Regulation of Postnatal Dentate Gyrus Neurogenesis and its Alteration in Experimental Epilepsy.

Medial temporal lobe epilepsy (mTLE) is a common, intractable epilepsy of unknown cause. In rodent mTLE, prolonged seizures, termed status epilepticus, stimulate neurogenesis, but many newborn dentate granule cells (DGCs) migrate and integrate aberrantly. We hypothesized that adult-born, rather than pre-existing, neurons contribute to epileptic pathology in the hippocampal dentate gyrus. Using the rat pilocarpine model, which recapitulates many human mTLE features, we tested our hypothesis by injecting green fluorescent protein-carrying retrovirus to label neural stem cells, or by killing dividing stem cells to suppress neurogenesis pre or post-epileptic injury. We found that an epilepsy-inciting injury differentially influences developing neurons depending upon their ages. Fully mature neurons at the time of injury are resistant, whereas developing neurons of differing maturities contribute to distinct, specific epileptic pathologies. To address the molecular underpinnings of this phenomenon, we investigated the Reelin pathway. Reelin is secreted into the extracellular matrix, binds its receptors and is internalized, leading to phosphorylation of disabled-1 (Dab1), an adaptor protein. Evidence implicates the Reelin/Dab1 pathway in DGC development, and mice with Reelin, Dab1, or Reelin receptor mutations have abnormalities similar to those in experimental mTLE. To better understand the role of Dab1 in neurogenesis, we suppressed Dab1 expression using a mouse line with conditional Dab1 knock-in alleles, or by injecting retroviral vector carrying a Dab1 shRNA into the adult rat dentate gyrus. In Dab1-conditional knock-in mice, Dab1 deletion led to aberrant DGC migration, impaired dendritic maturation and axonal disorganization. In rats, retroviral Dab1 shRNA delivery decreased dendritic arborization of DGCs and induced numerous labeled glia in the hilus and DGC layer that were not seen with control shRNA. Aberrant neurogenesis is a proposed cause of seizures and cognitive deficits common in mTLE, and this work supports an important role for Dab1 signaling in both neuronal migration, dendrite formation, and directing DGC progenitors to a neuronal fate. Taken together, these data suggest that neurons of distinct maturities contribute to specific epileptic abnormalities and that the Reelin/Dab1 pathway may underlie some of these aberrations. Correcting signaling of this pathway after epileptogenic insult may offer a novel strategy to prevent mTLE.Ph.D.NeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91485/1/mkron_1.pd

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

Cell-autonomous inactivation of the reelin pathway impairs adult neurogenesis in the hippocampus

Adult hippocampal neurogenesis is thought to be essential for learning and memory, and has been implicated in the pathogenesis of several disorders. Although recent studies have identified key factors regulating neuroprogenitor proliferation in the adult hippocampus, the mechanisms that control the migration and integration of adult-born neurons into circuits are largely unknown. Reelin is an extracellular matrix protein that is vital for neuronal development. Activation of the Reelin cascade leads to phosphorylation of Disabled-1, an adaptor protein required for Reelin signaling. Here we used transgenic mouse and retroviral reporters along with Reelin signaling gain-of-function and loss-of-function studies to show that the Reelin pathway regulates migration and dendritic development of adultgenerated hippocampal neurons. Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprogenitor cells resulted in aberrant migration, decreased dendrite development, formation of ectopic dendrites in the hilus, and the establishment of aberrant circuits. Our findings support a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and the integration of adult-generated granule cells and point to this pathway as a key regulator of adult neurogenesis. Moreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential implications for the pathogenesis of several neurological and psychiatric disorders. © 2012 the authors.This project was supported by Grant BFU2008-3980 from the Ministerio de Ciencia e Innovación (MICINN), Spain; by grants from the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Caixa Catalunya-Obra Social Foundations to E.S.; by grants from the Spanish Ministry of Science and Innovation (SAF2009-07367 and CONSOLIDER CSD2007-00023) to V.B.; by the Fred Annegers Fellowship from the Epilepsy Foundation (M.M.K.); and by NIH Grant NS058585 to J.M.P. I.R. was recipient of a Formación de Personal Universitario predoctoral fellowship from MINECO (Spain).Peer Reviewe

First comparison of hypothermic oxygenated perfusion versus static cold storage of human donation after cardiac death liver transplants: an international-matched case analysis

BACKGROUND: Exposure of donor liver grafts to prolonged periods of warm ischemia before procurement causes injuries including intrahepatic cholangiopathy, which may lead to graft loss. Due to unavoidable prolonged ischemic time before procurement in donation after cardiac death (DCD) donation in 1 participating center, each liver graft of this center was pretreated with the new machine perfusion "Hypothermic Oxygenated PErfusion" (HOPE) in an attempt to improve graft quality before implantation. METHODS: HOPE-treated DCD livers (n = 25) were matched and compared with normally preserved (static cold preservation) DCD liver grafts (n = 50) from 2 well-established European programs. Criteria for matching included duration of warm ischemia and key confounders summarized in the balance of risk score. In a second step, perfused and unperfused DCD livers were compared with liver grafts from standard brain dead donors (n = 50), also matched to the balance of risk score, serving as baseline controls. RESULTS: HOPE treatment of DCD livers significantly decreased graft injury compared with matched cold-stored DCD livers regarding peak alanine-aminotransferase (1239 vs 2065 U/L, P = 0.02), intrahepatic cholangiopathy (0% vs 22%, P = 0.015), biliary complications (20% vs 46%, P = 0.042), and 1-year graft survival (90% vs 69%, P = 0.035). No graft failure due to intrahepatic cholangiopathy or nonfunction occurred in HOPE-treated livers, whereas 18% of unperfused DCD livers needed retransplantation. In addition, HOPE-perfused DCD livers achieved similar results as control donation after brain death livers in all investigated endpoints. CONCLUSIONS: HOPE seems to offer important benefits in preserving higher-risk DCD liver grafts

University of Michigan Undergraduate Research Forum, Issue 6, Winter 2009

Articlehttp://deepblue.lib.umich.edu/bitstream/2027.42/96993/1/UMURF-Issue06_2009.pd

Is reiki or prayer effective in relieving pain during hospitalization for cesarean? A systematic review and meta-analysis of randomized controlled trials

ABSTRACT CONTEXT AND OBJECTIVE: This systematic review compared reiki and prayer with drug use for relieving pain during hospitalization for cesarean, given that the popularity of integrative medicine and spiritual healing has been increasing. It had the aim of evaluating whether reiki or prayer is effective in relieving pain during cesarean section. DESIGN AND SETTING: Systematic review with meta-analysis conducted at Botucatu Medical School, UNESP, São Paulo, Brazil. METHODS: The following databases were searched up to March 2016: MEDLINE, Embase, LILACS and CENTRAL. Randomized controlled trials published in English or Portuguese were included in the review. Two reviewers independently screened eligible articles, extracted data and assessed the risk of bias. A GRADE table was produced to evaluate the risk of bias. RESULTS: There was evidence with a high risk of bias showing a statistically significant decrease in pain score through use of reiki and prayer, in relation to the protocol group: mean difference = -1.68; 95% confidence interval: -1.92 to -1.43; P < 0.00001; I2 = 92%. Furthermore, there was no statistically significant difference in heart rate or systolic or diastolic blood pressure. CONCLUSION: Evidence with a high risk of bias suggested that reiki and prayer meditation might be associated with pain reduction