This dissertation explores the role of brainstem structures in the development and expression of generalized tonic-clonic seizures. The functional consequences of brainstem seizures are investigated using the kindling paradigm in order to understand the behavioral and cognitive effects of generalized seizures. <BR><BR> I begin by investigating the general characteristics of brainstem kindling. The first experiment demonstrates that certain brainstem sites are indeed susceptible to kindling and begins to delineate the features that distinguish brainstem seizures from those evoked at other brain regions. Further investigation of the EEG signal features using wavelet analysis reveals that changes in the spectral properties of the electrographic activity during kindling include significant changes to high-frequency activity and organized low-frequency activity. I also identify transitions that include frequency sweeps and abrupt seizure terminations. The changing spectral features are shown to be critically associated with the evolution of the kindled seizures and may have important functional consequences. The surprising responsiveness of some brainstem structures to kindling forces us to reconsider the overall role of these structures in epileptogenesis as well as in the healthy dynamical functioning of the brain. <BR><BR> In order to study the functional consequences, a series of experiments examines the changes in behavior, cognition and affect that follow these brainstem seizures. Although the results show no effects on spatial learning or memory, there are significant and complex effects on anxiety- and depression-like behavior that appear to be related to motivation. In order to further study the cognitive effects, a second set of behavioral experiments considers how context (i.e., the environment) interacts with the behavioral changes. The results indicate that changes in affect may only be apparent when choice between seizure-related and seizure-free contexts is given, suggesting that the environment and choice can play key roles in the behavioral consequences of seizures. This thesis also includes an appendix that applies synchrotron imaging to investigate the anatomical consequences of electrode implantation in kindling and shows that significantly increased iron depositions occur even with purportedly biocompatible electrodes widely used in research and clinical settings. <BR><BR> Examination of the role of brainstem structures in generalized seizures in this dissertation offers new perspectives and insights to epileptogenesis and the behavioral effects of epilepsy. The changes in EEG features, behavior, affect and motivation observed after brainstem seizures and kindling may have important clinical implications. For example, the results suggest a need to reexamine the concept of psychogenic seizures, a potential connection to Sudden Unexplained Death in Epilepsy (SUDEP), and the contribution of environmental factors. It is hoped that these findings will help elucidate the complex issues involved in understanding and improving the quality of life for people with epilepsy.

This dissertation explores the role of brainstem structures in the development and expression of generalized tonic-clonic seizures. The functional consequences of brainstem seizures are investigated using the kindling paradigm in order to understand the behavioral and cognitive effects of generalized seizures. <BR><BR> I begin by investigating the general characteristics of brainstem kindling. The first experiment demonstrates that certain brainstem sites are indeed susceptible to kindling and begins to delineate the features that distinguish brainstem seizures from those evoked at other brain regions. Further investigation of the EEG signal features using wavelet analysis reveals that changes in the spectral properties of the electrographic activity during kindling include significant changes to high-frequency activity and organized low-frequency activity. I also identify transitions that include frequency sweeps and abrupt seizure terminations. The changing spectral features are shown to be critically associated with the evolution of the kindled seizures and may have important functional consequences. The surprising responsiveness of some brainstem structures to kindling forces us to reconsider the overall role of these structures in epileptogenesis as well as in the healthy dynamical functioning of the brain. <BR><BR> In order to study the functional consequences, a series of experiments examines the changes in behavior, cognition and affect that follow these brainstem seizures. Although the results show no effects on spatial learning or memory, there are significant and complex effects on anxiety- and depression-like behavior that appear to be related to motivation. In order to further study the cognitive effects, a second set of behavioral experiments considers how context (i.e., the environment) interacts with the behavioral changes. The results indicate that changes in affect may only be apparent when choice between seizure-related and seizure-free contexts is given, suggesting that the environment and choice can play key roles in the behavioral consequences of seizures. This thesis also includes an appendix that applies synchrotron imaging to investigate the anatomical consequences of electrode implantation in kindling and shows that significantly increased iron depositions occur even with purportedly biocompatible electrodes widely used in research and clinical settings. <BR><BR> Examination of the role of brainstem structures in generalized seizures in this dissertation offers new perspectives and insights to epileptogenesis and the behavioral effects of epilepsy. The changes in EEG features, behavior, affect and motivation observed after brainstem seizures and kindling may have important clinical implications. For example, the results suggest a need to reexamine the concept of psychogenic seizures, a potential connection to Sudden Unexplained Death in Epilepsy (SUDEP), and the contribution of environmental factors. It is hoped that these findings will help elucidate the complex issues involved in understanding and improving the quality of life for people with epilepsy.

科学研究費補助金 研究種目:一般研究(B) 課題番号:06454236 研究代表者:豊嶋 英明 研究期間:1994-1995年度

Der plötzliche Kindstod (engl. Sudden Infant Death Syndrome-SIDS) ist die häufigste Todesursache bei Säuglingen innerhalb des ersten Lebensjahres. Die zugrundeliegenden pathophysiologischen Veränderungen sowie die genaue Todesursache sind bis dato ungeklärt. Viele Forschungsbereiche setzen sich intensiv mit der Klärung dieses „Phänomens“ auseinander. Ein Schwerpunkt liegt auf dem genetischen Gebiet und der Betrachtung verschiedener Polymorphismen. Ein Fokus wird hierbei auf die genetischen Polymorphismen der mitochondrialen DNA (mtDNA) gesetzt. In der vorliegenden Arbeit wurden daher drei Polymorphismen der mtDNA und mögliche Risikofaktoren im Bezug zu SIDS-Fällen untersucht. Die Folge eines mitochondrialen Polymorphismus kann beispielsweise die verminderte Genexpression der Untereinheiten der Atmungskette zur Folge haben. Daraus kann ein Defizit in der ATP (Adenosintriphosphat)-Produktion resultieren. Der physiologische Kreislauf einer menschlichen Zelle ist durch dieses Defizit nur eingeschränkt gewährleistet. Im Rahmen der Forschungsarbeit wurden die SNPs G3010A, T16519C und C7028T der mtDNA in Hinblick auf einen möglichen Zusammenhang mit dem SIDS untersucht. Schon 2003 untersuchten Divne et al. (2003) einen möglichen Zusammenhang der SNPs G3010A und C7028T im Zusammenhang mit SIDS, jedoch ohne signifikantes Ergebnis. Boles et al. (2010) konnten eine Assoziation zwischen den Polymorphismen G3010A und T16519C mit dem plötzlichen Kindstod herstellen. Da bislang jedoch keine ausführliche Publikation zu dieser Frage vorliegt, wurde mit der vorliegenden Arbeit die Rolle der Polymorphismen G3010A und T16519C in Bezug auf den plötzlichen Kindstod gemeinsam mit der (bei Europäern) häufigsten Variation C7028T untersucht. Die DNA von 176 SIDS-Fällen und einer Kontrollgruppe von 113 Erwachsenen wurde mittels Singleplex-PCR und RFLP-Analyse genotypisiert. Anhand der Genotypisierung konnten die SNPs quantifiziert und im Hinblick auf einen möglichen Unterschied zwischen SIDS-Fällen und der Kontrollgruppe untersucht werden. Bei Betrachtung der einzelnen SNPs G3010A, T16519C und C7028T lassen sich keine signifikanten Unterschiede zwischen den SIDS-Fällen und der Kontrollgruppe feststellen. Das gehäufte Vorliegen einer erhöhten Mutationsrate in einem Individuum bei SIDS-Fällen im Vergleich zur Kontrollgruppe, sowie die von Opdal et al. (1999) geäußerte Annahme, dass beim Vorliegen einer Mutation in der D-Loop-Region weitere Mutationen im kodierenden Bereich vorkommen, konnten durch diese Arbeit bestätigt werden.

The aim was to investigate associations of fitness and types and levels of physical activity with subsequent risk of cardiovascular disease. Four large-scale longitudinal cohort studies were used. The exposures were different measures related to physical activity and the outcomes were obtained through linkage to the Swedish In-Patient Register. In a cohort of 466 elderly men without pre-existing cardiovascular disease, we found that skeletal muscle morphology was associated with risk of cardiovascular events. A high amount of type I (slow-twitch, oxidative) skeletal muscle fibres was associated with lower risk of cardiovascular events and high amount of type IIx was associated with higher risk of cardiovascular events. This association was only seen among physically active men. Among 39,805 participants in a fundraising event, higher levels of both total and leisure time physical activity were associated with lower risk of heart failure. The associations were strongest for leisure time physical activity. In a cohort of 53,755 participants in the 90 km skiing event Vasaloppet, a higher number of completed races was associated with higher risk of atrial fibrillation and a higher risk of bradyarrhythmias. Further, better relative performance was associated with a higher risk of bradyarrhythmias. Among 1,26 million Swedish 18-year-old men, exercise capacity and muscle strength were independently associated with lower risk of vascular disease. The associations were seen across a range of major vascular disease events (ischemic heart disease, heart failure, stroke and cardiovascular death). Further, high exercise capacity was associated with higher risk of atrial fibrillation and a U-shaped association with bradyarrhythmias was found. Higher muscle strength was associated with lower risk of bradyarrhythmias and lower risk of ventricular arrhythmias. These findings suggest a higher rate of atrial fibrillation with higher levels of physical activity. The higher risk of atrial fibrillation does not appear to lead to a higher risk of stroke. In contrast, we found a strong inverse association of higher exercise capacity and muscle strength with vascular disease. Further, high exercise capacity and muscle strength are related to lower risk of cardiovascular death, including arrhythmia deaths. From a population perspective, the total impact of physical activity on cardiovascular disease is positive.

Thesis (Ph.D.); Submitted to Univ. of California, Berkeley, CA (US); 1 Jun 2003. / Published through the Information Bridge: DOE Scientific and Technical Information. "LBNL--54350" Scielzo, Nicholas David. USDOE Director. Office of Science. Nuclear Physics (US) 06/01/2003. Report is also available in paper and microfiche from NTIS.

Thesis (M.S.)--Uniformed Services University of the Health Sciences, 2005. / Typescript (photocopy).

Thesis (MMed (Pathology. Forensic Medicine))--University of Stellenbosch, 2010. / Bibliography / ENGLISH ABSTRACT: Background - The workload of the forensic pathologist and Forensic Pathology Services staff is increased by the referral of potentially unnecessary natural cases to the Forensic Pathology Services. The primary aims of the medico-legal autopsy are limited to establishing a cause of death in presumed unnatural cases, and to exclude criminality or negligence. Objective – To determine the final outcomes of forensic post-mortem examinations in “sudden and unexpected” adult deaths over a 5 year period. Methods - An observational, retrospective, descriptive study was conducted. ”Sudden and unexpected” adult deaths referred to Tygerberg Forensic Pathology Services between 1 January 2001 and 31 December 2005 were reviewed. Data was collected from the autopsy reports, contemporaneous notes and hospital records. Findings – A total of 816 adult cases of sudden and unexpected death were referred to Tygerberg Forensic Pathology Services over the 5 year period studied. Complete autopsies had been performed in 74% (601/816) of cases. The presumed manner of death was natural in 79 % of cases, and an increase in the number of natural cases autopsied per year was noted over the 5-year study period. Diseases of the cardiovascular, respiratory and central nervous systems were responsible for the majority of natural deaths. Infectious diseases were responsible for most deaths in the youngest age group studied (18-29 years). Acute alcohol poisoning was responsible for the deaths of 35 (6%) cases, with an average blood alcohol concentration of 0.38g/100mL in these cases. Eight deaths were drug-/substance related. Waiting times for blood alcohol and toxicology results increased over the 5-year study period. No cause of death was found in 10.6% of cases. Conclusions -The questionnaire and interviewing structure could possibly be improved in order to obtain better pre-autopsy information and to reduce the number of “unnecessary” medicolegal autopsies, thereby reducing the burden of cost on the Forensic Pathology Services. / AFRIKAANSE OPSOMMING: Agtergrond – Die werkslading van die forensiese patoloog en ander personeel van die Forensiese Patologie Dienste word vermeerder deur die verwysing van moontlik onnodige natuurlike gevalle na die Forensiese Patologie Dienste. Die primêre doelwitte van die medies-geregtelike nadoodse ondersoek is beperk tot die bepaling van ‘n oorsaak van dood in vermoedelik onnatuurlike gevalle, en om nalatigheid of kriminele aksies uit te skakel. Doelwit – Om die finale uitkomste van medies-geregtelike nadoodse ondersoeke in “skielike en onverwagte” volwasse sterftes oor ‘n 5-jaar tydperk te bepaal. Metodes – ‘n Observasionele, retrospektiewe, beskrywende studie is uitgevoer. “Skielike en onverwagte” volwasse sterftes wat verwys is na Tygerberg Forensiese Patologie Dienste vanaf 1 Januarie 2001 tot 31 Desember 2005 is hersien. Inligting is versamel vanaf die nadoodse ondersoekverslae, kontemporêre notas en hospitaalnotas. Bevindinge – Agthonderd en sestien volwasse gevalle van skielike en onverwagte sterftes is oor die 5-jaar periode verwys na Tygerberg Forensiese Patologie Dienste. Volledige lykskouings is uitgevoer in 74% (601/816) van die gevalle. Die vermoedelike wyse van die sterfte was natuurlik in 79.04% en ‘n toename in die aantal natuurlike gevalle wat lykskouings ondergaan het, is waargeneem oor die 5-jaar studie tydperk. Siektes van die kardiovaskulêre, respiratoriese en sentrale senuweestelsel was verantwoordelik vir die meerderheid natuurlike sterftes. Infektiewe toestande was verantwoordelik vir die meeste sterftes in die jongste ouderdomsgroep (18-29 jaar) wat bestudeer is. Akute alkoholvergiftiging was verantwoordelik vir die sterftes van 35 (6%) gevalle, met ‘n gemiddelde bloed-alkohol-konsentrasie van 0.38g/100mL in hierdie gevalle. Agt sterftes was dwelm-/middelverwant. Die wagtyd vir bloed-alkohol en toksikologie resultate het vermeerder oof die 5-jaar studie tydperk. Die oorsaak van dood was nie gevind in 10.6% van gevalle. Afleidings – Die vraelys en onderhoud-struktuur kan moontlik verbeter word om sodoende beter inligting te verkry voor die uitvoering van ‘n lykskouing, en om die aantal “onnodige” medies-geregtelike nadoodse ondersoeke te verminder, en sodoende die kostedruk te verminder op die Forensiese Patologie Dienste.

Les canalopathies cardiaques congénitales constituent la principale hypothèse diagnostique dans les cas de mort subite inexpliquée chez les sujets de moins de 35 ans. Notre travail a eu pour objectif demettre au point une stratégie de détection post-mortem des mutations sur les gènes connus pour être impliqués dans les canalopathies cardiaques, applicable en routine, à partir de la principale source d’ADN post-mortem disponible en France à savoir les prélèvements fixés au formol et inclus en paraffine (FFIP). A partir d’une cohorte de 12 cas, deux techniques de détection de variants génétiques ont été évaluées, une technique de criblage par l’analyse des courbes de fusion haute résolution et une technique de génotypage par spectrométrie de masse MALDI-TOF, respectivement sur le gène KCNQ1 et le gène RyR2. Quelle que soit la technique utilisée, il n’est pas possible de s’affranchir du séquençage de type Sanger afin d’explorer les séquences d’intérêts qui n’ont pu être optimisées avec l’une ou l’autre des méthodes à la fois sur les prélèvements congelés et FFIP. L’arrivée des séquenceurs de nouvelles générations ouvrent ainsi de nouvelles perspectives dans ce domaine. / The congenital cardiac channelopathies constitute the principal diagnostic hypothesis in autopsynegative sudden unexplained death concerning people younger than 35 years old. The present study aimed to develop a strategy of mutations detection on known genes implicated in the cardiac channelopathies. This strategy of mutations detection had to be applicable to routine and has been studied on formalin-fixed and paraffin-embedded (FFPE) tissues which are the principal DNA source available in France. On a cohort of 12 cases, two technique of sequence variants detection wereevaluated: the screening method of High Resolution Melt and the genotyping method based on a MALDI-TOF mass spectrometry, respectively on KCNQ1 and RyR2 genes. Whatever the technique, there is a necessity of resorting to the Sanger sequencing to explore the sequence of interest none optimized with one or the other technology both on FFEP and frozen tissues. That’s why the next generation sequencing method should open new perspectives in the post-mortem diagnostic of cardiac channelopathies.

No description available.