Desde hace quince años han sido descritos nuevos casos de encefalitis primitivas esporádicas en Europa Occidental, siendo su clasificación anatomo-clínica uno de los problemas actuales de la neuropatología. Sin embargo, las encefalitis de origen desconocido han sido bien estudiadas desde el punto de vista clínico e histo-patológico y han sido agrupadas por Krucke y Haymaker bajo el nombre encefalitis víricas con inclusiones, aunque en algunas de dichas encefalitis las inclusiones sean raras o inexistentes. Pero, en los últimos años, han sido publicadas formas atípicas de dichas encefalitis, lo cual complica el problema ya difícil de su clasificación, problema que solamente el descubrimiento de su estilogía podrá resolver. Los casos que aquí estudiaremos están próximos a una de las formas del grupo de encefalitis antes mencionadas, a saber, las panencefalitis subagudas progresivas, aunque solamente desde el punto de vista evolutivo e histopatológico con algunas características que le son propias ya que, clínicamente, recuerdan lo que hasta el momento se ha descrito como romboencefalitis o encefalitis del tronco cerebral. Las encefalitis del tronco cerebral constituyen un síndrome clínico y evolutivo característico que describiremos más adelante presentando como particularidad su benignidad, lo que implica una ausencia de documentos anatómicos que ha hecho que, hasta ahora, muy pocos casos anatomo-clínicos hayan sido publicados. Con la aportación de dos observaciones anatomo-clínicas de la Clínica Neurológica del Profesor Garcin (Hospital de la Salpetriére) intentaremos hacer una revisión del concepto de encefalitis del tronco cerebral completándola con una discusión del lugar que podrían ocupar los casos estudiados entre las formas atípicas de las encefalitis primitivas esporádicas actuales. Dedicaremos el primer capítulo de esta tesis a un breve resumen histórico del concepto de encefalitis, haciendo hincapié en las formas bulbo-protuberanciales de las encefalitis víricas epidémicas mejor conocidas hasta ahora. Hemos dedicado especial atención también a las formas subagudas de dichas encefalitis. En el capitulo segundo intentaremos centrar brevemente el problema que hoy constituyen las encefalitis esporádicas actuales, pasando a describir en el capítulo tercero las encefalitis del tronco cerebral, con especial referencia a las principales publicaciones de los casos que han ido perfilando las características de dichas encefalitis. Presentaremos a continuación los casos que hemos aportado, discutiendo en el último capitulo el lugar que ocuparían nuestros casos entre las formas atípicas de las encefalitis esporádicas actuales y terminando en las conclusiones a las que hemos llegado.

Thesis (doctoral)--München, 1983.

Thesis (M.S.)--University of Wisconsin--Madison, 1969. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is a recently described autoimmune encephalopathy defined by the presence of serum antibodies that bind NMDARs (NMDAR-Abs). NMDAR-Ab encephalitis is a severe, but treatmentresponsive encephalitis with subacute onset. It can be associated with tumours and affects mainly young adults. Patients present with cognitive dysfunction, seizures, psychiatric and sleep disorders and most develop dyskinesias, autonomic instability and reduced consciousness. To explore further the NMDAR-Abs and their potential pathogenicity, a series of in vitro investigations were performed and preliminary attempts at passive transfer of disease. Human embryonic kidney (HEK) cells transfected with the NR1 and NR2B subunits, and live cultured neurons, were used first to detect NMDAR-Ab binding. Immunocytochemistry and ow cytometry demonstrated that binding to transfected HEK cells could be improved when NMDAR were presented in clusters by cotransfection with the postsynaptic density protein PSD-95. The NR1 subunit was identified as the target of NMDAR-Abs, and a novel quantitative assay based on immunoprecipitation of NR1 tagged by fusion with green uorescent protein was developed. Measurement of NMDAR-Ab levels showed that antibody levels corresponded to the clinical disease score within individual patients. Although the purification of full length NR1 was not successful, a secreted N-terminal construct was created and expressed in HEK cells. The binding of NMDAR-Abs was confirmed and this construct will be used for active immunisation in future. To explore pathogenic mechanisms in vitro, the main antibody subclasses were shown to be IgG1 and IgG3. Moreover the patients' autoantibodies, but not healthy control antibodies, were able to activate the complement cascade in vitro in cell lines and primary cultures. Finally, the NMDAR-Abs were shown to bind to primary microglial cultures and to cause morphological changes corresponding to early activation processes after prolonged exposure. The research has developed new assays that could be used for diagnosis and serial studies and revealed new potential mechanisms in NMDAR-Ab encephalitis.

Masernvirus (MV) ist ein negativ-strängiges RNA-Virus, das im Menschen und im Nagermodell zu akuten und subakuten Enzephalitiden führen kann. Es wurde beschrieben, dass bestimmte Antikörperescape-Mutanten des MV neurovirulent, andere nicht neurovirulent sind (Liebert et al., 1994). Mit Hilfe von rekombinanten Masernviren, konnte ich diejenigen Aminosäuren charakterisieren, die einerseits für die Bindung monoklonaler, neutralisierender anti-MV-H-Antikörper (K29, K71, Nc32 und L77) und andererseits für die Neurovirulenz verantwortlich sind. Bei den rekombinanten MV wurde das von Duprex et al. (1999) als Neurovirulenz vermittelnd beschriebene H-Gen des nagerhirnadaptierten neurovirulenten CAM/RB-Stammes in das Grundgerüst des nicht neurovirulenten Edtag (molekularer Klon des Vakzinestammes Edm) kloniert. Über gerichtete Mutagenese wurden die jeweiligen Mutationen in dieses CAM/RB H-Gen eingefügt. Mittels der FACS-Analyse konnten die Aminosäureänderungen identifiziert werden, die für die Bindung der jeweiligen Antikörper verantwortlich sind. Sie befinden sich nach einem Strukturmodell der H-Proteine (Langedijk et al., 1997) im Membran-distalen Teil, den so genannten Propellern. Im Einzelnen sind folgende Aminosäureänderungen im Hämagglutinin-Protein für den Escape verantwortlich: L77 – 377 Arg -> Gln und 378 Met -> Lys; Nc32 – 388 Gly -> Ser; K71 – 492 Glu -> Lys und 550 Ser -> Pro; K29 – 535 Glu -> Gly. Es konnte ferner gezeigt werden, dass die beiden Aminosäureveränderungen an den Positionen 195 und 200 gemeinsam für die Neurovirulenz verantwortlich sind und nicht assoziiert sind mit den Mutationen für den Antikörperescape. Der Aminosäureaustausch an Position 200 bei neurovirulenten Viren führt zum Verlust einer benutzten Glykosylierungsstelle. Diese Mutation ist jedoch nicht alleine für das unterschiedliche Neurovirulenzverhalten der Viren verantwortlich, sondern es muss gleichzeitig der Austausch an Position 195 vorhanden sein, der eine positive Ladung im H-Molekül entfernt. Diese beiden Mutationen sind nach dem Strukturmodell nach Langedijk im Stamm2-Bereich angesiedelt. Sind im H-Protein an Stelle 195 und 200 die Aminosäuren Gly und Ser vorhanden, so findet im Gehirn neugeborener Lewis-Ratten eine verstärkte Virusvermehrung und Ausbreitung statt, die die akute Enzephalitis mit Expression typischer proinflammatorischer Zytokine zur Folge hat. Werden an Stelle 195 und 200 die Aminosäuren Arg und Asn exprimiert, so ist der Verlauf der Infektion inapparent. In dieser Arbeit wurde auch ein Zellkultursystem gemischter Hirnzellen neugeborener Lewis-Ratten etabliert, das die Unterschiede der Virusausbreitung in vivo reflektiert und mit dem weitere Untersuchungen zum Mechanismus der Neurovirulenz durchgeführt werden könnten. Anhand der durchgeführten Untersuchungen mit Ratten des CD46 transgenen Lewis-Modells konnte gezeigt werden, dass die Anwesenheit des Rezeptors CD46 das Virulenzverhalten der getesteten Viren nicht beeinflusst. Weder mit dem Vakzinestamm Edm noch mit einem nicht an Nager adaptierten Wildtypstamm, konnte nach intracerebraler Injektion eine akute Enzephalitis induziert werden. Die Untersuchungen zeigen, dass die Neurovirulenz des an Nager-adaptierte MV-Stammes CAM/RB essentiell von den Aminosäuren Gly und Ser an Position 195 und 200 im H-Protein abhängt und nicht durch die transgene Expression zellulärer Rezeptoren für MV vermittelt werden kann. / Measles virus (MV) is a negative stranded RNA-virus, which may lead to acute and subacute encephalitis in men and experimentally also in rodents. It has been described that certain antibody escape mutants of MV are neurovirulent, whereas others are non-virulent (Liebert et al., 1994). Here I determined with the help of recombinant MV the amino acids which are responsible for the binding of neutralizing monoclonal anti MV-H-antibodies (K29, K71, Nc32 and L77) or for neurovirulence of MV. The H-gene of the rodent brain adapted strain CAM/RB which was described for determining neurovirulence by Duprex et al. (1999) was introduced into the non-neurovirulent backbone of Edtag, which is the molecular clone of the vaccine strain Edm. The respective mutations were introduced by site directed mutagenesis. In FACS-analysis I could determine the amino acid changes which are responsible for the binding of the anti H-antibodies. In a structural model for MV-H (Langedijk et al., 1997) this amino acids reside in the membrane distal part of the molecule - the so called propeller. The following amino acid changes in the hemagglutinin protein are responsible for the antibody escape: L77 – 377 Arg -> Gln und 378 Met -> Lys; Nc32 – 388 Gly -> Ser; K71 – 492 Glu -> Lys und 550 Ser -> Pro; K29 – 535 Glu -> Gly. In addition I found that the combined amino acid changes at positions 195 and 200 are responsible for neurovirulence but are not associated with the antibody escape. The amino acid change at position 200 leads to the loss of a used glycosylation site in neurovirulent strains. The mutation at position 200 is not alone responsible for the neurovirulence but requires the second associated mutation at position 195, which deletes an additional positive charge in the H-protein. These two mutations which are responsible for the neurovirulence reside in the stem2 region of the structural model according to Langedijk. If in the H-protein the amino acids at position 195 and 200 are Gly and Ser, the virus multiplication and spread is enhanced in the brain of newborn Lewis-rats and causes an acute encephalitis with expression of typical proinflammatory cytokines. If at position 195 and 200 the amino acids Arg and Asn are present, the infection stays inapparent. I could also establish a cell culture system of mixed primary rat brain cells, which reflects the difference in the viral spread in vivo and which may be to used further to investigate the mechanisms responsible for neurovirulence. Results obtained with CD46 transgenic Lewis-rats showed that the presence of the MV receptor CD46 does not influence the virulence of the tested strains. Neither the vaccine strain nor a wildtype strain not adapted to rodents could induce acute encephalitis after intracerebral injection. These findings suggest that the neurovirulence of the rodent-brain adapted MV-strain CAM/RB depends essentially on amino acids Gly and Ser at positions 195 and 200 in the H-protein, and cannot be mediated by the transgenic expression of cellular receptors for MV.

Thesis advisor: Kenneth Williams / Approximately 15% of individuals infected with Human Immunodeficiency Virus (HIV) develop a neurological condition that consists of motor dysfunction and cognitive deterioration in late stage disease that is known as the AIDS dementia complex (ADC). This condition is mirrored in rhesus macaques infected with Simian Immunodeficiency Virus (SIV), which can be more easily studied. This project analyzed different macrophage populations in rhesus macaques infected and uninfected with SIV at early and terminal stage disease. Single and double immunohistochemistry stains were performed for the known macrophage and microglial markers CD163, CD16, CD68, Mac387, HAM56, and Iba-1, as well as for the SIV-p28 viral protein. Photographs and observations of the tissue stainings demonstrated that early after infection with SIV, there is an increase in perivascular macrophages and monocytes surrounding vessels and tissue edges, and the SIV-p28 protein is already present. There is also an observed change in the morphology of the microglia to an active, ramified state. After the development of AIDS and SIVE, the increase in all of the macrophage markers and the accumulation of activated microglia are clearly visible, especially surrounding and within lesions. Furthermore, these markers can be used to categorize the encephalitic lesions as “new” or “old” based on the presence or absence of Mac387 within the cells. All lesions contained CD68+ and HAM56+ macrophages, but “new” lesions presented with a relatively high count of Mac387+ macrophages that were newly imported from the periphery, whereas “old” lesions lacked Mac387+ cells. / Thesis (BS) — Boston College, 2009. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: College Honors Program. / Discipline: Biology.

Thesis advisor: Kenneth C. Williams / Factors that impact the development of neuroAIDS include monocyte expansion and activation, viral neuroinvasion and replication, and accumulation of activated and infected macrophages in the CNS. To better understand changes in monocyte/macrophage biology associated with the development of SIV encephalitis (SIVE) and neuroAIDS, we: 1) performed gene expression analyses using high density microarrays to characterize the response of monocyte subsets to SIV infection, 2) serially labeled CNS macrophages with fluorescent dextrans by intracranial injection and labeled myeloid progenitors in the bone marrow with BrdU to determine the timing of SIV neuroinvasion and macrophage recruitment/turnover in the CNS, and 3) performed in vitro studies to determine the role of PCNA expression in macrophages with SIV infection. We found the majority of macrophages in SIVE lesions were present in the CNS early in infection and productively infected macrophages were recruited to the CNS terminally with AIDS. We observed differences in the timing of recruitment, rate of turnover, PCNA expression, and productive infection between CD163+ and MAC387+ macrophages in the CNS. SIV infection was associated with induction of interferon stimulated genes in all monocytes, maturation of the intermediate monocyte subset, and increased rate of monocyte/macrophage recruitment to the CNS. Greater ratios of CD163+ to MAC387+ macrophages in the CNS were associated with SIVE. We also found that PCNA expression decreased macrophage apoptosis with SIV infection. Together, these studies suggest that the development of SIVE is a dynamic process and that continuous recruitment of activated monocyte/macrophage and reintroduction of virus from the periphery is required to drive CNS disease. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Foi realizado um estudo epidemiológico da epidemia de encefalite por arbovírus na região do Vale do Ribeira, São Paulo, Brasil, durante o período de março de 1975 a julho de 1978. A epidemia, iniciada em 1975, atingiu o pico em 1976. A partir de 1978 a moléstia se manteve em níveis baixos sob presumível endemicidade. A letalidade nos anos epidêmicos de 1976 e 1977 variou em sentido inverso ao da morbidade, que apresentou picos nas épocas de maior temperatura e pluviosidade. Ao que parece, a epidemia teria se deslocado em onda em direção leste-oeste e leste-sudoeste tendo atingido a região litorânea vizinha. A cadeia montanhosa situada ao norte e noroeste teria atuado como barreira à propagação da moléstia. Considerou-se a hipótese que o agente etiológico, arbovírus Rocio, só recentemente deva ter começado a infectar a população humana, tendo sido veiculado ao homem a partir de reservatórios silvestres, aves e pequenos mamíferos, por culicídeos silvestres. Discutiram-se também prováveis formas de transmissão domiciliar da arbovirose ocorrida em número bem menor de casos. Verificou-se que os grupos populacionais que apresentaram as formas mais graves da doença foram os das idades extremas e os de piores condições de vida. Considerou-se que a perspectiva epidemiológica desta arbovirose é que ela persista na região, uma vez que existem condições ótimas para o desenvolvimento dO agente etiológico, de reservatórios e de vetores biológicos, além do contínuo afluxo de população suscetível, constituída por migrantes ou por turistas. / An epidemiological study of the encephalitis epidemic by arbovirus was carried out in Ribeira River Valley, State of São Paulo, Brazil, from March 1975 to July 1978. The epidemic began in 1975 and reached its peak in 1976. From 1978 onwards the disease maintained low levels in a presurnable endemicity. The lethality of the disease in the epidemic years of 1976 and 1977 varied in the opposite direction of its morbility, which presented peaks when the temperature and pluvial levels were higher. It seems that the epidemic swept from east to west and from east to southwest in a wave towards the neighbouring coastland region. The mountain chain situated towards the north and northwest acted as a barrier to the spreading of the disease. The hypothesis that the etiological agent, arbovirus Rocio, must have infected the human population recently, having been veiculated to man from forest reservoirs, birds and small mammals, by wild mosquitoes, was considered. Probable forms of domiciliar transmission of the arbovirosis which ocurred in a significantly smaller number of cases were also discussed. It was verified that the population groups which presented the worst forms of the disease were those at extreme ages and those under worst living conditions. It was considered that the epidemiological perspective of the arbovirosis is that it ought to persist in the area, as it presents excellent conditions for the development of the etiological agent, reservoirs and biological vectors, besides continuously receiving susceptible people, migrants or tourists.

No description available.

Background: West Nile Virus (WNV) is a serious mosquito-borne disease that can potentially lead to death. The purpose of this study is to spatially examine known risk factors for WNV within Georgia at the county level. The study produces maps that relate known WNV cases to high, medium, and low risk factor areas for additional analyses. Methodology: Cartographic visualization and statistical analysis software was used to examine the relationships between: the geographical distribution of age, race, gender, urbanicity, and population density of Georgians in relation to WNV cases by county. Chi-square analysis and odds rations were calculated to determine whether or not associations of risk and the likelihood of WNV case reports were significant. Results: Gender was found to be significantly associated with the distribution of reported WNV cases. Identification of high risk areas throughout the state was determined through the use of Geographic Information System software. Conclusion: Insights into the visual distribution of WNV risk factors throughout the state of Georgia can assist policy makers and public health planners to optimize resources in WNV transmission and prevention abatement and education efforts. This exploratory study provides a critical first glimpse into the distribution of WNV risk factors throughout the state.