Promoting Regeneration and Functional Recovery following SCI through Transcriptional Regulation

Spinal cord injury (SCI) is a devastating condition due to the permanent neurological deficits it causes, and the abruptness these impairments take place. To date there is no curative therapy for SCI, therefore finding efficient treatment candidates for clinical translation is a compelling need. With the purpose of promoting regeneration and functional recovery after SCI in adult mice, in this work we addressed different but interdependent molecular mechanisms to awake the intrinsic growth machinery of central neurons and to modulate the extrinsic environment within the injury site. It was already known that PCAF also forms a multiprotein complex with CBP/P300 and p53 to drive the transcription of several regeneration associated genes. Thus, our second strategy was to manipulate p53 in order to enhance the p53-dependent regenerative response and improve functional recovery. By disrupting the p53 interaction with its main negative regulators MDM2 or MDM4, either by local Nutlin-3a inhibition or conditional deletion in SMC neurons, respectively, we enhanced p53 transactivation. This led in fact to increased sprouting of descending tracts and improved locomotor behavior of adult mice after SCI without increasing cell death. Furthermore, we showed for the first time that these pro-regenerative effects of p53 are dependent on IGF1 signaling. Nutlin-3a is already under scrutiny in clinical trials for cancer therapy and might be clinically available in the near future. Therefore this work opens an exciting possibility to bring a new candidate for translation in the SCI clinical context

Dor lombar associada à vértebra de transição lombossacra: dificuldades no diagnóstico e manejo da síndrome de Bertolotti

OBJECTIVE: Bertolotti's syndrome is a spine disorder characterized by the occurrence of a congenital lumbar transverse mega-apophysis in a transitional vertebral body that usually articulates with the sacrum or the iliac bone. It has been considered a possible cause of low back pain. METHOD: We analyzed the cases of Bertolotti's syndrome that failed clinical treatment and reviewed the literature concerning this subject. RESULTS: Five patients in our series had severe low back pain due to the neo-articulation and two of them were successfully submitted to surgical resection of the transverse mega-apophysis. Taking into account the clinical and surgical experience acquired with these cases, we propose a diagnostic-therapeutic algorithm. CONCLUSION: There is still no consensus about the most appropriate therapy for Bertolotti's syndrome. In patients in whom the mega-apophysis itself may be the source of back pain, surgical resection may be a safe and effective procedure.OBJETIVO: A síndrome de Bertolotti é uma desordem congênita da coluna vertebral caracterizada pela ocorrência de uma mega-apófise transversa lombar em uma vértebra de aspecto transicional, que geralmente se articula com o sacro ou com o osso ilíaco. Tal síndrome tem sido considerada possível causa de dor lombar. MÉTODO: Análise dos casos de síndrome de Bertolotti que apresentavam dor lombar sem melhora com tratamento conservador e revisão dos artigos publicados. RESULTADOS: Foram revisados cinco pacientes que não apresentaram melhora com o tratamento clínico, sendo que dois foram submetidos à ressecção cirúrgica da mega-apófise transversa. Considerando a experiência adquirida com estes casos, os autores propõem um algoritmo para diagnóstico e tratamento da Síndrome de Bertolotti. CONCLUSÃO: Ainda não há consenso sobre qual é a terapia mais apropriada para a Síndrome de Bertolotti. Em pacientes em que a mega-apófise parece ser a origem da lombalgia, a ressecção cirúrgica parece ser um procedimento seguro e efetivo.Instituto de Neurologia de Curitiba Department of NeurosurgeryUniversidade Federal de São Paulo (UNIFESP) Department of Neurosurgery/NeurologyUNIFESP, Department of Neurosurgery/NeurologySciEL

Case Report Cerebral Venous Thrombosis with Migraine-Like Headache and the Trigeminovascular System

Cerebral venous thrombosis-(CVT-) associated headache is considered a secondary headache, commonly presenting as intracranial hypertension headache in association with seizures and/or neurological signs. However, it can occasionally mimic migraine. We report a patient presenting with a migraine-like, CVT-related headache refractory to several medications but intravenous dihydroergotamine (DHE). The response to DHE, which is considered to be an antimigraine medication, in addition to the neurovascular nature of migraine, points out to a probable similarity between CVT-headache and migraine. Based on experimental studies, we discuss this similarity and hypothesize a trigeminovascular role in the genesis of CVT-associated headache

Cerebral Venous Thrombosis with Migraine-Like Headache and the Trigeminovascular System

Cerebral venous thrombosis- (CVT-) associated headache is considered a secondary headache, commonly presenting as intracranial hypertension headache in association with seizures and/or neurological signs. However, it can occasionally mimic migraine. We report a patient presenting with a migraine-like, CVT-related headache refractory to several medications but intravenous dihydroergotamine (DHE). The response to DHE, which is considered to be an antimigraine medication, in addition to the neurovascular nature of migraine, points out to a probable similarity between CVT-headache and migraine. Based on experimental studies, we discuss this similarity and hypothesize a trigeminovascular role in the genesis of CVT-associated headache.Peer Reviewe