Objetivo: Determinar la sensibilidad, especificidad, valor predictivo positivo y negativo del TEST de ADA en el diagnostico de Meningoencefalitis tuberculosa (MEC-TB) en pacientes de ambos sexos infectados con el VIH, hospitalizados en los pabellones de Medicina Interna del Hospital Nacional Arzobispo Loayza (HNAL). Periodo Enero-Diciembre 2006. Material y Métodos: Se realizó un estudio Transversal donde se revisó 201 historias clínicas de pacientes con VIH/SIDA hospitalizados durante Enero-Diciembre 2006. Solo 48 cumplieron los criterios de selección. Resultados: 29 casos fueron varones (60.4%) y 19 mujeres (39.5%). El rango de edades donde se concentro la mayor proporción de casos fue de 26 a 35 años (39.5%). Se encontró Meningitis Tuberculosa en 16 casos (33.3%), Meningocriptococosis 20 casos (41.6%), Toxoplasmosis cerebral 6 casos (12.5%), MEC viral 4 casos (10.4%), y un proceso neoplásico. La prevalencia de MEC-TB fue de 33.3%. Así también la Sensibilidad fue de 93.8 (71.7- 98.9), la especificidad de 71.9 (84.5- 59.6) y los valores predictivos positivo y negativo fueron de 62.5 (42.7-78.8) y 95.8 (79.8- 99.3) respectivamente, con un nivel de confianza del 95%. La Curva de ROC dio como punto de corte 6.1U/L con sensibilidad de 93.8% y especificidad de 71.9%, encontrándose un área de 89% bajo la curva. Conclusión: El test de ADA es una prueba confiable para el diagnostico de MEC-TB en pacientes con VIH. / Objective: To determine sensitivity, specificity, positive and negative predictive value of the ADA TEST for the tuberculous Meningoencephalitis (TB-MEC) diagnosis in both sexes patients infected with the HIV, hospitalized at the Internal Medicine pavilions of the “Arzobispo Loayza National Hospital”. January – December 2006. Material and Methods: A Cross-sectional study was made. 201 clinical histories of patients with HIV/AIDS hospitalized during January - December 2006 were reviewed. Only 48 histories fulfilled the selection criteria. Results: 29 cases were men (60.4%) and 19 women (39.5%). The greater proportion of cases was found in the range from 26 to 35 years (39.5%). There was found tuberculous meningitis in 16 cases (33.3%), cryptoccocal meningitis in 20 cases (41.6%), cerebral toxoplasmosis in 6 cases (12.5%), viral meningoencephalitis in 4 cases (10.4%), and one neoplasic case. The prevalence of tuberculous meningoencephalitis was 33.3%. The sensitivity was 93,8 (71,7- 98,9), the specificity was 71,9 (84,5- 59,6) and the predictive values positive and negative were 62,5 (42.7-78.8) and 95,8 (79,8- 99,3) respectively, with a 95% of confidence value. The ROC Curve gave a 6.1 U/L as cut point with a sensitivity of 93,8% and a specificity of 71.9%, with an area under the curve of 89%. Conclusion: The ADA test is a reliable test for the diagnosis of tuberculous meningoencephalitis in HIV patients. Key words: sensitivity, specificity, predictive values, ADA test, HIV infection, tuberculosis / Tesis

Made available in DSpace on 2015-04-14T13:35:47Z (GMT). No. of bitstreams: 1 450580.pdf: 16336840 bytes, checksum: eacde9172f8788d4129d99eee0bd7651 (MD5) Previous issue date: 2013-06-26 / Objective: The authors present a study with the use of sodium fluorescein (SF) to enhance skull base meningiomas and perform a quantitative digital analysis of the tumors enhancement. The study intends to observe the grade of cranial base meningiomas enhancement by SF. Methods: A prospective within-subjects study was performed including twelve patients with skull base meningiomas. Digital pictures were obtained before and after the SF systemic injection, using the same light-source of the microsurgical field. The pictures were analyzed by Image Pro Plus 4.5.1 software, which calculated the wavelength of the sodium fluorescein pre and post injection. Results: The group of meningiomas was composed as it follows: one cavernous sinus, one olfactory groove, three petroclival, one tuberculum sellae, three sphnoid wing, one anterior clinoid and two temporal floor. The SF enhancement in all tumors was strongly positive. The digital analysis of the pictures, considering the SF wavelength pre and post injection, presented p=0.002 (Wilcoxon T test). Conclusions: The enhancement of the skull base meningiomas by SF was consistent. The introductory results suggest the possibility of using SF as an adjuvant tool for the skull base meningioma surgery. Further studies should test the clinical application of the SF in skull base tumors. / Objetivo: Apresenta-se o primeiro estudo com o uso de Fluoresce?na S?dica (FS) para contrastar meningeomas localizados na base do cr?nio e realiza-se uma an?lise quantitativa digital do contraste tumoral. O estudo tem por objetivo observar o grau de capta??o de FS pelos meningeomas da base do cr?nio. M?todos: Estudo descritivo com observa??o intragrupo (antes e depois), incluindo 12 pacientes com les?es da base do cr?nio. Fotografias digitais foram realizadas antes e ap?s a administra??o sist?mica de FS, utilizando-se a mesma fonte de ilumina??o do campo microcir?rgico. As fotografias pr? e p?s-inje??o de FS foram analisadas usando-se o software Image Pro Plus 4.5.1, que calculou o comprimento de onda da FS nas respectivas imagens. Resultados: O grupo de meningeomas foi distribu?do topograficamente da seguinte forma: um do seio cavernoso, um da goteira olfat?ria, tr?s petroclivais, um do tub?rculo selar, tr?s da asa do esfen?ide,um da clin?ide anterior e dois do assoalho temporal. O contraste dos tumores pela FS foi fortemente positivo. A an?lise digital das fotografias, considerando a presen?a do comprimento de onda da FS nas imagens obtidas pr? e p?s-inje??o de FS, apresentou uma diferen?a significativa, com p=0,002 (Teste T de Wilcoxon). Conclus?es: A capta??o da FS pelos meningeomas foi consistente. Os resultados introdut?rios sugerem a possibilidade de uso da FS como uma ferramenta adjuvante para a cirurgia dos meningeomas de base de cr?nio. Estudos complementares s?o necess?rios para definir aplica??o cl?nica da FS em tumores da base do cr?nio.

Made available in DSpace on 2015-05-14T16:53:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-11-26Bitstream added on 2015-05-14T16:59:12Z : No. of bitstreams: 1 000829044.pdf: 414488 bytes, checksum: 9ccb90602e34bd027befe2e9c3a9d742 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Introdução: O câncer é doença caracterizada por desvio dos mecanismos de controle que regulam a sobrevida, proliferação e diferenciação de células. A cirurgia, quimioterapia e a radioterapia são os tratamentos utilizados em pacientes oncológicos. Agentes quimioterápicos como o metotrexate (MTX) são considerados antineoplásicos efetivos. Ele pertence à classe dos antimetabólitos que atuam sobre o metabolismo intermediário das células em proliferação. Por ser cada vez mais utilizado nos protocolos de tratamento de câncer, e com doses progressivamente maiores, a ocorrência de toxicidade do tecido nervoso central pelo MTX está aumentada. O mecanismo exato desencadeador de neurotoxicidade não foi elucidado. A manifestação clínica da neurotoxicidade após sua administração pela via subaracnóidea é a aracnoidite química e ocorre em aproximadamente 50% dos pacientes. Relatos de casos associaram-no também a síndrome da cauda equina. Objetivo: Avaliar os efeitos que doses múltiplas de MTX administradas pela via subaracnoidea determinam sobre a medula espinal e as meninges de coelhos. Método: Trinta coelhos adultos jovens, machos, da raça Grupo Genético de Botucatu, pesando entre 3000 g e 3900 g, comprimento de coluna vertebral entre 36 e 40 cm e superfície corpórea entre 0,19 e 0,22 m2 foram divididos, por sorteio, em três grupos (G): G1, punção subaracnóidea, G2, solução fisiológica e G3, MTX. Após anestesia venosa com xilaziana e cetamina foi realizada a punção subaracnoidea em S1-S2 e injetada a solução sorteada no G2 e G3. Os animais de G3 receberam MTX em volume correspondente a 12 mg.m2 de superfície corpórea (0,1mL), os de G2 igual volume de solução fisiológica e nos de G1 foi realizada somente punção subaracnóidea. Este procedimento foi repetido quatro vezes em intervalos de 7 dias. Os animais foram avaliados clinicamente quanto à sensibilidade e motricidade por 21 dias e após ... / Background: Cancer is a disease characterized by deviation of control mechanisms that regulate the survival, proliferation and differentiation of cells. Surgery, chemotherapy and radiotherapy are treatments used in oncology patients. Chemotherapeutic agents such as methotrexate (MTX) are considered effective antineoplastic agents. MTX belongs to the class of antimetabolites that act on the intermediary metabolism of cells on proliferation. For being increasingly used in cancer treatment protocols with progressively larger doses, the occurrence of central nervous tissue toxicity by MTX is increasing. The exact mechanism for triggering neurotoxicity has not been elucidated. The most common clinical manifestation of neurotoxicity after MTX administration is chemical aracnoiditis. Cases of cauda equina syndrome were also described. Objectives: To evaluate the effects of multiple subarachnoid doses of MTX over spinal cord and meninges of rabbits. Method: Thirty male young adults rabbits, breed genetic Group Botucatu, weighing between 3000 and 3900 g, with spinal length between 36 and 40 cm, and corporeal surface area between 0.22 and 0.19 m2 were divided by lot into three groups (G): G1, subarachnoid puncture; G2, saline solution; and G3, methotrexate. After intravenous anesthesia with xilaziana and ketamine, subarachnoid puncture was performed in S1-S2. Solution ion was performed inject in G2 and G3. G3 animals received MTX volume corresponding to 12 mg. m2 (0.1 mL); in G2, an equal volume of saline solution, was administered G1 only subarachnoid puncture was performed in S1- S2 intervertebral space. Solution injection was performed in G2 and G3. G3 animals received intrathecal MTX volume corresponded to 12mg.m2 (0.1 ml); in G2, an equal volume of saline solution was administered, while in G1 only subarachnoid puncture was performed. The same procedure was repeated four times at 7 days interval. Animals ... / FAPESP: 2011/02291-7

Orientador: Eliana Marisa Ganem / Coorientador: Lais Helena Navarro e Lima / Banca: Guilherme Antonio Moreira de Barros / Banca: Geraldo Rolim Rodrigues Junior / Banca: Giane Makamura / Banca: Eneida Maria Vieira / Resumo: Introdução: O câncer é doença caracterizada por desvio dos mecanismos de controle que regulam a sobrevida, proliferação e diferenciação de células. A cirurgia, quimioterapia e a radioterapia são os tratamentos utilizados em pacientes oncológicos. Agentes quimioterápicos como o metotrexate (MTX) são considerados antineoplásicos efetivos. Ele pertence à classe dos antimetabólitos que atuam sobre o metabolismo intermediário das células em proliferação. Por ser cada vez mais utilizado nos protocolos de tratamento de câncer, e com doses progressivamente maiores, a ocorrência de toxicidade do tecido nervoso central pelo MTX está aumentada. O mecanismo exato desencadeador de neurotoxicidade não foi elucidado. A manifestação clínica da neurotoxicidade após sua administração pela via subaracnóidea é a aracnoidite química e ocorre em aproximadamente 50% dos pacientes. Relatos de casos associaram-no também a síndrome da cauda equina. Objetivo: Avaliar os efeitos que doses múltiplas de MTX administradas pela via subaracnoidea determinam sobre a medula espinal e as meninges de coelhos. Método: Trinta coelhos adultos jovens, machos, da raça Grupo Genético de Botucatu, pesando entre 3000 g e 3900 g, comprimento de coluna vertebral entre 36 e 40 cm e superfície corpórea entre 0,19 e 0,22 m2 foram divididos, por sorteio, em três grupos (G): G1, punção subaracnóidea, G2, solução fisiológica e G3, MTX. Após anestesia venosa com xilaziana e cetamina foi realizada a punção subaracnoidea em S1-S2 e injetada a solução sorteada no G2 e G3. Os animais de G3 receberam MTX em volume correspondente a 12 mg.m2 de superfície corpórea (0,1mL), os de G2 igual volume de solução fisiológica e nos de G1 foi realizada somente punção subaracnóidea. Este procedimento foi repetido quatro vezes em intervalos de 7 dias. Os animais foram avaliados clinicamente quanto à sensibilidade e motricidade por 21 dias e após ... / Abstract: Background: Cancer is a disease characterized by deviation of control mechanisms that regulate the survival, proliferation and differentiation of cells. Surgery, chemotherapy and radiotherapy are treatments used in oncology patients. Chemotherapeutic agents such as methotrexate (MTX) are considered effective antineoplastic agents. MTX belongs to the class of antimetabolites that act on the intermediary metabolism of cells on proliferation. For being increasingly used in cancer treatment protocols with progressively larger doses, the occurrence of central nervous tissue toxicity by MTX is increasing. The exact mechanism for triggering neurotoxicity has not been elucidated. The most common clinical manifestation of neurotoxicity after MTX administration is chemical aracnoiditis. Cases of cauda equina syndrome were also described. Objectives: To evaluate the effects of multiple subarachnoid doses of MTX over spinal cord and meninges of rabbits. Method: Thirty male young adults rabbits, breed genetic Group Botucatu, weighing between 3000 and 3900 g, with spinal length between 36 and 40 cm, and corporeal surface area between 0.22 and 0.19 m2 were divided by lot into three groups (G): G1, subarachnoid puncture; G2, saline solution; and G3, methotrexate. After intravenous anesthesia with xilaziana and ketamine, subarachnoid puncture was performed in S1-S2. Solution ion was performed inject in G2 and G3. G3 animals received MTX volume corresponding to 12 mg. m2 (0.1 mL); in G2, an equal volume of saline solution, was administered G1 only subarachnoid puncture was performed in S1- S2 intervertebral space. Solution injection was performed in G2 and G3. G3 animals received intrathecal MTX volume corresponded to 12mg.m2 (0.1 ml); in G2, an equal volume of saline solution was administered, while in G1 only subarachnoid puncture was performed. The same procedure was repeated four times at 7 days interval. Animals ... / Doutor

Une réduction de l'inhibition segmentaire contribue vraisemblablement à l'hypersensibilité douloureuse persistante – qui se manifeste par l'hyperalgie, l'allodynie, et la douleur spontanée – au cours d'états douloureux chroniques. L'association fréquente d'une allodynie avec la migraine – une céphalée épisodique – suggère qu'une perte de l'inhibition synaptique contribue aussi à la manifestation de la douleur migraineuse. Cependant, la grande prévalence de la migraine – plus de 10% de la population générale – soulève la question de savoir si le traitement des informations méningées par le réseau neuronal – associant interneurones excitateurs et inhibiteurs – dans le complexe trigéminal, premier relais sur les voies nociceptives de la face et des méninges, est le même que celui des autres informations, par exemple cutanées. Nous avons caractérisé l'effet du blocage pharmacologique des récepteurs à la glycine (GlyR) et des récepteurs GABAA (GABAAR) sur la transmission synaptique entre fibres afférentes primaires, cutanées ou méningées, et neurones de second ordre en enregistrant des potentiels de champ dans le sous-noyau caudal superficiel (Sp5C). Une stimulation électrique transcutanée évoque trois potentiels de champ négatifs dus à l'activation, du plus précoce au plus tardif, de fibres afférentes primaires de type Aβ, Aδ et C. Bloquer les GlyRs et/ou GABAARs segmentaires facilite les potentiels de champ polysynaptiques excitateurs évoqués par l'activation des fibres afférentes primaires de type A et, au contraire, inhibe, ou même abolit, les potentiels de champ C. Bloquer les récepteurs GABAB (GABABR) segmentaires prévient cette suppression. Il est intéressant de noter que bloquer les GABABRs, potentialise aussi les potentiels de champ C en condition controle. Une stimulation électrique méningée évoque deux potentiels de champ négatifs dus à l'activation, du plus précoce au plus tardif, des fibres afférentes primaires de type Aδ et C. Au contraire du potentiel de champ C cutané, le potentiel de champ C méningé est potentialisé après blocage des GlyRs et/ou GABAARs segmentaires. Ces résultats démontrent que le traitement des informations cutanées et méningées par le Sp5C est différent. Seule l'activation des fibres afférentes primaires cutanées de type A inhibe les inputs cutanés de type C vers le Sp5C par l'intermédiaire d'un circuit polysynaptique excitateur, d'interneurones GABAergiques de dernier ordre et de GABABRs présynaptiques. La théorie du "gate control" postule que l'activité des afférences non-nociceptives ferme la porte à la transmission des inputs nociceptifs vers les centres supérieurs. Nos résultats suggèrent que l'état de la porte dépend de l'activité non seulement dans les fibres afférentes primaires de type A mais aussi dans les circuits polysynaptiques excitateurs de la corne dorsale. / Pathological disruption of segmental inhibition is thought to contribute to persistent pain hypersensitivity – including hyperalgesia, allodynia and spontaneous pain – that occurs during chronic pain states. That allodynia is also often associated with migraine – an episodic headache – suggests that a loss of synaptic inhibition is also involved in the manifestation of headache pain. However, the very high prevalence of migraine – more than 10% of the general population – raises the question as to whether processing of meningeous inputs by local neuronal network – consisting of excitatory and inhibitory interneurons – within the trigeminal nucleus, the first relay station for incoming nociceptive signals of the face and meninges, is the same as that of others, for instance cutaneous. We sought to characterize how pharmacological blockade of glycine and GABAA receptors modifies synaptic transmission between either cutaneous or meningeous primary afferent fibers and second order neurons by recording field potentials in the rat superficial medullary dorsal horn (MDH). Transcutaneous electrical stimulation evokes three negative field potentials elicited by, from the earliest to the latest, Aβ-, Aδ- and C-fiber primary afferents. Blocking segmental glycine and/or GABAA receptors strongly facilitates A-fiber-activated polysynaptic excitatory field potentials but, conversely, inhibits, or even abolishes, C-fiber field potentials. Blocking segmental GABAB receptors reverses such suppression. Interestingly, it also potentiates C-fiber field potentials under control conditions. Meningeous electrical stimulation evokes two negative field potentials elicited by, from the earliest to the latest, Aδ- and C-fiber primary afferents. Unlike cutaneous C-fiber field potentials, meningeous ones are facilitated by blocking segmental glycine and/or GABAA receptors. These results demonstrate that MDH processing of cutaneous and meningeous inputs are different. Only activation of cutaneous A-fiber primary afferents inhibits cutaneous C-fiber inputs to the MDH by the way of polysynaptic excitatory pathways, last-order GABAergic interneurons and presynaptic GABAB receptors. In view of the gate control theory postulating that afferent volleys in non-nociceptive afferents close the gate to central transmission of nociceptive inputs, our results suggest that the state of the gate depends on firing activities of both A-fiber primary afferents and polysynaptic excitatory circuits, i.e. the inhibitory tone, within the dorsal horn.

Made available in DSpace on 2014-07-29T15:07:54Z (GMT). No. of bitstreams: 1 dissertacao Filipe ciencia Animal - Clinica e Cirurgia Animal.pdf: 1546193 bytes, checksum: 01b61544014ff3cebd3f43ddb04b8408 (MD5) Previous issue date: 2009-01-30 / The adhesions formation after surgical procedures in the spine is a subject well studied in neurosurgery, according to the discomfort and postoperative pain suffered by patients. Several studies have been performed using anti-inflammatories, autologous grafts, xenografts and xenologer biomaterials and even in film form and gel with the aim of reducing or preventing adhesion formation. The aim of this study was to compare the film based on chitosan with autogenous fat in preventing dural adhesions in rabbits. This technique was compared to the technique used routinely by neurosurgeons who, in most cases, using autogenous fat. We used 24 adult male rabbits of New Zealand, and 15 and 30 days postoperatively (PO) the spinal cords of animals underwent myelography and histological evaluation. The animals were randomly divided equally into two groups (group G and Q), and further subdivided into four subgroups: G15, Q15, G30 and Q30 according to time points and the material used. In the group Q, a laminectomy performed between L1-L2 was occluded with the film based on chitosan and in the Group G the defect was repaired with autogenous free fat graft. In assessing myelography, there was a moderate compression of the column spinal cord both in group G as in group Q. In two rabbits of group Q the compression was attributed to severe disruption of the stabilization made with surgical steel wire. There was no significant difference (p ≤ 0.05) between groups and subgroups. After the pre-established postoperatively, fibrous adhesion from mild to intense between the dura and the implant was noted in animals from both groups, with fibrosis and collagen fibers interspread with the tissue and implant withought, no statistically significant difference (p ≤ 0.05) between groups and subgroups. There were cell infiltrates and giant cells that were more intense in the group Q. At 15 and 30 days postoperatively, the films based on chitosan were coated by inflammatory cells with areas of central necrosis. At 30 days postoperatively, the material had a fibrous capsule surrounding the inflammatory focus and the implant was noticed statistically significant (p ≤ 0.05) of 5% when comparing the groups and subgroups. Based on the results we can conclude that the film based on chitosan, as well as a free autogenous fat reduces the extent of dural adhesions in rabbits, however, the film based on chitosan as well as any foreign body, induces crhonic and intenses inflammatory responses in the rabbit / A formação de aderências após procedimentos cirúrgicos na coluna vertebral é um tema bastante estudado na neurocirurgia, em função do desconforto e dores pós-operatórias sofridas pelos pacientes operados. Diversos estudos já foram realizados utilizando antiinflamatórios, enxertos autólogos, heterólogos e xenólogos e ainda biomateriais na forma de filme e gel com a finalidade de reduzir ou prevenir a formação de aderências. O objetivo deste estudo foi comparar o filme à base de quitosana com a gordura autógena na prevenção de aderências durais em coelhos. Tal técnica foi comparada à técnica realizada rotineiramente pelos neurocirurgiões que, na maioria dos casos, utilizam a gordura autógena. Foram utilizados 24 coelhos da raça Nova Zelândia, machos, adultos, e após 15 e 30 dias de pós-operatório (PO) as medulas espinhais dos animais foram submetidas à avaliação mielográfica e histológica. Os animais foram distribuídos aleatoriamente em dois grupos (grupo G e grupo Q) de igual número, sendo posteriormente subdivididos nos subgrupos G15,Q15, G30 e Q30 de acordo com os momentos de avaliação e o material utilizado. Nos animais do grupo Q, a laminectomia realizada entre L1-L2 foi ocluida com o filme à base de quitosana e no grupo G o defeito foi reparado com enxerto de gordura autógena livre. Na avaliação mielográfica, foi observada compressão moderada na coluna dorsal da medula espinhal tanto nos animais do grupo G quanto nos animais do grupo Q. Em dois coelhos do grupo Q ocorreu compressão grave atribuída à ruptura da estabilização feita com fio de aço cirúrgico. Não foi observada diferença significativa (p≤0,05) entre os grupos e subgrupos. Decorridos os períodos pré-estabelecidos de PO, foi notado nos animais de ambos os grupos, aderência fibrosa de leve a intensa entre a dura-máter e o implante, com fibrose e fibras colágenas entremeadas ao tecido conjuntivo e implante, sem diferença estatística significativa (p≤0,05) entre os grupos e subgrupos. Verificou-se infiltrados celulares e células gigantes, sendo este achado mais intenso nos animais do grupo Q. Aos 15 e 30 dias de PO, os filmes à base de quitosana encontravam-se revestidos por células inflamatórias com áreas de necrose central. Aos 30 dias de PO, o material apresentava cápsula fibrosa circundando o foco inflamatório e o implante, tendo sido notada diferença estatística significância (p≤0,05) de 5%, quando comparados os grupos e os subgrupos entre si. Com base nos resultados pode-se concluir que o filme à base de quitosana, assim como a gordura autógena livre reduz a extensão das aderências durais em coelhos, porém, o filme à base de quitosana assim como todo corpo estranho, induz respostas inflamatórias tissulares crônicas e intensas no coelho

Indiana University-Purdue University Indianapolis (IUPUI) / Retinoids play an important role in tissue patterning during development as well as in epithelial formation and health. In the mammalian central nervous system, the meninges are a source of retinoids for brain tissue. Retinoid production has been described in juvenile Axolotl ependymal cells. Retinoid effects may possess a significant role in the regeneration-permissive interaction of the meninges and ependyma of the Axolotl spinal cord after penetrating injury. During spinal cord regeneration in urodele amphibians, the pattern of retinoid production changes as the meninges interact with the injury-reactive ependymal cells reconstructing the injured spinal cord. In order to determine which components of the retinoid metabolism and intracellular signaling pathway act in Urodele spinal cord regeneration, we employed antibody/horseradish peroxidase staining of both intact and regenerating Axolotl spinal cord tissues obtained from adult animals as well as cell culture techniques to determine expression of three retinoid pathway components: Cellular Retinoic Acid Binding Protein II (CRABP 2), Cellular Retinol Binding Protein I (CRBP 1), and Retinaldehyde Dehydrogenase II (RALDH 2). Current results demonstrate the following in the intact cord: 1) CRBP 1 is expressed in the pia and dura mater meningeal layers, in gray matter neurons (including their axonal processes), and the ependymal cell radial processes that produce the glia limitans, 2) CRABP 2 is expressed in the arachnoid and/or dura mater meningeal layers surrounding the spinal cord, and 3) RALDH 2 is expressed in the meninges as well as cytoplasm of grey matter neurons and some ependymal/sub-ependymal cells. In the regenerating cord, CRBP 1 is expressed in ependymal cells that are undergoing epithelial-to-mesenchymal transition (EMT), as is CRABP 2. RALDH 2 staining is very strong in the reactive meninges; in addition, expression is also upregulated in the cytoplasmic and perinuclear regions of reactive grey matter neurons, including motor neurons and in the apical region of ependymal. Preliminary studies culturing reactive meninges and ependymal cells together suggested that the meninges could drive re-epithelialization of the reactive ependymal cells. Experiments to characterize this interaction show an unusual proliferation pattern: Proliferating Cell Nuclear Antigen (PCNA) labeling is present in intact and regenerating cord ependymal cells. However, in culture, the presence of meninges results in no proliferation proximal to the explant, but extensive proliferation in leading cell outgrowth; also, the cultured meninges is positive for RALDH2. In summary, the intact adult cord shows meningeal production of RA, which is upregulated following injury; in addition, during this time, RA production is upregulated in the adult ependymal cells as well. In culture, the reactive meninges appears to modulate the behavior of reactive ependymal cells.

T cells infiltrate the degenerating brain and influence central nervous system (CNS) inflammation and neuronal health. In mice, the choroid plexus and the meninges have been implicated in regulating T cell entry and egress from the CNS, respectively. Further, antigen presenting cells in the mouse meninges present CNS-derived antigens to T cells and may represent a method for the peripheral immune system to sense and respond to CNS immune triggers. However, whether these processes occur in the human choroid plexus and meninges has not been comprehensively studied. Further, the antigens towards which T cells in the degenerating human brain and its borders respond remain unknown. Therefore, I implemented a multi-omics approach using fresh postmortem tissue from patients diagnosed with amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and non-neurodegenerative controls to identify not only the T cell-associated changes that occur in the degenerating human CNS and surrounding tissues but also identified a library of putative antigen targets for disease-associated T cell populations. Specifically, using single cell RNA and TCR sequencing information from paired postmortem choroid plexus, leptomeninges, and brain I lineage traced T cells using their TCR information and found that T cell access to leptomeninges and brain is likely limited and controlled by anti-inflammatory macrophage activity at the blood/CSF barrier (BCSFB). Once past the BCSFB, I present evidence that T cells access the CNS where they interact with MHC expressed by microglia. T cells also accumulate in the leptomeninges where they become tissue resident memory T cells. These tissue resident memory T cells likely serve as a reservoir for a rapid antigen-driven immune response to future CNS inflammatory insults. Finally, by performing immunopeptidomics to identify peptides presented by MHC in the same patients’ CNS and border tissues, I identified a library of putative antigenic triggers that may drive high levels of T cell clonal expansion in the brain and surrounding tissues. Altogether, this thesis serves as a resource for understanding the trajectory of T cells as they travel into the degenerating human brain and as a foundation for the development of antigen-specific precision medicines to treat neurodegeneration.