of 3.8%. In 50.4% of the patients, the clinical diagnosis of TEP was not performed. CONCLUSION: We certified ICVA, brain cancer, undetermined cancer, COPD, CHF and UTI with significant association with PE. Some weaknesses of the present study should be refined, and maybe will explain the disagreement with the literature to some diseases. The identification of factors associated to PE will help in precocious diagnosis

INTRODUÇÃO: A literatura demonstra que tromboembolismo venoso permanece como uma doença subdiagnosticada entre os pacientes hospitalizados, com aproximadamente 25% dos casos associados à internação. OBJETIVOS: Avaliar as doenças associadas ao desenvolvimento de tromboembolismo pulmonar (TEP) diagnosticado em autópsias, e demonstrar a frequência de TEP como causa do óbito ou fator contributivo. MÉTODOS: Estudo caso-controle retrospectivo, realizado no Instituto Central do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de 1995 a 2004. Revisamos os relatórios diagnósticos das autópsias, identificando TEP fatal, quando TEP foi a causa de morte, e TEP não fatal, quando TEP foi doença associada. RESULTADOS: 1.506 pacientes (502 casos e 1.004 controles), 18.359 óbitos no período, média 2.040; 71,2% desses submetidos a autópsias. Observou-se importante declínio nas taxas de autópsias. De 1995-1999 (87,2%) e 2000-2004 (54,4%); p = 0,016. Dos 502 casos (3,8%), em 328 (2,5%) TEP foi causa de morte e 174 (1,3%), causa contributiva. Gênero: 51,6% homens e 48,4% mulheres. Idade: TEP fatal (328) vs controles (1.004), diferença estatisticamente significativa (p = 0,013). Condições prevalentes: câncer grupo, 31,4%, pós-operatório grupo, 17,2%, infecção grupo, 11,7%, e AVC grupo, 11%. Câncer de pulmão, 3,5%, câncer de cérebro e linfoma, 2,8%. Tempo de internação foi utilizado como indicador de imobilização. Outras doenças: AVCH (7,7%), pós-operatório de abdome (6,7%), pneumonia (5,9%), AVCI (3,1%) e pós-operatório vascular (4%) foram frequentes no grupo controle. Em contrapartida, aterosclerose (1,4%), ITU (1,2%), pós-operatório de ginecologia (0,8%), pós-operatório de obstetrícia (0,6%) e doença falciforme (0,6%) foram frequentes no grupo TEP. Cirrose, média de 14,9 dias de internação dos controles vs TEP com 4,4 dias (p < 0,001). Análise multivariada incluiu as condições com p 0,20 da univariada, idade e tempo de internação. Fator protetor para TEP: aneurisma de aorta (OR 0,02, IC 95% 0,46-0,56; p = 0,004), cirrose (OR 0,16, IC 95% 0,08-0,34; p < 0,001) e SIDA (OR 0,44, IC 95% 0,23-0,84; p = 0,013). Entretanto, AVCI (OR 1,82, IC 95% 1,04-3,19; p = 0,035), câncer de cérebro (OR 2,47, IC 95% 1,28-4,78; p = 0,007), câncer indeterminado (OR 3,12, IC 95% 1,01-9,68; p = 0,049), DPOC (OR 2,83, IC 95% 1,47-5,43; p = 0,002), ICC (OR 1,71, IC 95% 1,11-2,62; p = 0,015) e ITU (OR 4,34, IC 95% 1,05-17,82; p = 0,042) mostraram associação positiva com TEP. Idade vs TEP (OR 1,10, IC 95% 1,04-1,16; p = 0,001). Tempo de internação vs TEP (OR 1,19, IC 95% 1,05-1,36; p = 0,008). DISCUSSÃO: A porcentagem dos pacientes com TEP permanece inalterada, ocorrência de 4,1% e 3,4% no primero e no segundo períodos, com uma média de 3,8%. Em 50,4% dos pacientes não foi realizado o diagnóstico clínico de TEP. CONCLUSÃO: Constatou-se AVCI, câncer de cérebro indeterminado, DPOC, ICC e ITU com significância estatística e associação com TEP. Algumas fraquezas do presente estudo devem ser apuradas, e talvez explicarão as discordâncias com a literatura para algumas doenças. A identificação de fatores associados a TEP auxiliarão no diagnóstico precoce / INTRODUCTION: Literature shows that venous thromboembolism (VTE) remains as a sub-diagnostic disease among hospitalized patients, approximately 25% of all cases are associated to hospitalization. PURPOSE: Evaluate diseases associated to pulmonary thromboembolism (PE) development diagnosed in autopsies, and demonstrate the frequency of PE as cause of death or as a contributive factor. METHOD: The reports performed from 1995 to 2004 in a Brazilian tertiary referral medical school we reviewed for a retrospective study the autopsies diagnosis, identified as fatal PE, when PE was the cause of death and nonfatal PE, when PE was an associated disease. RESULTS: 1,506 patients (502 cases and 1004 controls), 18,359 deaths during the period, average 2,040; 71.2% of these were submitted to autopsies. It was observed an important decline in the autopsies rates. From 1995-1999 (87.2%) and 2000-2004 (54.4%) p = 0.016. From 502 cases (3.8%), 328 (2.5%) PE was the cause of death and 174 (1.3%) PE was contributive cause. Gender: 51.6% males and 48.4% females. AGE: fatal PE (328) vs controls (1,004) significant statistic difference (p = 0.013). Prevalent Conditions: cancer group, 31.4%, postsurgical group, 17.2%, infectious group, 11.7%, and CVA group, 11%. Pulmonary Cancer, 3.5%, Brain cancer and Lymphoma, 2.8%. Hospitalization period was taken as immobilization indicator. Other diseases: HCVA (7.7%), abdomen postsurgical (6.7%), pneumonia (5.9%), ICVA (3.1%) and vascular postsurgical (4%) were frequent in the control group. On the other hand, atherosclerosis (1.4%), UTI (Urinary Tract Infection) (1.2%), gynecology postsurgical (0.8%), obstetrics postsurgical (0.6%) and sickle cell anemia (0.6%) were frequent in the PE group. Cirrhosis, average of 14.9 hospitalization days of the controls vs PE with 4.4 days (p < 0.001). Logistic regression analysis includes the in univariated analysis with p 0.20, age and the hospitalization period. Protector factor for PE: Aortic aneurysm (OR 0.02, 95% CI 0.46-0.56; p = 0.004), cirrhosis (OR 0.16, 95% CI 0.08-0.34; p < 0.001) and SIDA (OR 0.44, 95% CI 0.23-0.84; p = 0.013). However, ICVA (OR 1.82, 95% CI 1.04-3.19; p = 0.035); brain cancer (OR 2.47, 95% CI 1.28-4.78; p = 0.007); undetermined cancer (OR 3.12, 95% CI 1.01-9.68, p= 0.049), COPD (OR 2.83, 95% CI 1.47-5.43; p = 0.002), CHF (OR 1.71, 95% CI 1.11-2.62; p = 0.015) and UTI (OR 4.34, 95% CI 1.05-17.82; p = 0.042), showed positive association with PE. Age vs PE (OR 1.10, 95% CI 1.04-1.16; p = 0.001). Hospitalization Period vs PE (OR 1.19, 95% CI 1.05-1.36; p = 0.008). DISCUSSION: The percentage of patients with PE remains unchanged, occurrence of 4.1% and 3.4% in the first and second periods, with an average of 3.8%. In 50.4% of the patients, the clinical diagnosis of TEP was not performed. CONCLUSION: We certified ICVA, brain cancer, undetermined cancer, COPD, CHF and UTI with significant association with PE. Some weaknesses of the present study should be refined, and maybe will explain the disagreement with the literature to some diseases. The identification of factors associated to PE will help in precocious diagnosis

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Sousa.pdf: 1096991 bytes, checksum: da8da100fb2a808f8f87866c498e9b4f (MD5) Previous issue date: 2016-09-30 / FAPEAM - Fundação de Amparo à Pesquisa do Estado do Amazonas / Objective: To analyze meanings attributed by indigenous to suicides occurred in the urban area of São Gabriel da Cachoeira city. Methodology: Cases of suicide were selected on the urban area of São Gabriel da Cachoeira city in period 2001 to 2014. Community Health Agents mediate contact with the families of the selected cases. To family members were applied a semi-structured interview guide called Psychosocial Autopsy, through which were drawn family narratives about the suicide of the selected cases. The interviews, conducted after obtaining the free and informed consent, were recorded and transcribed. After transcription, comprehensive analysis of the narratives was performed for the identification of empirical categories, the narratives were divided into sections so both were identified explicit ideas as implied in the text. The Psychosocial Autopsy was employed in two ways: in order to reconstruct the speeches made during the narratives and as a means of listing the categories used in the analysis. Results: Suicidal were mostly young males and used not to show violent behavior. The preferred method used to commit suicide was hanging. It was identified through the Psychosocial Autopsies that relatives associated suicides existing family conflicts, the high consumption of alcohol and other drugs, or even due to a shamanic witchery, as "blowing" or "damage" poisoning, motivated by envy of another person. It also highlights the concern of relatives to know what happened to the suicidal after his death. Conclusion: Family through their narratives seek to understand the suicide of their relatives through a complex system causality in which articulate family conflicts, use of substances and witchery, which ultimately leads to a relational context. This model does not relate to classic biomedical model that tends to associate suicide to individual psychiatric or psychological problems. In addition the narrative of death does not end with death itself, concerns the post-mortem permeate the afflictions of the family. These aspects should be considered when seeking strategies both prevention and post event to suicide. / Objetivo: Analisar os significados atribuídos por indígenas, aos suicídios ocorridos na área urbana de São Gabriel da Cachoeira. Metodologia: Foram selecionados os casos de suicídio ocorridos na área urbana de São Gabriel da Cachoeira no período de 2001 a 2014. Agentes Comunitários de Saúde mediaram o contato com os familiares dos casos selecionados. Aos familiares foi aplicado um roteiro de entrevista semiestruturado chamado Autópsia Psicossocial, por meio do qual foram extraídas narrativas dos familiares sobre o suicídio dos casos selecionados. As entrevistas, realizadas após obtenção do termo de consentimento livre e esclarecido, foram gravadas e transcritas. Após a transcrição, foi realizada a leitura compreensiva das narrativas para a identificação das categorias empíricas, as narrativas foram então decompostas em recortes de trechos para que fossem identificadas tanto as ideias explícitas, quanto as implícitas presentes no texto. Para finalizar, foi realizada a síntese interpretativa das narrativas, privilegiando os sentidos mais amplos presentes em cada caso, através da articulação entre os objetivos propostos, o referencial teórico e os dados empíricos. A Autópsia Psicossocial foi utilizada de duas maneiras: com a finalidade de reconstruir os discursos proferidos durante as narrativas e como meio de elencar as categorias utilizadas na análise. Resultados: Os suicidas em sua maioria eram jovens do sexo masculino e que não costumavam apresentar comportamento violento. O método preferencial utilizado para cometer o suicídio foi o enforcamento. Identificou-se através das Autópsias Psicossociais que os parentes associaram os suicídios aos conflitos familiares existentes, ao consumo elevado de álcool e outras drogas ou, ainda devido a algum feitiço xamânico, como “sopro” ou “estrago”, motivado pela inveja de uma outra pessoa. Destaca-se ainda a preocupação dos parentes em saber o que ocorreu com o suicida após a sua morte. Conclusão: Os familiares por meio de suas narrativas buscam compreender o suicídio de seus parentes por meio de um complexo sistema de causalidade no qual se articulam conflitos familiares, uso de substancias e feitiços, que em última análise remetem a um contexto relacional. Tal modelo não se prende ao modelo biomédico clássico que tende a associar o suicídio a problemas psiquiátricos ou psicológicos individuais. Ademais a narrativa da morte não termina com a morte em si,preocupações com o post-mortem permeiam as aflições dos familiares. Tais aspectos deveriam ser considerados a se buscar estratégias tanto de prevenção, como de pósvenção ao suicídio.

Direct Volume Rendering (DVR) is a technique for creating images directly from a representation of a function defined over a three-dimensional domain. The technique has many application fields, such as scientific visualization and medical imaging. A striking property of the data sets produced within these fields is their ever increasing size and complexity. Despite the advancements of computing resources these data sets seem to grow at even faster rates causing severe bottlenecks in terms of data transfer bandwidths, memory capacity and processing requirements in the rendering pipeline. This thesis focuses on efficient methods for DVR of large data sets. At the core of the work lies a level-of-detail scheme that reduces the amount of data to process and handle, while optimizing the level-of-detail selection so that high visual quality is maintained. A set of techniques for domain knowledge encoding which significantly improves assessment and prediction of visual significance for blocks in a volume are introduced. A complete pipeline for DVR is presented that uses the data reduction achieved by the level-of-detail selection to minimize the data requirements in all stages. This leads to reduction of disk I/O as well as host and graphics memory. The data reduction is also exploited to improve the rendering performance in graphics hardware, employing adaptive sampling both within the volume and within the rendered image. The developed techniques have been applied in particular to medical visualization of large data sets on commodity desktop computers using consumer graphics processors. The specific application of virtual autopsies has received much interest, and several developed data classification schemes and rendering techniques have been motivated by this application. The results are, however, general and applicable in many fields and significant performance and quality improvements over previous techniques are shown. / On the defence date the status of article IX was Accepted.

Direct Volume Rendering (DVR) is a visualization technique that has proved to be a very powerful tool in many scientific visualization applications. Diagnostic medical imaging is one domain where DVR could provide clear benefits in terms of unprecedented possibilities for analysis of complex cases and highly efficient work flow for certain routine examinations. The full potential of DVR in the clinical environment has not been reached, however, primarily due to limitations in conventional DVR methods and tools. This thesis presents methods addressing four major challenges for DVR in clinical use. The foundation of all methods is to incorporate the domain knowledge of the medical professional in the technical solutions. The first challenge is the very large data sets routinely produced in medical imaging today. To this end a multiresolution DVR pipeline is proposed, which dynamically prioritizes data according to the actual impact in the rendered image to be reviewed. Using this prioritization the system can reduce the data requirements throughout the pipeline and provide high performance and visual quality in any environment. Another problem addressed is how to achieve simple yet powerful interactive tissue classification in DVR. The methods presented define additional attributes that effectively captures readily available medical knowledge. The task of tissue detection is also important to solve in order to improve efficiency and consistency of diagnostic image review. Histogram-based techniques that exploit spatial relations in the data to achieve accurate and robust tissue detection are presented in this thesis. The final challenge is uncertainty visualization, which is very pertinent in clinical work for patient safety reasons. An animation method has been developed that automatically conveys feasible alternative renderings. The basis of this method is a probabilistic interpretation of the visualization parameters. Several clinically relevant evaluations of the developed techniques have been performed demonstrating their usefulness. Although there is a clear focus on DVR and medical imaging, most of the methods provide similar benefits also for other visualization techniques and application domains.

Derzeit erfolgt in Deutschland lediglich eine Erfassung anzeigepflichtiger Tierseuchen und meldepflichtiger Tierkrankheiten bei Equiden. Folglich besteht ein Bedarf an Informationen aus klinischen und post-mortem-Statistiken, um frühzeitig Hinweise auf Veränderungen im Erkrankungsspektrum dieser Tiere zu erhalten. Im Rahmen entsprechender Auswertungen ist es zudem möglich, Daten zu selten auftretenden Alterationen zu sammeln. Allerdings müssen bei der Interpretation der Ergebnisse Einflussfaktoren, die die Zusammensetzung des Untersuchungsgutes beeinflussen, berücksichtigt werden, da die ausgewerteten Fälle, insbesondere in retrospektiven Arbeiten, in der Regel nicht für eine bestimmte Population repräsentativ sind. Ziel dieser Arbeit war es daher, sich einen Überblick über die Hauptbefunde, welche in Equiden-Sektionen am Institut für Veterinär-Pathologie der Universität Leipzig und an der Tierärztlichen Hochschule Dresden zwischen 1890 und 2013 erhoben wurden, zu verschaffen. Darüber hinaus sollten Veränderungen im Krankheitsspektrum während des Untersuchungszeitraumes und epizootiologische Einflussfaktoren (Alter, Rasse, Geschlecht) untersucht sowie die Art und Prävalenz der haupt- und nebenbefundlich diagnostizierten Tumoren festgestellt werden. Anschließend sollten die getroffenen Beobachtungen unter Beachtung von zeitgeschichtlichen Aspekten und den Ergebnissen anderer Statistiken aus der Literatur interpretiert werden. Für die Statistik standen die Daten von 4743, zwischen 1890 und 2013 am Institut für Veterinär-Pathologie der Universität Leipzig bzw. an der Tierärztlichen Hochschule Dresden durchgeführten Equiden-Obduktionen zu Verfügung. Es erfolgte eine Erfassung der Angaben zu Monat und Jahr der Obduktion, Alter, Rasse, Geschlecht, Herkunftsort, weiterführenden Untersuchungen (Bakteriologie, Virologie, Toxikologie, Parasitologie, histologische Spezialfärbungen, Immunhistologie) und den erhobenen Befunden. Sofern vorhanden, wurden Informationen zur Anamnese und intra vitam festgestellten Diagnosen einbezogen. Nur in 79,6 %, 53,2 % bzw. 88,0 % der Fälle waren Angaben zu Alter, Rasse bzw. Geschlecht erhalten. Über den gesamten Untersuchungszeitraum betrachtet, waren die sezierten Equiden am häufigsten von einer Erkrankung der Verdauungsorgane (36,5 %), gefolgt von Alterationen der Atmungsorgane (10,5 %), des Nervensystems (9,6 %), der Kreislauforgane (8,4 %), des Stütz- und Bewegungsapparates (7,7 %) und generalisierten Veränderungen (7,4 %) als Hauptbefund betroffen. Weniger häufig traten Alterationen während der Trächtigkeit (5,2 %) oder im Bereich der großen Körperhöhlen (4,0 %), der Leber (3,1 %), des hämatopoetischen Systems (1,7 %), der Harnorgane und des Nabels (1,5 %), der Geschlechtsorgane (1,3 %), der Haut (0,9 %), des Endokriniums (0,2 %) sowie des Auges (0,0 %) auf. Unter dem Begriff „Sonstige Erkrankungen“ (2,0 %) wurden Fälle mit unklarer Genese, ohne Sektion oder Tiere mit ausgeprägter Autolyse und/oder Fäulnis zusammengefasst. Im Vergleich zum Beginn der Auswertungsperiode, nahm der Anteil der Veränderungen im Bereich des Verdauungstraktes, insbesondere infolge einer Reduktion der Fälle mit einer Quer- oder Längsachsendrehung bzw. der Tiere mit einer Obstipation (84/264 zwischen 1970 und 1989 diagnostiziert), im Verlauf der Jahrzehnte ab (1890-1899: 52,6 %; 1900-1909: 58,2 %; 2000-2009: 35,8 %; 2010-2013: 38,0 %). Demgegenüber traten in den 1990er Jahren die meisten Fälle mit dem Hauptbefund „Erkrankung des Nervensystems“, ausgelöst durch einen hohen Anteil an Equiden mit der Diagnose „Bornasche Krankheit“ (BD; 7,8 %), auf. Die Zunahme dieses Hauptbefundes unter den Obduktionstieren kann durch die deutsche Wiedervereinigung im Jahr 1990 und die damit verbundenen Änderungen im Bereich des Tierseuchenrechts erklärt werden. Seit 2000 ist der Anteil der Equiden mit dem Nachweis einer BD wieder rückläufig (2000-2009: 5,3 %; 2010-2013: 1,3 %). Im Vergleich zum gesamten Untersuchungszeitraum (1890-2013) fanden sich zudem zwischen 1990 und 2013 häufiger Alterationen während der Trächtigkeit (8,8 %) bzw. mehr Veränderungen im Bereich des Stütz- und Bewegungsapparates (10,4 %), der Haut (1,2 %) oder des Endokriniums (0,5 %). Während die Zunahme der Aborte am ehesten mit einer Änderung des Forschungsschwerpunktes des Institutes für Veterinär-Pathologie der Universität Leipzig erklärt werden kann, lässt sich mit hoher Wahrscheinlichkeit der Anstieg der Fälle mit Läsionen des Stütz- und Bewegungsapparates, zumindest teilweise, auf die wirtschaftlich bessere Situation der Gesamtbevölkerung zum Ende des Untersuchungszeitraumes, und einem damit verbundenen Rückgang an Pferdeschlachtungen, zurückführen. Des Weiteren nahm die Bedeutung von Veränderungen der Atmungsorgane, der großen Körperhöhlen oder von generalisierten Erkrankungen, welche häufig infolge einer bakteriellen Infektion auftreten, seit den 1950er Jahren im Sektionsgut ab. Für diese Entwicklung können Verbesserungen in der Therapie (u.a. der Einsatz von Antibiotika in der Tiermedizin) und der klinischen Diagnostik (z.B. bei der Diagnose der chronisch-obstruktiven Bronchitis oder „Recurrent Airway Obstruction“) sowie der Erfolg tierseuchenhygienischer Maßnahmen (u.a. Bekämpfung von Rotz, Druse und Tuberkulose) verantwortlich gemacht werden. Des Weiteren ergab die Auswertung, dass 5,2 % der obduzierten Einhufer (248/4743) entweder haupt- (3,2 %) oder nebenbefundlich von 285 Tumoren betroffen waren. Bei 78,2 % (223/285) der Läsionen wurde die Diagnose histologisch bestätigt. Meist lag ein einzelner neoplastischer Prozess vor (n=221), vereinzelt fanden sich multiple Neoplasien (zwei unterschiedliche Tumoren pro Tier: n=19; drei Tumoren pro Tier: n=6; vier Tumoren pro Tier: n=2). Das mediane Alter der betroffenen Einhufer mit Altersangabe (n=219) lag bei 14 Jahren, wobei 87,9 % der Fälle älter als 6 Jahre alt waren. Deutlich ausgeprägte Schwankungen zeigten sich im Verlauf des Untersuchungszeitraumes in der Verteilung des Tumorvorkommens. Zwischen 1990 und 2013 wurden drei Viertel (214/285) aller im Untersuchungszeitraum festgestellten Neoplasien diagnostiziert, wobei sich die Läsionen mehrheitlich (180/214) nach 1999 zeigten. Das für die unterschiedlichen Zeitabschnitte der Auswertungsperiode ermittelte mediane Alter scheint bei dieser Entwicklung nicht im Vordergrund zu stehen. Die Läsionen (n=285) fanden sich meist im Bereich der großen Körperhöhlen (24,2 %), des Endokriniums (17,5 %), des hämatopoetischen Systems (14,7 %) und/oder der Haut (12,3 %). Dabei zeigten sich am häufigsten Lipome (23,2 %; n=66), Leukosen (12,6 %; n=36), maligne Melanome (8,4 %; n=24), Adenome der Hypophyse (6,3 %; n=18) und/oder Plattenepithelkarzinome (5,6 %; n=16). Zusammenfassend lässt sich feststellen, dass, in Übereinstimmung mit den Ergebnissen anderer Studien, Erkrankungen der Verdauungsorgane nach wie vor zu den häufigsten Abgangsursachen bei Equiden zählen. Die Prävalenz von Veränderungen des Nervensystems hingegen schwankt, in Abhängigkeit zum Vorkommen endemischer Erkrankungen, in verschiedenen Statistiken. Die Bedeutung der BD ist im eigenen Sektionsmaterial (Einzugsgebiet der Universität Leipzig und der Tierärztlichen Hochschule Dresden) seit 2000 rückläufig. Demgegenüber nimmt die Anzahl der diagnostizierten Tumoren in der vorliegenden Auswertung in den letzten Jahren (2000-2013) stark zu. Obwohl sich das Spektrum der diagnostizierten Tumorarten erweitert hat, zählen Neoplasien weiterhin zu den selten diagnostizierten Erkrankungen bei Einhufern.:I INHALTSVERZEICHNIS II ABKÜRZUNGSVERZEICHNIS 1 EINLEITUNG 2 LITERATURÜBERSICHT 2.1 Übersichts-Statistiken zu Equiden-Sektionen 2.1.1 Material und Methoden der Übersichts-Statistiken 2.1.2 Häufige Befunde in Übersichts-Statistiken 2.2 Klinische Übersichts-Statistiken zu Erkrankungen bei Equiden 2.3 Übersichts-Statistiken zu Tumoren bei Equiden 2.3.1 Sektionsstatistiken zu Tumoren bei Equiden 2.3.1.1 Methoden der Sektionsstatistiken 2.3.1.2 Häufig von Tumoren betroffene Organsysteme in Sektionsstatistiken 2.3.1.3 Häufige Tumorarten 2.3.2 Auswertungen von Biopsien bzw. Befunden aus klinischen Einrichtungen 2.3.2.1 Methoden der Tumor-Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.3.2.2 Häufig von Tumoren betroffene Organsysteme in Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.3.2.3 Übersicht der häufigsten Tumorarten in Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.4 Fazit aus der Literatur bezogen auf die initiale Fragestellung dieser Arbeit 3 MATERIAL UND METHODEN 3.1 Material 3.2 Methode 4 ERGEBNISSE 4.1 Auswertung der Hauptbefunde 4.1.1 Erkrankungen der Verdauungsorgane 4.1.2 Erkrankungen der Atmungsorgane 4.1.3 Erkrankungen des Nervensystems 4.1.4 Erkrankungen der Kreislauforgane 4.1.5 Erkrankungen des Stütz- und Bewegungsapparates 4.1.6 Generalisierte Erkrankungen 4.1.7 Pathologie der Trächtigkeit 4.1.8 Erkrankungen der großen Körperhöhlen 4.1.9 Erkrankungen der Leber 4.1.10 „Sonstige Erkrankungen“ 4.1.11 Erkrankungen des hämatopoetischen Systems 4.1.12 Erkrankungen der Harnorgane und des Nabels 4.1.13 Erkrankungen der Geschlechtsorgane 4.1.14 Erkrankungen der Haut 4.1.15 Erkrankungen des Endokriniums 4.1.16 Erkrankungen des Auges 4.2 Auswertung von Tumoren unter Berücksichtigung von Haupt- und Nebenbefunden 4.2.1 Häufigkeit und Klassifikation 4.2.2 Multiple Neoplasien 4.2.3 Häufigkeit benigner, semimaligner und maligner Tumoren 4.2.4 Metastasierende bzw. multizentrische Tumoren 5 DISKUSSION 5.1 Ziel der Arbeit 5.2 Kritische Beurteilung des Untersuchungsmaterials 5.3 Auswertung der Hauptbefunde 5.3.1 Erkrankungen der Verdauungsorgane 5.3.2 Erkrankungen der Atmungsorgane 5.3.3 Erkrankungen des Nervensystems 5.3.4 Erkrankungen der Kreislauforgane 5.3.5 Erkrankungen des Stütz- und Bewegungsapparates 5.3.6 Generalisierte Erkrankungen 5.3.7 Pathologie der Trächtigkeit 5.3.8 Erkrankungen der großen Körperhöhlen 5.3.9 Erkrankungen der Leber 5.3.10 „Sonstige Erkrankungen“ 5.3.11 Erkrankungen des hämatopoetischen Systems 5.3.12 Erkrankungen der Harnorgane und des Nabels 5.3.13 Erkrankungen der Geschlechtsorgane 5.3.14 Erkrankungen der Haut 5.3.15 Erkrankungen des Endokriniums 5.3.16 Erkrankungen des Auges 5.3.17 Fazit 96 5.4 Tumoren als Haupt- und Nebenbefund 5.4.1 Prävalenz von Tumoren bei Equiden 5.4.1.1 Prävalenz einzelner Tumorarten in klinischen Auswertungen 5.4.1.2 Prävalenz einzelner Tumorarten in Sektions- und Schlachthofstatistiken 5.4.2 Multiple Neoplasien 5.4.3 Metastasierende Tumoren 5.4.4 Fazit 6 ZUSAMMENFASSUNG 7 SUMMARY 8 LITERATUR 9 ANHANG 9.1 Klinische Übersichtsstatistiken zu dem Erkrankungskomplex „Kolik“ 9.2 Übersicht über die ausgewerteten Dokumente 9.2.1 Tabellarische Übersicht 9.2.2 Bilddokumentation zu den erhaltenen Sektions-Journalen bzw. Sektions-Tagebüchern 9.3 Tabellen zur Auswertung der Tumoren im Sektionsgut 9.4 Überblick über Übersichts-Sektionsstatistiken zu Erkrankungen der Verdauungsorgane bei Equiden 10 DANKSAGUNG / Currently only notifiable diseases in Equidae are monitored in Germany. Therefore, information from clinical trials and post-mortem-examinations can be helpful to give early indications of changes in the spectrum of equine diseases. Furthermore, within those evaluations it is possible to collect data of rare illnesses. However, influencing factors, which affect the structure of the test material, must be considered when interpreting the results. Particularly in retrospective studies, the evaluated cases are not necessarily representative for a special population. The aim of this retrospective study was to get an overview of the main findings of 4743 equine autopsies, which were performed at the Institute of Pathology (Faculty of Veterinary Medicine, University of Leipzig respectively Dresden). In this context, changes in the spectrum of diseases during the investigated period and the influence of epizootiologic factors (age, race, sex) as well as the type and prevalence of tumours, detected as main or additional finding, were analysed. Moreover, the findings were evaluated in consideration of the actual animal health restrictions as well as historical and epidemiological aspects taking the scientific state-of-the art into account. The reports of 4743 Equidae, which were necropsied at the Institute of Pathology (Faculty of Veterinary Medicine, University of Leipzig respectively Dresden from 1890 to 1923) between 1890 and 2013, were available. The month and year of autopsy, age, race, sex, place of origin, further etiological examination procedures (e.g. parasitology, virology, microbiology, toxicology, histology, immunohistology) were taken into consideration. If applicable, information on anamnesis and diagnosis, which have been made intra vitam, was considered. Information on age, race respectively sex was available only in 79.6 %, 53.2 % respectively 88.0 % of the cases. During the investigation period, the necropsied Equidae were mostly affected by disorders (as a main finding) of the digestive tract (36.5 %), followed by alterations of the respiratory tract (10.5 %), the nervous system (9.6 %) or the cardiovascular system (8.4 %), locomotor system (7.7 %) and generalized changes (7.4 %). Less often abortions (5.2 %) or alterations in the area of the big body cavities (4.0 %), the liver (3.1 %), the haemopoietic system (1.7 %), the urinary organs or navel (1.5 %), the female and male genitalia (1.3 %), the skin (0.9 %), the endocrine system (0.2 %) or the eyes (0.0 %) appeared. The term “other diseases” (2.0 %) covers all cases with unknown origin, a distinct autolysis or animals without a necropsy. In comparison to the beginning of the investigation period, the amount of alterations of the alimentary canal, especially due to a reduction of cases with volvulus or torsion respectively animals with obstipation (84/264 diagnosed between 1970 and 1989), decreased over the decades (1890-1899: 52.6 %; 1900-1909: 58.2 %; 2000-2009: 35.8 %; 2010-2013: 38.0 %). In contrast most cases with the main finding ″disease of the nervous system″, characterised by a high percentage of Equidae with the diagnosis ″Borna Disease″ (BD, 7.8 %), arose during the 1990s. The increase of this main finding can be explained by the German reunification in 1990 and the related changes in animal health regulations. Since 2000 the percentage of Equidae with BD is declining again (2000-2009: 5.3 %; 2010-2013: 1.3 %). Compared to the whole investigation period (1890-2013) between 1990 and 2013 more alterations were found during pregnancy (8.8 %) respectively in the field of the musculosceletal system (10.4 %), the integument (1.2 %) or the endocrine system (0.5 %). The increase of abortions most likely can be explained by a change in the research priority of the Institute of Pathology of the Faculty of Veterinary Medicine (University of Leipzig) by the end of the observation period. Furthermore, the rise of cases with musculosceletal disorders is probably caused by the general improvement of the economic situation in Eastern Germany after the German reunification, coinciding with a reduction of equine slaughtering. In addition, a loss of importance in lesions of the respiratory organs, the big body cavities or generalized diseases, which often occur due to bacterial infections, can be observed in the investigated material since the 1950s. Improvements in treatment (among others the use of antibiotics in veterinary medicine) and in clinical diagnosis (e.g. in the diagnosis of the chronic obstructive pulmonary disease or ″recurrent airway obstruction″) as well as the success of animal health measures (e.g. eradication of glanders or tuberculosis) are responsible for this development. Moreover, the analysis showed that 5.2 % of the necropsied solipeds (248/4743) were affected as a main (3.2 %) or an additional finding by tumours (n=285). In 78.2 % of the lesions (223/285) the diagnosis ″neoplasia″ was confirmed histologically. Usually a single (n=221) tumour and occasionally multiple tumours (2 different tumours per animal: n=19; 3 different tumours per animal: n=6; 4 different tumours per animal: n=2) appeared. The median age of the affected solipeds with indication of age (n=219) was 14 years, whereas 87.9 % of the cases were older than 6 years. The appearance of tumours varied during the investigated period. Between 1990 and 2013 three quarters (214/285) of all diagnosed neoplasia were found, whereas most of them (180/214) are recorded after 1999. The median age, which was evaluated during the investigated period, is very likely not the only reason for this development. The lesions were mostly found in the region of the big body cavities (24.2 %), the endocrine (17.5 %) respectively the haematopoietic system (14.7 %) and/or the integuement (12.3 %). Mostly lipomas (23.2 %; n=66), leucosis (12.6 %; n=36), malignant melanomas (8.4 %; n=24), adenomas of the pituitary gland (6.3 %; n=18) and/or squamous cell carcinoma (5.6 %; n=16) occurred. In accordance with comparable studies, diseases of the digestive organs still are the most common cause of death in Equidae. The prevalence of alterations of the nervous system varies in different statistics, depending on the occurrence of endemic diseases. The importance of the BD in the own material (in the catchment area of the University of Leipzig and Dresden) has declined since 2000. Although, in this evaluation, the number and range of diagnosed tumours has increased considerably during the last years (2000-2013), neoplasia of solipeds rank among the rare diagnosed diseases of Equidae.:I INHALTSVERZEICHNIS II ABKÜRZUNGSVERZEICHNIS 1 EINLEITUNG 2 LITERATURÜBERSICHT 2.1 Übersichts-Statistiken zu Equiden-Sektionen 2.1.1 Material und Methoden der Übersichts-Statistiken 2.1.2 Häufige Befunde in Übersichts-Statistiken 2.2 Klinische Übersichts-Statistiken zu Erkrankungen bei Equiden 2.3 Übersichts-Statistiken zu Tumoren bei Equiden 2.3.1 Sektionsstatistiken zu Tumoren bei Equiden 2.3.1.1 Methoden der Sektionsstatistiken 2.3.1.2 Häufig von Tumoren betroffene Organsysteme in Sektionsstatistiken 2.3.1.3 Häufige Tumorarten 2.3.2 Auswertungen von Biopsien bzw. Befunden aus klinischen Einrichtungen 2.3.2.1 Methoden der Tumor-Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.3.2.2 Häufig von Tumoren betroffene Organsysteme in Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.3.2.3 Übersicht der häufigsten Tumorarten in Auswertungen von Biopsien bzw. von Befunden aus klinischen Einrichtungen 2.4 Fazit aus der Literatur bezogen auf die initiale Fragestellung dieser Arbeit 3 MATERIAL UND METHODEN 3.1 Material 3.2 Methode 4 ERGEBNISSE 4.1 Auswertung der Hauptbefunde 4.1.1 Erkrankungen der Verdauungsorgane 4.1.2 Erkrankungen der Atmungsorgane 4.1.3 Erkrankungen des Nervensystems 4.1.4 Erkrankungen der Kreislauforgane 4.1.5 Erkrankungen des Stütz- und Bewegungsapparates 4.1.6 Generalisierte Erkrankungen 4.1.7 Pathologie der Trächtigkeit 4.1.8 Erkrankungen der großen Körperhöhlen 4.1.9 Erkrankungen der Leber 4.1.10 „Sonstige Erkrankungen“ 4.1.11 Erkrankungen des hämatopoetischen Systems 4.1.12 Erkrankungen der Harnorgane und des Nabels 4.1.13 Erkrankungen der Geschlechtsorgane 4.1.14 Erkrankungen der Haut 4.1.15 Erkrankungen des Endokriniums 4.1.16 Erkrankungen des Auges 4.2 Auswertung von Tumoren unter Berücksichtigung von Haupt- und Nebenbefunden 4.2.1 Häufigkeit und Klassifikation 4.2.2 Multiple Neoplasien 4.2.3 Häufigkeit benigner, semimaligner und maligner Tumoren 4.2.4 Metastasierende bzw. multizentrische Tumoren 5 DISKUSSION 5.1 Ziel der Arbeit 5.2 Kritische Beurteilung des Untersuchungsmaterials 5.3 Auswertung der Hauptbefunde 5.3.1 Erkrankungen der Verdauungsorgane 5.3.2 Erkrankungen der Atmungsorgane 5.3.3 Erkrankungen des Nervensystems 5.3.4 Erkrankungen der Kreislauforgane 5.3.5 Erkrankungen des Stütz- und Bewegungsapparates 5.3.6 Generalisierte Erkrankungen 5.3.7 Pathologie der Trächtigkeit 5.3.8 Erkrankungen der großen Körperhöhlen 5.3.9 Erkrankungen der Leber 5.3.10 „Sonstige Erkrankungen“ 5.3.11 Erkrankungen des hämatopoetischen Systems 5.3.12 Erkrankungen der Harnorgane und des Nabels 5.3.13 Erkrankungen der Geschlechtsorgane 5.3.14 Erkrankungen der Haut 5.3.15 Erkrankungen des Endokriniums 5.3.16 Erkrankungen des Auges 5.3.17 Fazit 96 5.4 Tumoren als Haupt- und Nebenbefund 5.4.1 Prävalenz von Tumoren bei Equiden 5.4.1.1 Prävalenz einzelner Tumorarten in klinischen Auswertungen 5.4.1.2 Prävalenz einzelner Tumorarten in Sektions- und Schlachthofstatistiken 5.4.2 Multiple Neoplasien 5.4.3 Metastasierende Tumoren 5.4.4 Fazit 6 ZUSAMMENFASSUNG 7 SUMMARY 8 LITERATUR 9 ANHANG 9.1 Klinische Übersichtsstatistiken zu dem Erkrankungskomplex „Kolik“ 9.2 Übersicht über die ausgewerteten Dokumente 9.2.1 Tabellarische Übersicht 9.2.2 Bilddokumentation zu den erhaltenen Sektions-Journalen bzw. Sektions-Tagebüchern 9.3 Tabellen zur Auswertung der Tumoren im Sektionsgut 9.4 Überblick über Übersichts-Sektionsstatistiken zu Erkrankungen der Verdauungsorgane bei Equiden 10 DANKSAGUNG

Adverse drug reactions (ADRs) constitute a significant health problem with consequences for the patient as well as for society. Suspected ADRs have been reported to occur in about 2-14% of hospitalised patients. In about 5% of deceased hospitalised patients suspected ADRs may have caused or contributed to the fatal outcome. When a pharmaceutical drug is approved for marketing, the drug has been tested only on a limited number of patients (often &lt;6000) for a limited time period in a controlled environment. Hence mostly common ADRs are detected in these trials. Moreover, certain patient groups, for example patients with co-morbidities, elderly patients, children and pregnant women are often not included in these studies. Thus, it is important to closely monitor the use of drugs after marketing to observe new effects and detect new ADRs. The aim of this thesis is to describe the pattern of pharmaceutical substance use related to morbidity and mortality and to investigate two serious ADRs. We have studied the incidence of fatal ADRs, fatal intoxications, cerebral haemorrhage related to warfarin treatment and venous thromboembolism (VTE) related to treatment with antipsychotic drugs. Observational studies form the basis for this thesis. Data from the Swedish Cause of Death Register, medical case records, the Swedish database on ADRs, the forensic pathology and forensic toxicology databases, and Swedish and Danish hospital discharge registers, Danish prescription registers, and civil registry systems were used. In Paper I we found that 3% of all fatalities in a Swedish population were related to a suspected ADR. Of the deceased hospitalised patients, 6% were related to a suspected ADR. Haemorrhage was the most commonly observed fatal suspected ADR, accounting for almost two-thirds of the events and anticoagulantia was the most common drug group associated with fatal suspected ADRs (almost 50%). A suspected intoxication could have contributed to the fatal outcome in 0.6% of the deceased. Among the fatal intoxications in Swedish medico-legal autopsies studied in Paper II, on average four substances were detected per case. The five most commonly detected substances in individuals with a fatal intoxication were ethanol, propoxyphene, paracetamol, diazepam and flunitrazepam. Among patients diagnosed with cerebral haemorrhage, 10% (59 cases) were treated with warfarin at onset of symptoms (Paper III). Of these, 7 cases (12%) were considered to have been possibly avoidable since the patients were treated with concomitant drugs that have the potential to enhance warfarin effects. The results from Paper IV and Paper V in combination with the published literature suggest that patients treated with antipsychotic drugs have an increased risk for VTE. Compared with non-users, an adjusted odds ratio for VTE of 2.0 was found for users of any antipsychotic drugs in a Danish population. In a medico-legal autopsy series, an adjusted odds ratio for fatal pulmonary embolism of 2.4 and 6.9 was found for users of first-generation low-potency antipsychotics and second-generation antipsychotics, respectively. In summary, drug-related morbidity and mortality is a significant problem and suspected ADRs contribute to a substantial number of deaths. Fatal intoxications are relatively common and it is important to observe changes in patterns of substances associated with fatal intoxications to be able to discover new trends and monitor effects of preventive work. A significant proportion of warfarin-related cerebral haemorrhage was caused by drug-drug interactions and was considered possible to avoid. Users of antipsychotic drugs may increase the risk of VTE. / Idag finns det säkra och effektiva behandlingar mot många sjukdomar. Läkemedel är den vanligaste behandlingsformen i sjukvården och under 2006 hämtade sex miljoner svenskar (68%) ut ett eller fler recept på ett apotek i Sverige. Även om läkemedelsbehandling har många positiva effekter kan även oönskade och skadliga effekter vid läkemedelsbehandling uppkomma, dvs. läkemedelsbiverkningar. Innan ett läkemedel kommer ut för försäljning har man studerat effekter och biverkningar på ett begränsat antal individer (ofta &lt;6000) under en begränsad tidsperiod där patienterna övervakas noga. Dessutom är det i regel enbart patienter med få andra sjukdomar och läkemedel som ingår i dessa studier. Därför är oftast enbart de vanligaste biverkningarna kända när ett läkemedel börjar säljas till allmänheten. När ett läkemedel blir tillgängligt för ett stort antal patienter är det därför viktigt att man med olika metoder fortsätter att följa läkemedlets effekter och biverkningar. Tidigare har man visat att ungefär 2-14% av inläggningar på sjukhus beror på läkemedelsbiverkningar. Dessutom kan biverkningar ha bidragit eller orsakat dödsfallet i ungefär 5% av de som avlider på sjukhus. Biverkningar orsakar mycket lidande för patienten och kostar samhället både tid och pengar. Om det skulle vara möjligt att förhindra några av dessa sjukhusinläggningar eller dödsfall skulle man vinna mycket. Det är svårt att uppskatta hur många biverkningar som kan förhindras. Genom att studera faktorer som kan öka risken för en oönskad effekt kan man bättre anpassa behandlingen till den enskilde patienten och därmed förhindra biverkningar. Syftet med den här avhandlingen är att beskriva mönster av läkemedelsrelaterade sjukdomar och dödsfall, och att undersöka risken för två allvarliga läkemedelsbiverkningar. Förekomsten av misstänkta läkemedelsbiverkningar, vilka faktorer som kan öka risken för att få en läkemedelsbiverkan, samt vilka läkemedel och biverkningar som förekommer har studerats. Detta gjordes utifrån uppgifter hämtade från dödsorsaksregistret, svenska biverkningsregistret, journaler, rättsmedicinska register, slutenvårdsregister och receptregister. Genom att utnyttja sådan information har vi i närmare detalj studerat förekomsten av dödsfall där ett eller flera läkemedel kan ha haft betydelse för dödsfallet, förgiftningsdödsfall, blödningar i samband med blodförtunnande medicinering och blodproppar i samband med antipsykotisk medicinering. I de arbeten som ingår i avhandlingen har vi funnit att en läkemedelsbiverkan misstänks ha bidragit eller orsakat dödsfallet i ungefär 3% av de som avlidit i en svensk population (Arbete I). Blödningar står för nästan två tredjedelar av dessa biverkningar och blodförtunnande medel misstänks vara inblandade i nästan hälften av de misstänkta läkemedelsbiverkningarna. I den här svenska populationen avled 0,6% till följd av misstänkt läkemedelsförgiftning. Bland rättsmedicinskt undersökta förgiftningsdödsfall påvisades i genomsnitt fyra substanser per fall (Arbete II). De fem vanligaste påvisade substanserna i studien var alkohol, dextropropoxifen, paracetamol, diazepam och flunitrazepam. Bland patienter som får hjärnblödning behandlades 10% vid blödningstillfället med ett blodförtunnande medel, warfarin (Arbete III). I 7 fall (12%) skulle hjärnblödningen möjligen kunna ha förhindrats då patienterna samtidigt behandlades med andra läkemedel som kan ha ökat blödningsrisken. Den sammantagna bilden av den litteratur som finns publicerad och resultatet av Arbete IV och Arbete V, tyder på att patienter som behandlas med antipsykotiska preparat har en ökad risk för att få blodpropp. Flera faktorer har föreslagits som kan förklara den ökade risken för blodpropp bland patienter som behandlas med antipsykotika som har med sjukdomen att göra och/eller behandlingen med antipsykotiska läkemedel. Sammanfattningsvis visar detta avhandlingsprojekt att läkemedelsbiverkningar är ett väsentligt sjukvårdsproblem som bidrar till ett betydande antal dödsfall. Förgiftningsdödsfall med läkemedel är också relativt vanliga och det är viktigt att bevaka effekter av preventiva åtgärder och se om de substanser som används ändras över tid. En del läkemedelsrelaterade biverkningar skulle kunna förhindras då t.ex. en betydande andel av warfarinrelaterade hjärnblödningar beror på läkemedelsinteraktioner. Förekomsten av venösa blodproppar verkar vara förhöjd bland patienter som behandlas med antipsykotiska läkemedel, men fler studier behövs för att avgöra detta och vad det i så fall beror på.

This thesis describes two different sample preparation strategies for inductively coupled plasma atomic emission spectrometry (ICP-AES), and their ability regarding multi element quantification in complex samples. Sensitivity, repeatability, reproducibility and accuracy were investigated. The aim was to increase the over all efficiency, the speed of analysis, and/or the sensitivity of the analytical method. The intention was to measure analytes with concentrations ranging from ng/g to mg/g simultaneously. The aim was additionally to study chemical and physical processes occurring during the sample preparation, the sample transport to the plasma, and the atomization therein. In the first sample preparation strategy, a hydrophilic highly cross-linked iminodiacetate-agarose adsorbent, IDA-Novarose, was used for preconcentration of metal ions, and matrix elimination in natural water samples. The sorbent was synthesized with different binding capacities. The effect of the capacity on preconcentration, matrix elimination, and uptake capability at high flow rates was studied. For a high capacity IDA-Novarose (≥ 45 µmole/ml) quantitative uptake was seen even at high flow rates (100 ml/min) for Cu2+ with a high affinity to the adsorbent, and for Cd2+ with a moderate affinity. For lower capacities the uptake of Cd2+ was affected by the sample matrix and the flow rate. A method based on the determination of the conditional stability constant of the metal sorbent complex was suggested for the prediction of the sorbent capacity needed to obtain quantitative recovery and optimal matrix elimination. The sorbent was used in a flow system with online buffering for the analysis of a certified riverine water (SLRS-3), tap water and lake water. With few exceptions the results obtained by ICP-AES after preconcentration agreed well with the certified concentrations and results obtained by ICP-MS. The other sample preparation strategy discussed is a method for non digested biological samples from different animal organs for the multi element analysis by ICP-AES. This “mix and measure method” consists of a simple homogenization of the sample with a mixing rod in a small amount of neutral media, followed by dilution and direct measurement with ICP-AES. The total time of analysis is only a few minutes. The ability of this fast method to accurately quantify some elements of toxic, environmental, and/or physiological concern with the lowest possible sample dilution and the highest possible plasma load was evaluated. In 10 % liver slurry Cd, Co, and Sr, at concentration levels around 0.05 µg/g were quantified simultaneously with P and K around 2000 µg/g and with several other elements in between (Al, Ca, Cu, Fe, Mg, Mn, Pb, and Zn). The relative standard deviation of repeated measurements of samples was around 5 - 6 % for regardless of the concentration of the element. The method was also used for fast screening of the elemental distribution in mice organs (brain, heart, kidney, liver, lung and spleen).