Marginal zone B-cell lymphomas (MZBL) constitute 7% of all non-Hodgkin lymphomas, being the third most common subtype after diffuse large B-cell lymphoma(DLBCL) and follicular lymphoma. Extranodal MZBL (ENMZBL) most commonly arise from the mucosa-associated lymphoid tissue (MALT lymphoma), with stomach being the most common site. ENMZBL involving the dura is anatomically unusual and very rare. A 54 year old female presented to the hospital with worsening headaches and new onset generalized tonic clonic seizures. Complete blood counts and chemistry were unremarkable. No constitutional symptoms, new / progressive lymphadenopathy reported. Magnetic resonance Imaging( MRI) brain showed an enhancing right subdural soft tissue lesion overlying the right frontotemporal lobe suggestive of meningioma versus metastasis. Computed Tomography (CT) chest/abdomen/pelvis revealed no mass or lymphadenopathy. Lumbar Puncture cerebrospinal fluid cytology was negative for malignancy. She underwent brain biopsy. Pathology revealed diffuse infiltrate of small to medium-sized lymphoid cells, Immunohistochemical stains positive for CD 20, PAX5, CD 79a, Ki-67 at 5-10%, weakly positive for MUM1 and BCL2, negative for CD3, CD5, CD10, BCL6, cyclin D1, consistent with ENMZBL. Bone marrow biopsy and aspiration negative for involvement with lymphoma. Patient received local/regional therapy with radiation (XRT), total dose 24 Gy in 12 fractions. She presented six months later with worsening neck pain. MRI cervical spine revealed diffuse thick dural based enhancement within the spinal canal at C1-C4 levels leading to moderate-to-severe spinal canal stenosis at C2-C3 level with significant soft tissue extension. Repeat labs, systemic imaging, and bone marrow biopsy continued to show no evidence of systemic disease. She received low dose XRT to the entire craniospinal axis (dose-4Gy). Patient developed profound pancytopenia secondary to craniospinal XRT. After count recovery she initiated daily oral Ibrutinib (560 mg) with plans for a treatment duration of one year. Dural based ENMZL usually present as solitary masses, mimicking meningioma's. Marked female predilection is seen with median age of onset 50 years. Very few cases have been reported in literature with no standard therapy being described. ENMZL are usually indolent requiring less aggressive therapy. In contrast, primary CNS lymphoma (PCNSL) of diffuse large B cell histology is usually aggressive with high tendency to relapse, requiring treatment with high dose methotrexate based regimes. Dural based ENMZL therapy entails local treatments such as surgery and radiation therapy (relatively low dose radiation usually effective with prolonged durable responses). Systemic treatment with single agent Rituximab or with Tyrosine Kinase inhibitors like Ibrutinib with CNS penetration can also be considered. Long-term follow-up is recommended even in those patients who achieved complete remission as relapses may occur.

BACKGROUND:Migraine headache is one of the most common neurological disorders, but the pathophysiology contributing to migraine is poorly understood. Intracranial interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges and contribute to the development of headache.METHODS:Cutaneous allodynia was measured in rats following stimulation of the dura with IL-6 alone or in combination with the MEK inhibitor, U0126. The number of action potentials and latency to the first action potential peak in response to a ramp current stimulus as well as current threshold were measured in retrogradely-labeled dural afferents using patch-clamp electrophysiology. These recordings were performed in the presence of IL-6 alone or in combination with U0126. Association between ERK1 and Nav1.7 following IL-6 treatment was also measured by co-immunoprecipitation.RESULTS:Here we report that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia. The MEK inhibitor U0126 blocked IL-6-induced allodynia indicating that IL-6 produced this behavioral effect through the MAP kinase pathway. In trigeminal neurons retrogradely labeled from the dura, IL-6 application decreased the current threshold for action potential firing. In response to a ramp current stimulus, cells treated with IL-6 showed an increase in the numbers of action potentials and a decrease in latency to the first spike, an effect consistent with phosphorylation of the sodium channel Nav1.7. Pretreatment with U0126 reversed hyperexcitability following IL-6 treatment. Moreover, co-immunoprecipitation experiments demonstrated an increased association between ERK1 and Nav1.7 following IL-6 treatment.CONCLUSIONS:Our results indicate that IL-6 enhances the excitability of dural afferents likely via ERK-mediated modulation of Nav1.7 and these responses contribute to migraine-related pain behavior in vivo. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine headache.

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This dissertation will present the four manuscripts I published or am ready to publish on the study of the pathophysiology of migraine headache. The first chapter will discuss the background of the current understanding of migraine pathophysiology. Chapter 2 is focused on studying how Transient receptor potential vanilloid 4 (TRPV4) might play a role in migraine headache. Chapter 3 is the study of a novel cell type: dural fibroblasts might also play an active role in migraine headache. Chapter 4 is discussing Norepinephrine's role in headache pathophysiology. Chapter 5 is studying the combined effect of Acid and ATP in the pathophysiology of migraine headache. The dissertation will end in a conclusion in Chapter 6.

Orientador: Rui Seabra Ferreira Júnior / Resumo: Terapias efetivas de lesões na dura-máter representam um enorme desafio à medicina, devido à dificuldade de suturas com êxito e de vedação das meninges, aumentando os índices de mortalidade e morbidade destes pacientes. Biomateriais que possam favorecer a regeneração e impedir o extravasamento de líquido cefalorraquidiano sem produzir efeitos adversos são alvos da indústria farmacêutica. Este estudo avaliou a biocompatibilidade do Biopolimero de Fibrina (BPF) derivado de peçonha de serpente como arcabouço tridimensional para células-tronco mesenquimais (CTMs) em lesões na dura-máter de ratos wistar (Rattus norvegicus). As CTMs foram caracterizadas na quinta passagem por citometria de fluxo (ICAM, CD90, CD34, CD45, CD11b) e diferenciadas em linhagens osteogênica e adipogênica. Foram utilizados 4 grupos (n=20) de ratos Wistar machos adultos. O grupo C (controle) foi submetido à durotomia. Os grupos tratados foram submetidos à durotomia seguido de: Tratamento com Biopolimero de fibrina (BPF); células-tronco mesenquimais (CTMs); e BPF+CTMs, formado pela associação do Biopolimero de fibrina e células-tronco mesenquimais. As CTMs marcadas e associadas ao BPF foram avaliadas por imageamento da fluorescência in vivo. Os animais foram avaliados neurológica e clinicamente quanto à sensibilidade dolorosa, deiscência de pontos, infecção da ferida, consumo de alimento e água e habilidades motoras. Foram realizadas eutanásias dos animais aos 7 e 28 dias após cirurgia e coletado material pa... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Effective therapies to treat dura mater injuries represents a major challenge to medicine due to its lack of sutures with high seal properties upon meninges, increasing the rate of mortality and morbidity among these patients. Biomaterials that promotes regeneration and prevent extravasation of cerebrospinal fluid, without producing adverse effects, are targets of the pharmaceutical industry. The present study aimed to evaluate the biocompatibility of the use on Fibrin Biopolymer (FBP) derived from snake venom as tridimensional scaffold to mesenchymal stem cells (MSC) on rat’s dura mater injury. Mesenchymal stem cells characterization was performed at fifth passage by flow cytometry (ICAM, CD90, CD34, CD45, CD11b) and differentiated into osteogenic and adipogenic lineages. Four groups (n=20) os male Wistar rats were used. Group C (control) animals were submitted to durotomy only. Treatment groups were submitted to durotomy followed by: Fibrin Biopolymer (FBP); mesenchymal stem cells (MSC); and FBP+MSCs, consisting on the association between fibrin biopolymer and mesenchymal stem cells. Marked MSCs associated to FBP were evaluated through in vivo fluorescence imaging. Animals were evaluated neurologically and clinically regarding pain sensitivity, dehiscence of suture, wound infection, feeding e motor capacity parameters. Animals were euthanized at seven and 28 days after surgical procedure, and biological material was collected to histological and proteomic analysis. Protein ... (Complete abstract click electronic access below) / Doutor

Migraine is one of the most common neurological disorders. The pathological conditions that initiate and sensitize afferent pain signaling are poorly understood. The goal of this study is to identify the ion channels and signaling proteins underlying activation and sensitization of meningeal nociceptors.In trigeminal neurons retrogradely labeled from the cranial meninges, approximately 80% responded to a pH 6.0 application with a rapidly activating and desensitizing ASIC-like current. Pharmacological experiments and kinetics analysis demonstrated that dural afferent pH-sensitive currents were mediated via activation of ASIC3. In addition, applications of decreased pH solutions were able to excite these neurons and generate action potentials. In awake animals, application of decreased pH solutions to the dura produced dose-dependent facial and hindpaw allodynia, which was also mediated through activation of ASIC3. Accumulating evidence indicates that meningeal inflammation induced sensitization of dural afferents contributes to migraine headache. We have demonstrated here that in the presence of mast cell mediators, dural afferents showed a decreased pH threshold and increased activity in response to pH stimuli both in vivo and in vitro. These data provide a cellular mechanism by which decreased pH in the meninges directly excites afferent pain-sensing neurons potentially contributing to migraine headache. It also indicates that inflammatory events within the meninges could sensitize afferent pain signaling and result in increased sensitivity of dural afferents.Intracranial Interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges. Here we reported that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia via activation of the ERK signaling pathway. IL-6 application was also able to increase neuronal excitability in a manner consistent with phosphorylation of Nav1.7. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine.These findings are discussed in relation to how activation and sensitization of primary afferent neurons might initiate migraine pain signaling and how the research included in this dissertation relates to the development of new therapeutic strategies for migraine.

Submitted by João Arthur Martins (joao.arthur@ufpe.br) on 2015-04-08T18:36:49Z No. of bitstreams: 2 TESE- Jane.pdf: 6562508 bytes, checksum: 06d9295d462f44e6e1568f8e4761cc13 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) / Made available in DSpace on 2015-04-08T18:36:49Z (GMT). No. of bitstreams: 2 TESE- Jane.pdf: 6562508 bytes, checksum: 06d9295d462f44e6e1568f8e4761cc13 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2012-08-30 / Justificativa e objetivos: Os critérios diagnósticos de cefaleia pós-punção dural (CPPD) estabelecidos pela International Classification of Headache Disorders (ICHD-II, 2004), afirmam que a cefaleia postural aparece até o quinto dia após a punção e desaparece espontaneamente dentro de uma semana, ou até 48 horas após um tampão sangüíneo peridural ser realizado e deve ser acompanhada de pelo menos um dos seguintes sintomas: rigidez de nuca, zumbido, hipoacusia, fotofobia e náuseas. Neste estudo foram avaliadas as características clínicas da CPPD e a validade desses critérios diagnósticos da (ICHD-II, 2004). Métodos: Durante o período de um ano, foram acompanhados 640 pacientes (332 mulheres e 308 homens), com idade entre 8 e 65 anos, submetidos à punção da duramáter/ aracnoide para raquianestesia, com agulhas tipo Quincke, 25G (n=239) e 27G (n=401). Cefaleia postural, i.e., a dor piora ou surge após o indivíduo sentar-se ou ficar de pé e alivia ou desaparece após deitar-se, foi investigada por um único pesquisador, por meio de visitas diárias aos pacientes e/ou contato telefônico até o sétimo dia após a anestesia. Nos pacientes que apresentaram cefaleia com essas características foram avaliados: (1) o período de latência entre a punção e o aparecimento da cefaleia; (2) a localização e intensidade da dor; (3) a presença de sintoma (s) acompanhante (s); e (4) o tempo de duração. Os procedimentos de estatística descritiva empregados foram medidas de tendência central: média, dispersão (desvio-padrão e amplitude de variação) e distribuição de frequências. O teste do quiquadrado foi aplicado e considerado estatisticamente significativo quando p < 0,05. Este estudo foi aprovado pelo Comitê de Ética em Pesquisa e o consentimento livre e esclarecido foi obtido dos pacientes ou de seus responsáveis legais. Resultados: 48 pacientes (7,5%) apresentaram cefaleia postural. O período de latência variou de 6 a 72 horas (24,0±16,8 horas) e o tempo de duração de 3 a 15 dias (4±2 dias). A dor foi referida nas regiões: occipital em 26 (54%) pacientes, frontal em 19 (40%) e holocraniana em 3 (6%). Em 85% dos pacientes a intensidade da cefaleia, nas primeiras 24 horas, foi moderada ou forte. Um ou mais de um sintoma acompanharam a cefaleia postural em 34 (70,8%) pacientes, em contrapartida 14 (29,2%) não apresentaram sintoma (s) acompanhante (s). Conclusões: Os resultados deste estudo não estão em concordância com os critérios diagnósticos da ICHD-II em dois aspectos: (1) que a cefaleia postural deve ser acompanhada de pelo menos um dos sintomas acompanhantes descritos na classificação; e (2) na resolução espontânea da cefaleia em uma semana. Em raras situações, a CPPD pode persistir além do período estabelecido, desde que 9 Amorim JA Cefaleia pós-punção dural: características clínicas e critérios para o diagnóstico os exames de neuroimagem mostrem ausência de lesão expansiva intracraniana e o exame do líquido cerefalorraquidiano ausência de infecção ou hemorragia. Foram sugeridas algumas modificações nos critérios diagnósticos de CPPD da ICHD-II, 2004.

Reproduction de : Thèse d'exercice : Médecine : Nancy 1 : 2006. / Titre provenant de l'écran-titre.

Reproduction de : Thèse d'exercice : Médecine. Médecine générale : Paris 12 : 2008. / Titre provenant de l'écran-titre. Bibliogr. f. 138-149.

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