Background: There is not enough evidence to prove either invasive Wada or non-invasive fMRI test predicts postoperative memory changes more accurately in patients with refractory temporal lobe epilepsy (TLE). In this study, concordance between fMRI and Wada test for postoperative assessment of visual memory is investigated. Methods: fMRI test with a novel scene-encoding task were conducted on our cohort of patients. fMRI laterality indices (LI) were then defined as a ratio (L-R)/(L+R) between the number of activated voxels in the left and right of two regions: hippocampus+parahippocampus (Region A) and temporal lobe - (hippocampus+parahippocampus) (Region B). fMRI results were divided into the right (LI < -0.2), left (LI > 0.2) or bilateral (-0.2 < LI <0.2) hemispheric memory dominance and compared to the results of the Wada test. Results: 19 patients were studied (14 left TLE, 3 right TLE and 2 bilateral TLE). The concordance rate between Wada and fMRI tests was 36.8% and 42.1% for regions A and B. Conclusions: Based on the results, the concordance rate between the Wada test and the fMRI test is not high. As a future work, we will investigate the correlation of each test to postoperative memory outcome.

William Osler’s 1892 textbook The Principles and Practice of Medicine became the dominant medical text in the English-speaking world. Osler was labeled a therapeutic nihilist by some. The topic of migraine, including treatment, was succinctly covered in his text. The objectives of this study were to review Osler’s thoughts on migraine, and outline his therapeutic recommendations. Preventively Osler mentioned bromides, iron, arsenic, nitroglycerin, and cannabis. Acutely he recommended coffee, chloroform, cannabis, antipyrin, antifebrin, phenacetin, caffeine citrate, nux vomica, or ergot. He thought cannabis was the most satisfactory remedy. Osler was not a therapeutic nihilist when it came to migraine, and his treatment recommendations were similar to other writers of his time. Osler did not draw upon his personal experience to contribute new knowledge about migraine. Regardless, given the popularity and clarity of his text, Osler’s well-summarized migraine chapter had a great influence on practicing physicians.

Background: The hedgehog pathway (Hh) is an important developmental signaling pathway that is commonly dysregulated in brain tumors, most notably in medulloblastomas. To identify novel therapeutic targets within the Hh pathway, we performed the first quantitative proteome-wide evaluation of phosphorylation events resulting from in vitro SHH administration and occurring throughout Hh-driven cerebellar development in vivo. Methods: Multiplexed quantitative mass spectrometry was done using Tandem Mass Tags 10-plex reagents, TiO2 phosphopeptide enrichment and HPLC-MS/MS/MS. Results: Motif analysis of 2-fold changing phosphorylation events suggested casein kinase 2 (CK2) was responsible for mediating 45% of all changes in phosphorylation. Epistasis studies revealed that CK2 activity is necessary for hedgehog signaling and affects terminal signaling components, thereby circumventing challenges of emergence of resistance and a priori resistance that are commonly encountered with existing small molecule inhibitors in medulloblastoma. In vivo, mice harboring MB allografts resistant to current therapies showed near-complete cessation of tumor growth in response to a CK2 inhibitor. Conclusion: Our use of developmental phosphoproteomics revealed casein kinase 2 as a key regulator of hedgehog signaling and therapeutic target in medulloblastoma. Our success establishes a foundation for us, and others, to apply a similar approach in different tumor initiating pathways.

Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the selective degeneration of motor neurons in the brain and spinal cord resulting in progressive paralysis and death. Current diagnosis of ALS is based on clinical assessment of related symptoms, which appear only late in the disease course after degeneration of a significant number of motor neurons. As a result, the identification and development of disease-modifying therapies is difficult, making ALS an incurable disease. Novel strategies for early diagnosis of ALS, to monitor disease progression and to assess response to existing and future treatments are urgently needed.

Many neurological disorders, including ALS, are accompanied by skin changes that often precede the onset of neurological symptoms. We have developed a unique ALS tissue-engineered skin model (ALS-TES), derived from the cells of ALS patients, in order to study the earliest stages of ALS-related skin pathology. For each participant, two skin biopsies were collected using a 6-mm diameter punch biopsy. Tissue-engineered skin was then generated from isolated keratinocytes and fibroblasts, and examined by routine histochemistry and immunohistochemistry, as well as by confocal microscopy. The ALS-TES model presents a number of striking features including altered epidermal differentiation, abnormal dermo-epidermal junction, delamination, keratinocyte infiltration, collagen disorganization and cytoplasmic TDP-43 inclusions, which are not seen in skin models derived from healthy subjects. The same abnormal skin model changes were detected skin models derived from the cells of pre- symptomatic C9orf72-linked ALS patients carrying the GGGGCC DNA repeat expansion. Consequently, our ALS-TES skin model could represent a renewable source of human tissue to better understand the physiopathological mechanisms underlying this disease, including cytoplasmic TDP43 accumulation, and lead to better tools for early diagnosis and disease monitoring.

Background: Malignant brain tumors have a dismal prognosis, with residual after surgery necessitating adjuvant chemoradiotherapy. We previously demonstrated that targeted Natural Killer (NK-92) cells could be delivered to the brain using a combination of MRI-guided focused ultrasound and Definity microbubbles. Once in the CNS, they can track to malignant tissues without inflicting collateral damage. The HER2 receptor is expressed by epithelial tumours including both breast and glioblastoma; breast tumors with HER2-amplification have a higher risk of CNS metastasis, and poorer prognosis. Methods: We investigated whether multiple combined treatments of targeted NK-92 cells and focused ultrasound with microbubbles could slow tumour growth and improve survival in an orthotopic HER2-amplified rodent brain tumour model using a human breast cancer line as a prototype. Results: Early daily treatments with targeted NK-92 cells and ultrasound improved survival and decreased tumour volumes compared with bi-weekly treatments, or either treatment alone. The intensive treatment paradigm resulted in cure in 50% of subjects. Conclusions: Many tumour proteins could be exploited for targeted therapy with the NK-92 cell line, and combined with the mounting safety evidence for transcranial ultrasound, this may soon provide a non-invasive and highly targeted treatment option for patients with brain tumours.