Concise Review: Exciting Cells: Modeling Genetic Epilepsies with Patient‐Derived Induced Pluripotent Stem Cells

Human induced pluripotent stem cell (iPSC) models of epilepsy are becoming a revolutionary platform for mechanistic studies and drug discovery. The skyrocketing pace of epilepsy gene discovery is vastly outstripping the development of in vivo animal models. Currently, antiepileptic drug prescribing to patients with specific genetic epilepsies is based on small‐scale clinical trials and empiricism; however, rapid production of patient‐derived iPSC models will allow for precision therapy. We review iPSC‐based studies that have already afforded novel discoveries in diseases with epileptic phenotypes, as well as challenges to using iPSC‐based neurological disease models. We also discuss iPSC‐derived cardiomyocyte studies of arrhythmia‐inducing ion channelopathies that exemplify novel drug discovery and use of multielectrode array technology that can be translated to epilepsy research. Beyond initial studies of Rett, Timothy, Phelan‐McDermid, and Dravet syndromes, the stage is set for groundbreaking iPSC‐based mechanistic and therapeutic discoveries in genetic epilepsies with the potential to impact patient treatment and quality of life. Stem Cells 2016;34:27–33Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134416/1/stem2203_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134416/2/stem2203.pd

Network structure determines patterns of network reorganization during adult neurogenesis

New cells are generated throughout life and integrate into the hippocampus via the process of adult neurogenesis. Epileptogenic brain injury induces many structural changes in the hippocampus, including the death of interneurons and altered connectivity patterns. The pathological neurogenic niche is associated with aberrant neurogenesis, though the role of the network-level changes in development of epilepsy is not well understood. In this paper, we use computational simulations to investigate the effect of network environment on structural and functional outcomes of neurogenesis. We find that small-world networks with external stimulus are able to be augmented by activity-seeking neurons in a manner that enhances activity at the stimulated sites without altering the network as a whole. However, when inhibition is decreased or connectivity patterns are changed, new cells are both less responsive to stimulus and the new cells are more likely to drive the network into bursting dynamics. Our results suggest that network-level changes caused by epileptogenic injury can create an environment where neurogenic reorganization can induce or intensify epileptic dynamics and abnormal integration of new cells.Comment: 28 pages, 10 figure

Exploring the treatment of epilepsy through intrahippocampal GABA modulation with an HSVvector expressing GAD67

Articlehttp://deepblue.lib.umich.edu/bitstream/2027.42/96990/1/UMURF-Issue06_2009-MMooney.pd

Inverse Association between Dietary Intake of Selected Carotenoids and Vitamin C and Risk of Lung Cancer.

While diets rich in fruit and vegetables appear to reduce lung cancer risk, the evidence for individual carotenoid and vitamin intakes has been judged too limited to reach firm conclusions. Data from a case-control study of lung cancer (Montreal, QC, Canada, 1996-2002) were used to investigate the role of dietary intakes of β-carotene, α-carotene, β-cryptoxanthin, lutein/zeaxanthin, lycopene, and vitamin C in lung cancer risk. In-person interviews elicited dietary information from 1,105 incident cases and 1,449 population controls. Usual frequency of consumption of 49 fruits and vegetables 2 years prior to diagnosis/interview was collected. Odds ratios (ORs) and 95% confidence intervals (CIs) between intake variables and lung cancer were estimated using logistic or polytomous regression, adjusting for potential confounding factors including a detailed smoking history. ORs associated with upper versus lower tertiles of intake were 0.66 (95% CI = 0.51-0.84) for β-carotene, 0.70 (95% CI = 0.55-0.90) for α-carotene, 0.65 (95% CI = 0.51-0.84) for β-cryptoxanthin, 0.75 (95% CI = 0.59-0.95) for lycopene, and 0.74 (95% CI = 0.58-0.96) for vitamin C. ORs suggestive of a protective effect were found for elevated intakes of β-carotene, α-carotene, β-cryptoxanthin, and lycopene in male heavy smokers and of vitamin C in female heavy smokers. Selected antioxidants were also associated with a lower risk of lung cancer in female moderate smokers, and of squamous cell carcinoma, adenocarcinoma, and small cell carcinoma. These results suggest that several dietary antioxidants found in common food sources may protect against lung cancer, even among heavy smokers

Speech Preservation during Language-dominant, Left Temporal Lobe Seizures: Report of a Rare, Potentially Misleading Finding

Purpose: To evaluate the prevalence and mechanism of ictal speech in patients with language-dominant, left temporal lobe seizures. Methods: We retrospectively reviewed the video-EEG telemetry records for the presence of ictal speech in 96 patients with surgically proven left temporal lobe epilepsy and studied the seizure-propagation patterns in three patients who required intracranial EEG recordings for seizure localization. Results: Ictal speech preservation was observed in five patients. One patient's seizures demonstrated rapid propagation of the ictal discharges to the contralateral temporal area where the seizure evolved, resembling a nondominant temporal lobe seizure. The other two patients had ictal discharges that remained confined to the inferomesial temporal areas, sparing language cortex. Conclusions: Preservation of speech in complex partial seizures of language-dominant, left temporal lobe origin is rare. Based on intracranial EEG recordings, the likely mechanism underlying this potentially misleading clinical finding is the preservation of language areas due to limited seizure-propagation patterns.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65559/1/j.1528-1167.2006.00606.x.pd

Categories and order systems : Claude Parent and the Serving Library. Intersections of architecture, art and editorial design

This paper discusses the work of Claude Parent and The Serving Library, considering the critiques generated by their intersecting of architecture, art and editorial design. Through focus on the ways in which hosting environment, architecture and forms of expanded publishing can serve to dissolve disciplinary boundaries and activities of production, spectatorship and reception, it draws on the lineage of 1960s/70s Conceptual Art in considering these practices as a means through which to escape medium specificity and spatial confinement. Relationships between actual and virtual space are then read against this broadening of aesthetic ideas and the theory of critical modernity

From network structure to network reorganization: implications for adult neurogenesis

Networks can be dynamical systems that undergo functional and structural reorganization. One example of such a process is adult hippocampal neurogenesis, in which new cells are continuously born and incorporate into the existing network of the dentate gyrus region of the hippocampus. Many of these introduced cells mature and become indistinguishable from established neurons, joining the existing network. Activity in the network environment is known to promote birth, survival and incorporation of new cells. However, after epileptogenic injury, changes to the connectivity structure around the neurogenic niche are known to correlate with aberrant neurogenesis. The possible role of network-level changes in the development of epilepsy is not well understood. In this paper, we use a computational model to investigate how the structural and functional outcomes of network reorganization, driven by addition of new cells during neurogenesis, depend on the original network structure. We find that there is a stable network topology that allows the network to incorporate new neurons in a manner that enhances activity of the persistently active region, but maintains global network properties. In networks having other connectivity structures, new cells can greatly alter the distribution of firing activity and destroy the initial activity patterns. We thus find that new cells are able to provide focused enhancement of network only for small-world networks with sufficient inhibition. Network-level deviations from this topology, such as those caused by epileptogenic injury, can set the network down a path that develops toward pathological dynamics and aberrant structural integration of new cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85406/1/ph10_4_046008.pd

Prolonged seizures recruit caudal subventricular zone glial progenitors into the injured hippocampus

Neurogenesis persists in the adult rat rostral forebrain subventricular zone (SVZ) and is stimulated by status epilepticus (SE). More caudal SVZ (cSVZ) neural progenitors migrate to the hippocampus after ischemic injury and contribute to CA1 pyramidal cell regeneration. Because SE also damages the hippocampus, we examined the effects of SE on cSVZ precursors. SE was induced in adult rats with pilocarpine, and cell proliferation in cSVZ and hippocampus was examined by bromodeoxyuridine (BrdU) and retroviral reporter labeling. Neural precursors were assayed by immunostaining for specfic markers between 1 and 35 days after SE. BrdU-positive cells labeled prior to SE markedly increased in numbers within 1–2 weeks in the cSVZ and infracallosal region, but not in the corpus callosum. Doublecortin-, polysialic acid neural cell adhesion molecule-, and TUC-4 (TOAD/Ulip/CRMP family-4)-immunostained cells with migrating morphology increased with a similar time course after SE and extended from the cSVZ to CA1 and CA3 regions. Retroviral reporters injected into the cSVZ of controls showed labeled cells with oligodendroglial morphology located in the cSVZ and corpus callosum; when injected 2 days prior to SE, many more reporter-labeled cells appeared several weeks later and were located in the cSVZ, corpus callosum, and hippocampus. Labeled cells showed glial morphologies and expressed astrocyte or oligodendrocyte markers. Neither BrdU- nor retroviral reporter-labeled cells coexpressed neuronal markers in controls or pilocarpine-treated rats. These results indicate that SE increases cSVZ gliogenesis and attracts newly generated glia to regions of hippocampal damage. Further study of seizure-induced gliogenesis may provide insight into mechanisms of adult neural progenitor regulation and epileptogenesis. © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49285/1/20166_ftp.pd

Delivery of Proteases in Aqueous Two‐Phase Systems Enables Direct Purification of Stem Cell Colonies from Feeder Cell Co‐Cultures for Differentiation into Functional Cardiomyocytes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/101762/1/1440_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/101762/2/adhm_201300049_sm_suppl.pd