Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2009. / Härtill 3 uppsatser.

Hypoxia is a common patho-physiological phenomenon in many types of diseases, including tumors, myocardial infarction and cerebral ischemia. It is believed that hypoxia not only affects the cellular regulation pathways, but also interferes genome, transcriptome and proteome inside tumor, eventually enhances tumor development by increasing malignancy and metastatic potential, induction of resistance towards radiotherapy and chemotherapy, activation of angiogenic mechanism, etc. One of the major biological events for hypoxia is induction of apoptosis, which is believed to provide a selective pressure for tumor progression. However, the mechanism of hypoxia induced apoptosis is not well established. In the present study, the molecular mechanism of hypoxia induced apoptosis was investigated and was found to be different in human squamous carcinoma A431 cells and human hepatocellular carcinoma HepG2 cells. In HepG2 cells, the conventional intrinsic apoptotic pathway that involved the activation of caspase-9 and -3 was found to be triggered by hypoxia through a newly identified p53 - Bnip-3 shunt. On the other hand, caspase-4 and -10 were found to be activated under hypoxia and may be related to hypoxia induced DNA fragmentation in A431 cells. Reoxygenation prior to hypoxia is the event after blood reperfusion in tumor vasculature. It is demonstrated in this study that reoxygenation is a distinctive stress from hypoxia, and it is very likely to be induced by reactive oxygen species. Apart from apoptosis, the mechanism for the development of drug resistance after hypoxia is also not yet clearly identified. In this study, resistance towards several common chemotherapeutic drugs after cells were subjected to hypoxia/reoxygenation cycles were demonstrated. Among them, the possible role of the genes related to methotrexate and cisplatin resistance were also investigated. / Ho Yiu Fung. / "August 2006." / Adviser: Tim-Tak Kwok. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1393. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 159-176). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 3 uppsatser.

This thesis sought to improve our understanding of how kidneys become injured as a consequence of organ donation, with the aim of improving the outcomes of transplantation. Every year, hundreds of patients on the waiting list die whilst awaiting a kidney transplant. With an ever-increasing demand for suitable organs, supply cannot keep up with the pressures on the transplant waiting list. As a consequence the transplant community are forced to use organs that previously would not have been considered suitable for transplant, including from older donors with additional comorbidities. This thesis aimed to develop an understanding as to how the kidney becomes injured during the donation process, identifying which key cellular homeostatic processes are disturbed as a consequence of donation. The thesis outlines the experimental development of rodent models of organ donation replicating the donation process for donation after brain death (DBD) and donation after circulatory death (DCD) donors and also the development of a kidney ischaemia reperfusion injury (IRI) model. Proteomics was subsequently used to identifying global protein alterations in the kidney as a consequence of brain death and ischemia reperfusion injury using bioinformatics tools to identify involvement of cellular pathways. The results indicated alterations in mitochondrial function and metabolic homeostasis occurring following brain death. Alterations in cellular metabolism and mitochondrial function were then confirmed using metabolomics and mitochondrial functional assays. I subsequently evaluated how alterations in cellular hypoxia and the hypoxia inducible factor system is altered in the brain dead organ donor kidney and aimed to target this system as a means of conditioning the brain dead organ donor to prevent mitochondrial and metabolic mediated injury to kidney cells following brain death. This involved exploring the role of prolyl hydroxylase inhibitors, including dimethyloxalylglycine, on mitochondrial function and whether this could be a therapeutic target in organ donation. This thesis provides important insights into the mechanism of injury of kidneys following brain death, providing evidence that even before procurement and preservation in the DBD donor alterations in mitochondrial function and metabolic homeostasis occur. I provide preliminary data on the use of prolyl hydroxylase inhibitors in altering mitochondrial function. I also outline my involvement in other ongoing projects in organ donation and machine perfusion that also aim to improve the outcomes of deceased donor kidney and liver transplantation.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Occupational Therapy. Johannesburg, 2013 / This study determined outcomes for motor developmental delay in infants, 12-14 months, diagnosed with HIE II and III, at Chris Hani Baragwanath Academic Hospital. Twenty nine infants diagnosed with HIE II and nine infants diagnosed with HIE III were assessed using the Peabody Development Motor Scale- 2, at their corrected age. Demographic, antenatal and perinatal factors similar to those in other studies were found for this sample. Infants with HIE III had significantly more developmental delay (p=0.01) than infants with HIE II. Fifty two percent of infants with HIE II had no delay while a 100% of infants with HIE III presented with disability. A greater percentage of infants had delay in fine motor skills. Infants with severe and moderate disabilities were receiving intervention whereas those mild disabilities were often missed in screening clinics. It is vital to ensure these infants are assessed and followed up to remediate difficulties as soon as they arise.

INTRODUÇÃO: A ressuscitação de baixo volume com solução salina hipertônica (SSH) ou terlipressina pode ser uma alternativa à administração de grandes volumes de cristaloides no tratamento do choque hemorrágico. O objetivo deste estudo foi avaliar os efeitos da HHS e terlipressina sobre a perfusão e oxigenação cerebral e investigar os mecanismos cerebrais envolvidos na microcirculação, função mitocondrial, atividade eletrocortical e vias apoptóticas cerebrais durante choque hemorrágico. MÉTODOS: Animais anestesiados com isofluorano foram submetidos ao choque hemorrágico [grupo Hemo; pressão arterial média (PAM) de 40 mmHg por 30 minutos] e tratados com Ringer lactato (RL) (3RL; 3x volume de sangue removido), terlipressina (grupo Terli; bolus) ou SSH (grupo SSH; 4 mL/kg bolus) e comparados ao grupo Sham. Um modelo porcino (n = 56) foi utilizado para avaliação da pressão de perfusão cerebral (PPC) e de oxigênio tecidual (PbtO2), e da expressão cerebral de marcadores teciduais da regulação de água (aquaporina-4), sódio (cotransportador-1 de Na-K-2Cl), estresse oxidativo (substâncias reativas ao ácido tiobarbitúrico e superóxido dismutase dependente de manganês) e apoptose. Um modelo murino (n = 179) foi utilizado para avaliação da microcirculação (fluorescência de FITC-dextrano) e função mitocondrial (potencial redox e de membrana mitocondrial, utilizando-se a fluorescência de flavoproteínas endógenas e do tetrametilrodamina metil éster, respectivamente) no córtex cerebral, utilizando-se a microscopia confocal in vivo, e para avaliação da atividade eletrocortical cerebral, por meio da monitorização do potencial evocado somatossensorial. No modelo murino foram avaliados três grupos adicionais, constituídos pela associação da terlipressina ao RL (1x, 2x ou 3x volume removido). RESULTADOS: No grupo Hemo porcino, houve uma redução significativa da PPC e PbtO2, associada ao aumento na expressão cerebral de marcadores da regulação do transporte de água e sódio, estresse oxidativo e apoptose em relação ao Sham. No modelo murino, a hipotensão induzida pelo choque hemorrágico foi correlacionada à diminuição na densidade vascular cortical e às disfunções mitocondriais e da atividade eletrocortical cerebral. No grupo 3RL porcino, a infusão de grandes volumes de RL recuperou a PbtO2, mas não a PPC, e foi acompanhada por uma maior expressão cerebral de marcadores da regulação de água, estresse oxidativo e apoptose comparada ao Sham. Nos ratos, a ressuscitação volêmica agressiva não recuperou a densidade vascular cortical, que foi correlacionada às disfunções mitocondrial e da atividade eletrocortical. No grupo Terli porcino, o aumento na PAM foi associado à restauração da PPC, PbtO2 e expressão dos marcadores da regulação de água e sódio, estresse oxidativo e apoptose no cérebro. Nos ratos tratados com terlipressina, associada ou não a 1x ou 2x RL, houve uma correlação positiva entre a recuperação da densidade vascular cortical e a restauração das funções mitocondrial e atividade eletrocortical cerebral. A SSH não promoveu melhora em nenhum dos modelos. CONCLUSÕES: RL e terlipressina recuperaram a oxigenação no córtex cerebral, mas apenas a terlipressina recuperou a perfusão cerebral, revertendo as disfunções mitocondrial e eletrocortical no cérebro e o aumento no transporte de água e sódio, estresse oxidativo e apoptose induzidos pelo choque hemorrágico. A SSH não recuperou a perfusão e oxigenação cerebral / INTRODUCTION: Small-volume resuscitation with hypertonic saline solution (HSS) or terlipressin can be an alternative to the administration of large amounts of crystalloids in haemorrhagic shock. The aim of this study was to evaluate the effects of HSS and terlipressin on cerebral perfusion and oxygenation and investigate the cerebral mechanisms associated with microcirculation, mitochondrial function, electrocortical activity and apoptotic pathways during haemorrhagic shock. METHODS: Isoflurane-anaesthetised animals were submitted to haemorrhagic shock [Haemo group; mean arterial pressure (MAP) of 40 mmHg for 30 minutes] and treated with lactated Ringer\'s solution (LR) (3LR group; 3x volume bled), terlipressin (Terli group; bolus) or HSS (HSS group; bolus 4 mL/kg) and were compared with a Sham group. A porcine model (n = 56) was used to assess the cerebral perfusion pressure (CPP) and tissue oxygenation (PbtO2) and the expression of tissue markers of water (aquaporin-4), sodium (Na-K-2Cl cotransporter-1), oxidative stress (thiobarbituric acid reactive substances and manganese superoxide dismutase) and apoptosis in cerebral samples. A murine model (n = 179) was used to assess microcirculation (FITC-dextran fluorescence) and mitochondrial function (redox and membrane potential, using the fluorescence of endogenous flavoproteins and tetramethylrhodamine methyl ester, respectively) in the cerebral cortex by using in vivo confocal microscopy, and to assess the electrocortical brain activity by monitoring the somatosensory evoked potential. In the murine model, three additional groups were evaluated, which received terlipressin associated to LR (1x, 2x or 3x blood withdrawn). RESULTS: In the porcine Hemo group, there was a significant decrease in the CPP and PbtO2, which were associated to an increased cerebral expression of markers of water and sodium transport, oxidative stress and apoptosis compared with Sham. In the murine model, the haemorrhagic shock-induced hypotension was correlated to a decrease in the cortical vascular density and to dysfunctions on brain mitochondria and electrocortical activity. In the porcine 3LR group, the infusion of large volumes of LR recovered the PbtO2, but not the CPP, and was accompanied by an increased cerebral expression of markers of water and sodium transport, oxidative stress and apoptosis compared with Sham. In the rats, the aggressive fluid resuscitation did not recover the cortical vascular density, which was correlated to the brain mitochondrial and electrocortical dysfunctions. In the porcine Terli group, the increase in the MAP was associated with the recovery of CPP, PbtO2, and expression of markers of water and sodium regulation, oxidative stress and apoptosis within the brain. In the rats treated with terlipressin, associated or not with 1x or 2x LR, there was a positive correlation between the recovery of the cortical vascular density and the recovery of the brain mitochondrial and electrocortical functions. Such improvements were not observed in none of the models treated with HSS. CONCLUSIONS: LR and terlipressin recovered tissue oxygenation in the cerebral cortex, but only terlipressin recovered the cerebral perfusion, reversing the brain mitochondrial and electrocortical dysfunctions and the increase in the markers of water and sodium transport, oxidative stress, and apoptosis induced by haemorrhagic shock. The HSS did not recover cerebral perfusion and oxygenation

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 8 uppsatser.

INTRODUÇÃO: A ressuscitação de baixo volume com solução salina hipertônica (SSH) ou terlipressina pode ser uma alternativa à administração de grandes volumes de cristaloides no tratamento do choque hemorrágico. O objetivo deste estudo foi avaliar os efeitos da HHS e terlipressina sobre a perfusão e oxigenação cerebral e investigar os mecanismos cerebrais envolvidos na microcirculação, função mitocondrial, atividade eletrocortical e vias apoptóticas cerebrais durante choque hemorrágico. MÉTODOS: Animais anestesiados com isofluorano foram submetidos ao choque hemorrágico [grupo Hemo; pressão arterial média (PAM) de 40 mmHg por 30 minutos] e tratados com Ringer lactato (RL) (3RL; 3x volume de sangue removido), terlipressina (grupo Terli; bolus) ou SSH (grupo SSH; 4 mL/kg bolus) e comparados ao grupo Sham. Um modelo porcino (n = 56) foi utilizado para avaliação da pressão de perfusão cerebral (PPC) e de oxigênio tecidual (PbtO2), e da expressão cerebral de marcadores teciduais da regulação de água (aquaporina-4), sódio (cotransportador-1 de Na-K-2Cl), estresse oxidativo (substâncias reativas ao ácido tiobarbitúrico e superóxido dismutase dependente de manganês) e apoptose. Um modelo murino (n = 179) foi utilizado para avaliação da microcirculação (fluorescência de FITC-dextrano) e função mitocondrial (potencial redox e de membrana mitocondrial, utilizando-se a fluorescência de flavoproteínas endógenas e do tetrametilrodamina metil éster, respectivamente) no córtex cerebral, utilizando-se a microscopia confocal in vivo, e para avaliação da atividade eletrocortical cerebral, por meio da monitorização do potencial evocado somatossensorial. No modelo murino foram avaliados três grupos adicionais, constituídos pela associação da terlipressina ao RL (1x, 2x ou 3x volume removido). RESULTADOS: No grupo Hemo porcino, houve uma redução significativa da PPC e PbtO2, associada ao aumento na expressão cerebral de marcadores da regulação do transporte de água e sódio, estresse oxidativo e apoptose em relação ao Sham. No modelo murino, a hipotensão induzida pelo choque hemorrágico foi correlacionada à diminuição na densidade vascular cortical e às disfunções mitocondriais e da atividade eletrocortical cerebral. No grupo 3RL porcino, a infusão de grandes volumes de RL recuperou a PbtO2, mas não a PPC, e foi acompanhada por uma maior expressão cerebral de marcadores da regulação de água, estresse oxidativo e apoptose comparada ao Sham. Nos ratos, a ressuscitação volêmica agressiva não recuperou a densidade vascular cortical, que foi correlacionada às disfunções mitocondrial e da atividade eletrocortical. No grupo Terli porcino, o aumento na PAM foi associado à restauração da PPC, PbtO2 e expressão dos marcadores da regulação de água e sódio, estresse oxidativo e apoptose no cérebro. Nos ratos tratados com terlipressina, associada ou não a 1x ou 2x RL, houve uma correlação positiva entre a recuperação da densidade vascular cortical e a restauração das funções mitocondrial e atividade eletrocortical cerebral. A SSH não promoveu melhora em nenhum dos modelos. CONCLUSÕES: RL e terlipressina recuperaram a oxigenação no córtex cerebral, mas apenas a terlipressina recuperou a perfusão cerebral, revertendo as disfunções mitocondrial e eletrocortical no cérebro e o aumento no transporte de água e sódio, estresse oxidativo e apoptose induzidos pelo choque hemorrágico. A SSH não recuperou a perfusão e oxigenação cerebral / INTRODUCTION: Small-volume resuscitation with hypertonic saline solution (HSS) or terlipressin can be an alternative to the administration of large amounts of crystalloids in haemorrhagic shock. The aim of this study was to evaluate the effects of HSS and terlipressin on cerebral perfusion and oxygenation and investigate the cerebral mechanisms associated with microcirculation, mitochondrial function, electrocortical activity and apoptotic pathways during haemorrhagic shock. METHODS: Isoflurane-anaesthetised animals were submitted to haemorrhagic shock [Haemo group; mean arterial pressure (MAP) of 40 mmHg for 30 minutes] and treated with lactated Ringer\'s solution (LR) (3LR group; 3x volume bled), terlipressin (Terli group; bolus) or HSS (HSS group; bolus 4 mL/kg) and were compared with a Sham group. A porcine model (n = 56) was used to assess the cerebral perfusion pressure (CPP) and tissue oxygenation (PbtO2) and the expression of tissue markers of water (aquaporin-4), sodium (Na-K-2Cl cotransporter-1), oxidative stress (thiobarbituric acid reactive substances and manganese superoxide dismutase) and apoptosis in cerebral samples. A murine model (n = 179) was used to assess microcirculation (FITC-dextran fluorescence) and mitochondrial function (redox and membrane potential, using the fluorescence of endogenous flavoproteins and tetramethylrhodamine methyl ester, respectively) in the cerebral cortex by using in vivo confocal microscopy, and to assess the electrocortical brain activity by monitoring the somatosensory evoked potential. In the murine model, three additional groups were evaluated, which received terlipressin associated to LR (1x, 2x or 3x blood withdrawn). RESULTS: In the porcine Hemo group, there was a significant decrease in the CPP and PbtO2, which were associated to an increased cerebral expression of markers of water and sodium transport, oxidative stress and apoptosis compared with Sham. In the murine model, the haemorrhagic shock-induced hypotension was correlated to a decrease in the cortical vascular density and to dysfunctions on brain mitochondria and electrocortical activity. In the porcine 3LR group, the infusion of large volumes of LR recovered the PbtO2, but not the CPP, and was accompanied by an increased cerebral expression of markers of water and sodium transport, oxidative stress and apoptosis compared with Sham. In the rats, the aggressive fluid resuscitation did not recover the cortical vascular density, which was correlated to the brain mitochondrial and electrocortical dysfunctions. In the porcine Terli group, the increase in the MAP was associated with the recovery of CPP, PbtO2, and expression of markers of water and sodium regulation, oxidative stress and apoptosis within the brain. In the rats treated with terlipressin, associated or not with 1x or 2x LR, there was a positive correlation between the recovery of the cortical vascular density and the recovery of the brain mitochondrial and electrocortical functions. Such improvements were not observed in none of the models treated with HSS. CONCLUSIONS: LR and terlipressin recovered tissue oxygenation in the cerebral cortex, but only terlipressin recovered the cerebral perfusion, reversing the brain mitochondrial and electrocortical dysfunctions and the increase in the markers of water and sodium transport, oxidative stress, and apoptosis induced by haemorrhagic shock. The HSS did not recover cerebral perfusion and oxygenation

OBJETIVO: Avaliar o desempenho em testes neuropsicológicos e a resposta hemodinâmica cerebral medida por ressonância magnética funcional (RMf) em tarefas de memória e motora numa amostra de pacientes vítimas de afogamento com perda de consciência comparados a um grupo de indivíduos saudáveis. MATERIAL E MÉTODO: Estudamos 15 voluntários com média de idade de 23,7 anos no grupo de pacientes, selecionados a partir de amostra de 157 vítimas de afogamento, tendo como critérios de inclusão grau 3 e 4 da Escala de Afogamento (Szpilman, D. 1997) e excluindo-se aqueles com lesões estruturais cerebrais, antecedentes de alterações neurológicas ou psiquiátricas. Este grupo foi comparado a 18 voluntários saudáveis com média de idade de 25,3 anos selecionados para o grupo controle, pareados por anos de educação formal, idade e sexo. As imagens estruturais para referência anatômica (T1 3D; FLAIR 2D) e imagens funcionais axiais eco-planar, gradiente de ecos com ponderação T2*, com voxels isotrópicos de 3mm foram adquiridas em sistema de RM de 3,0 Teslas e os estímulos apresentados visualmente e sincronizados com a aquisição das imagens. O estudo de RMf foi realizado em desenho em bloco, com tarefa motora e de memória. Os dados de RMf foram préprocessados para correção de movimento, filtro espacial e temporal e foi aplicado Modelo Geral Linearizado para identificação de áreas cerebrais associadas às tarefas e produção de mapas estatísticos limiarizados (p < 0,05) representado a resposta cerebral de cada grupo, corrigidos para comparações múltiplas. Foram realizados testes ANOVA na comparação entre os dois grupos quanto às áreas cerebrais detectadas nas duas tarefas, sem e com utilização de co-variáveis obtidas de parâmetros dos testes neuropsicológicos. Além disso, investigamos a conectividade entre as regiões de redes neurais de cada paradigma através da análise de PPI e análise de correlação média de regiões da rede clássica de memória e motora entre os grupos. RESULTADOS: O desempenho neuropsicológico dos grupos foi similar na maioria dos testes, porém os pacientes (GP) apresentaram diferença significativa com pior desempenho no teste FAS e Dígitos e melhor desempenho na parte do reconhecimento do teste BVMT em relação aos controles (GC) (FAS: GC=40,0±8,6; GP=31,7±8,9; P=0,010/ Dígitos: GC=14,3±3,7; GP=12,3±2,1; P=0,050/ BVMT reconhecimento: GC=5,6±0,05; P=6,0; P=0,005). Durante os exames de RMf o desempenho comportamental foi similar em ambos os grupos nas duas tarefas (média de acurácia: GC=70,2±11,3%; GP=73,0±10,1%; P=0,460/ Tempo de reação: GC=1328,6±196,8ms; GP=1163,7±198,5ms; P=0,020/ frequência: GC=2,9±0,9Hz; GP=2,5±0,5Hz; P=0,108). No paradigma de memória, os controles apresentaram maior ativação em relação aos pacientes na região do giro temporal médio à direita e cuneus, giro lingual e sulco intraparietal à esquerda; esta diferença foi modulada pelo desempenho em testes neuropsicológicos de Dígitos, FAS e BVMT; não houve diferença no padrão da rede neural desta tarefa na análise PPI; houve maior correlação da rede frontoparietal à direita no grupo controle. No paradigma motor, os pacientes apresentam maior ativação em relação aos controles na região do putame e ínsula à esquerda; esta diferença foi modulada pelo desempenho em testes neuropsicológicos de Dígitos e FAS; a rede neural motora apresentou diferença entre os grupos na análise PPI: houve decréscimo da conectividade funcional entre a área motora suplementar (AMS) e as regiões do giro pré e pós-central à esquerda e porção opercular do giro frontal médio à direita nos pacientes em relação aos controles; porém, houve maior correlação da série temporal dos pacientes entre a AMS e a área sensitivomotora à esquerda. CONCLUSÃO: O desempenho neuropsicológico encontrado nesta amostra de vítimas de afogamento pode ser considerado normal ou com alterações leves, o que difere de estudos nessa população com diferentes graus de agressão hipóxia. As diferenças de atividade cerebral na rede associada à tarefa de memória - uma função frequentemente descrita como alterada em casos de afogamento mais severo - pode representar mecanismo de reorganização neural. A alteração do padrão de funcionamento da rede neural motora nestes pacientes corrobora as hipóteses baseadas na literatura de pacientes com agressão severa, com alta probabilidade de acometimento estrutural em núcleos da base. Os nossos resultados mostram que alterações na rede cerebral associada à função de memória e motora estão presentes mesmo sem evidente comprometimento estrutural ou neuropsicológico / hemodynamic response measured by functional magnetic resonance imaging (fMRI) on memory and motor tasks in a sample of drowning victims with loss of consciousness compared to a group of healthy individuals. MATERIAL AND METHODS: We studied 15 volunteers (six men; mean age: 23.7 years) enlisted in the group of patients, which were selected from a sample of 157 drowning victims, with the inclusion criteria grade 3 and 4 Scale Drowning (Szpilman D., 1997) and excluding those with structural brain lesions , history of neurological or psychiatric disorders. This group was compared to 18 healthy volunteers (five men; mean age: 25.3 years matched for years of education, age and sex (control group). Structural images for anatomical reference (T1 3D, 1mm isotropic voxels; FLAIR 2D, voxels 1.2x1.2x5mm) and functional imaging axial echo - planar gradient echo T2*- weighted (Blood Oxygenation Level Dependent ) with 3mm isotropic voxels were acquired in MR system of 3.0 Tesla using a 8 Ch head coil, the stimuli presented visually and synchronized with image acquisition (Zurc & Zurc , São Paulo - Brazil). The study was conducted using fMRI block design, with motor task (finger tapping) and memory (visual recognition - part of the International Consortium for Brain Mapping). Subjects\' performance in the fMRI tasks were recorded using a response box and visual observation of hand movement frequency. fMRI data were preprocessed for motion correction , spatial and temporal filter was applied and General Linear Model (GLM) was used for identification of brain areas associated with the tasks. Statistical thresholded maps (p < 0.05) representing group response to each task were corrected for multiple comparisons. ANOVA tests were performed to compare the group maps in the two tasks, with and without using covariates obtained from neuropsychological. Furthermore, we investigated the connectivity between regions of each neural network paradigm by analyzing psychophysiological interaction (PPI) and direct correlation analysis between classical regions of the motor and memory networks. RESULTS : The neuropsychological performance of the groups were similar in most tests, but patients (PG) showed significant differences with worse performance in and Digit and FAS tests, and a better performance in the recognition part of the BVMT test compared to controls (CG) (FAS: CG =40,0±8,6; PG =31,7±8,9; P=0,010/ Digits: CG =14,3±3,7; PG =12,3±2,1; P=0,050/ Recognition BVMT: CG =5,6±0,05; PG =6,0; P=0,005). Behavioral performance was similar in both groups on both fMRI tasks (mean accuracy: CG =70,2±11,3%; PG =73,0±10,1%; P=0,460 / RT: CG =1328,6±196,8ms; PG =1163,7±198,5ms; P=0,020 / frequency: CG =2,9±0,9Hz; PG =2,5±0,5Hz; P=0,108). In the memory task, controls showed greater activation compared to patients in the middle temporal gyrus and right cuneus, lingual and borders of the left intraparietal sulcus; this difference was modulated by performance on Digits, FAS and BVMT tests; we found no difference in the pattern of neural network on PPI analysis; there was, however, a higher correlation of the right frontoparietal network in the control group. In the motor task, patients showed greater activation than controls in the region of the putamen and left insula; this difference was modulated by performance on neuropsychological tests of Digits and FAS in the left hand task; the motor neural network differed between groups in PPI analysis: there was a decrease of functional connectivity between the supplementary motor area (SMA) and the regions of the left pre- and post-central gyrus and opercular portion of the right middle frontal gyrus in patients compared to controls; on the other hand, there was greater correlation between the time series of the AMS and the left sensorimotor area in patients. CONCLUSION: The neuropsychological performance differences found in this sample of drowning victims can be considered normal or mild abnormalities, which differ from studies using drowning population with varying degrees of hypoxia. Differences in brain activity in the network associated with memory task - a function often affected in more severe cases of drowning - may represent a neural reorganization mechanism. The changes in the motor neural network in these patients confirm the hypotheses based on the literature of patients with severe aggression, who have a high probability of structural involvement in the basal ganglia. Our results show that changes in brain network associated with memory function and motor are present even without apparent structural or neuropsychological impairment

OBJETIVO: Avaliar o desempenho em testes neuropsicológicos e a resposta hemodinâmica cerebral medida por ressonância magnética funcional (RMf) em tarefas de memória e motora numa amostra de pacientes vítimas de afogamento com perda de consciência comparados a um grupo de indivíduos saudáveis. MATERIAL E MÉTODO: Estudamos 15 voluntários com média de idade de 23,7 anos no grupo de pacientes, selecionados a partir de amostra de 157 vítimas de afogamento, tendo como critérios de inclusão grau 3 e 4 da Escala de Afogamento (Szpilman, D. 1997) e excluindo-se aqueles com lesões estruturais cerebrais, antecedentes de alterações neurológicas ou psiquiátricas. Este grupo foi comparado a 18 voluntários saudáveis com média de idade de 25,3 anos selecionados para o grupo controle, pareados por anos de educação formal, idade e sexo. As imagens estruturais para referência anatômica (T1 3D; FLAIR 2D) e imagens funcionais axiais eco-planar, gradiente de ecos com ponderação T2*, com voxels isotrópicos de 3mm foram adquiridas em sistema de RM de 3,0 Teslas e os estímulos apresentados visualmente e sincronizados com a aquisição das imagens. O estudo de RMf foi realizado em desenho em bloco, com tarefa motora e de memória. Os dados de RMf foram préprocessados para correção de movimento, filtro espacial e temporal e foi aplicado Modelo Geral Linearizado para identificação de áreas cerebrais associadas às tarefas e produção de mapas estatísticos limiarizados (p < 0,05) representado a resposta cerebral de cada grupo, corrigidos para comparações múltiplas. Foram realizados testes ANOVA na comparação entre os dois grupos quanto às áreas cerebrais detectadas nas duas tarefas, sem e com utilização de co-variáveis obtidas de parâmetros dos testes neuropsicológicos. Além disso, investigamos a conectividade entre as regiões de redes neurais de cada paradigma através da análise de PPI e análise de correlação média de regiões da rede clássica de memória e motora entre os grupos. RESULTADOS: O desempenho neuropsicológico dos grupos foi similar na maioria dos testes, porém os pacientes (GP) apresentaram diferença significativa com pior desempenho no teste FAS e Dígitos e melhor desempenho na parte do reconhecimento do teste BVMT em relação aos controles (GC) (FAS: GC=40,0±8,6; GP=31,7±8,9; P=0,010/ Dígitos: GC=14,3±3,7; GP=12,3±2,1; P=0,050/ BVMT reconhecimento: GC=5,6±0,05; P=6,0; P=0,005). Durante os exames de RMf o desempenho comportamental foi similar em ambos os grupos nas duas tarefas (média de acurácia: GC=70,2±11,3%; GP=73,0±10,1%; P=0,460/ Tempo de reação: GC=1328,6±196,8ms; GP=1163,7±198,5ms; P=0,020/ frequência: GC=2,9±0,9Hz; GP=2,5±0,5Hz; P=0,108). No paradigma de memória, os controles apresentaram maior ativação em relação aos pacientes na região do giro temporal médio à direita e cuneus, giro lingual e sulco intraparietal à esquerda; esta diferença foi modulada pelo desempenho em testes neuropsicológicos de Dígitos, FAS e BVMT; não houve diferença no padrão da rede neural desta tarefa na análise PPI; houve maior correlação da rede frontoparietal à direita no grupo controle. No paradigma motor, os pacientes apresentam maior ativação em relação aos controles na região do putame e ínsula à esquerda; esta diferença foi modulada pelo desempenho em testes neuropsicológicos de Dígitos e FAS; a rede neural motora apresentou diferença entre os grupos na análise PPI: houve decréscimo da conectividade funcional entre a área motora suplementar (AMS) e as regiões do giro pré e pós-central à esquerda e porção opercular do giro frontal médio à direita nos pacientes em relação aos controles; porém, houve maior correlação da série temporal dos pacientes entre a AMS e a área sensitivomotora à esquerda. CONCLUSÃO: O desempenho neuropsicológico encontrado nesta amostra de vítimas de afogamento pode ser considerado normal ou com alterações leves, o que difere de estudos nessa população com diferentes graus de agressão hipóxia. As diferenças de atividade cerebral na rede associada à tarefa de memória - uma função frequentemente descrita como alterada em casos de afogamento mais severo - pode representar mecanismo de reorganização neural. A alteração do padrão de funcionamento da rede neural motora nestes pacientes corrobora as hipóteses baseadas na literatura de pacientes com agressão severa, com alta probabilidade de acometimento estrutural em núcleos da base. Os nossos resultados mostram que alterações na rede cerebral associada à função de memória e motora estão presentes mesmo sem evidente comprometimento estrutural ou neuropsicológico / hemodynamic response measured by functional magnetic resonance imaging (fMRI) on memory and motor tasks in a sample of drowning victims with loss of consciousness compared to a group of healthy individuals. MATERIAL AND METHODS: We studied 15 volunteers (six men; mean age: 23.7 years) enlisted in the group of patients, which were selected from a sample of 157 drowning victims, with the inclusion criteria grade 3 and 4 Scale Drowning (Szpilman D., 1997) and excluding those with structural brain lesions , history of neurological or psychiatric disorders. This group was compared to 18 healthy volunteers (five men; mean age: 25.3 years matched for years of education, age and sex (control group). Structural images for anatomical reference (T1 3D, 1mm isotropic voxels; FLAIR 2D, voxels 1.2x1.2x5mm) and functional imaging axial echo - planar gradient echo T2*- weighted (Blood Oxygenation Level Dependent ) with 3mm isotropic voxels were acquired in MR system of 3.0 Tesla using a 8 Ch head coil, the stimuli presented visually and synchronized with image acquisition (Zurc & Zurc , São Paulo - Brazil). The study was conducted using fMRI block design, with motor task (finger tapping) and memory (visual recognition - part of the International Consortium for Brain Mapping). Subjects\' performance in the fMRI tasks were recorded using a response box and visual observation of hand movement frequency. fMRI data were preprocessed for motion correction , spatial and temporal filter was applied and General Linear Model (GLM) was used for identification of brain areas associated with the tasks. Statistical thresholded maps (p < 0.05) representing group response to each task were corrected for multiple comparisons. ANOVA tests were performed to compare the group maps in the two tasks, with and without using covariates obtained from neuropsychological. Furthermore, we investigated the connectivity between regions of each neural network paradigm by analyzing psychophysiological interaction (PPI) and direct correlation analysis between classical regions of the motor and memory networks. RESULTS : The neuropsychological performance of the groups were similar in most tests, but patients (PG) showed significant differences with worse performance in and Digit and FAS tests, and a better performance in the recognition part of the BVMT test compared to controls (CG) (FAS: CG =40,0±8,6; PG =31,7±8,9; P=0,010/ Digits: CG =14,3±3,7; PG =12,3±2,1; P=0,050/ Recognition BVMT: CG =5,6±0,05; PG =6,0; P=0,005). Behavioral performance was similar in both groups on both fMRI tasks (mean accuracy: CG =70,2±11,3%; PG =73,0±10,1%; P=0,460 / RT: CG =1328,6±196,8ms; PG =1163,7±198,5ms; P=0,020 / frequency: CG =2,9±0,9Hz; PG =2,5±0,5Hz; P=0,108). In the memory task, controls showed greater activation compared to patients in the middle temporal gyrus and right cuneus, lingual and borders of the left intraparietal sulcus; this difference was modulated by performance on Digits, FAS and BVMT tests; we found no difference in the pattern of neural network on PPI analysis; there was, however, a higher correlation of the right frontoparietal network in the control group. In the motor task, patients showed greater activation than controls in the region of the putamen and left insula; this difference was modulated by performance on neuropsychological tests of Digits and FAS in the left hand task; the motor neural network differed between groups in PPI analysis: there was a decrease of functional connectivity between the supplementary motor area (SMA) and the regions of the left pre- and post-central gyrus and opercular portion of the right middle frontal gyrus in patients compared to controls; on the other hand, there was greater correlation between the time series of the AMS and the left sensorimotor area in patients. CONCLUSION: The neuropsychological performance differences found in this sample of drowning victims can be considered normal or mild abnormalities, which differ from studies using drowning population with varying degrees of hypoxia. Differences in brain activity in the network associated with memory task - a function often affected in more severe cases of drowning - may represent a neural reorganization mechanism. The changes in the motor neural network in these patients confirm the hypotheses based on the literature of patients with severe aggression, who have a high probability of structural involvement in the basal ganglia. Our results show that changes in brain network associated with memory function and motor are present even without apparent structural or neuropsychological impairment