Background and Purpose: Ischemic injury triggers multiple pathological responses in the brain tissue, including spreading depolarizations across the cerebral cortex (cortical spreading depolarizations [CSD]). Microglia have been recently shown to play a significant role in the propagation of CSD. However, the intracellular responses of myeloid cells during ischemic stroke have not been investigated. Methods: We have studied intracellular calcium activity in cortical microglia in the stroke model of the middle cerebral artery occlusion, using the murine Polr2a-based and Cre-dependent GCaMP5 and tdTomato reporter (PC::G5-tdT). High-speed 2-photon microscopy through cranial windows was employed to record signals from genetically encoded indicators of calcium. Inflammatory stimuli and pharmacological inhibition were used to modulate microglial calcium responses in the somatosensory cortex. Results: In vivo imaging revealed periodical calcium activity in microglia during the hyperacute phase of ischemic stroke. This activity was more frequent during the first 6 hours after occlusion, but the amplitudes of calcium transients became larger at later time points. Consistent with CSD nature of these events, we reproducibly triggered comparable calcium transients with microinjections of potassium chloride (KCl) into adjacent cortical areas. Furthermore, lipopolysaccharide-induced peripheral inflammation, mimicking sterile inflammation during ischemic stroke, produced significantly greater microglial calcium transients during CSD. Finally, in vivo pharmacological analysis with CRAC (calcium release-activated channel) inhibitor CM-EX-137 demonstrated that CSD-associated microglial calcium transients after KCl microinjections are mediated at least in part by the CRAC mechanism. Conclusions: Our findings demonstrate that microglia participate in ischemic brain injury via previously undetected mechanisms, which may provide new avenues for therapeutic interventions.

Spontaneous cerebrospinal fluid (CSF) rhinorrhea is a rare occurrence. We present a case of spontaneous CSF rhinorrhea in a 57-year-old patient secondary to a sphenoid osseous defect involving the foramen rotundum and maxillary nerve with an associated arachnoid cyst and meningocele compressing the maxillary nerve. The location of the defect made correction amenable to an open skull-based approach. To the best of our knowledge, this is the first reported case of a spontaneous meningocele herniating into the sphenoid osseous defect through the medial aspect of the foramen rotundum. Early detection of these defects, open or endoscopic approaches and definitive treatment by closing the defect can result in excellent outcomes.

Innovation and entrepreneurship (I&E) programs in medical education have become available as medical schools recognize the need to train forward-thinking physicians. There is considerable diversity in the design and implementation of these curricula, which represents a challenge and possibly serves as a deterrent for the development of additional I&E programs. A comprehensive search of medical school I&E programs and review of all Association of American Medical Colleges member websites (n = 171) were conducted. This review sought to (1) identify all American and Canadian allopathic medical schools with I&E curricula, (2) evaluate their structure/integration in the context of medical education, (3) outline core learning themes, and (4) describe the evaluative metrics. Information was collected through published or publicly available websites and through a questionnaire sent to identified I&E program leaders. Twentyeight I&E-oriented medical education programs were identified from 26 schools; all of the programs integrated faculty leadership with backgrounds in medicine, engineering, and/or business/entrepreneurship. Of the programs, 57% (16/28) had been launched within the past four years and 75% (21/28) based program enrollment on a selective application process. Nearly all (27/28) incorporated lecture series and/or hands-on modules as a teaching technique. The most prevalent metric was completion of a capstone project (22/28; 79%). At least 15.2% (26/171) of American and Canadian allopathic medical schools include the option for students to participate in an I&E curriculum-based program. This review can be used to help medical school faculty with developing I&E curricula.