Garman R.H.,University of Pittsburgh |
Jenkins L.W.,University of Pittsburgh |
Switzer R.C.,NeuroScience Associates |
Bauman R.A.,U.S. Army |
And 10 more authors.
Journal of Neurotrauma | Year: 2011
Blast-induced traumatic brain injury (TBI) is the signature insult in combat casualty care. Survival with neurological damage from otherwise lethal blast exposures has become possible with body armor use. We characterized the neuropathologic alterations produced by a single blast exposure in rats using a helium-driven shock tube to generate a nominal exposure of 35 pounds per square inch (PSI) (positive phase duration ∼4 msec). Using an IACUC-approved protocol, isoflurane-anesthetized rats were placed in a steel wedge (to shield the body) 7 feet inside the end of the tube. The left side faced the blast wave (with head-only exposure); the wedge apex focused a Mach stem onto the rat's head. The insult produced ∼25% mortality (due to impact apnea). Surviving and sham rats were perfusion-fixed at 24 h, 72 h, or 2 weeks post-blast. Neuropathologic evaluations were performed utilizing hematoxylin and eosin, amino cupric silver, and a variety of immunohistochemical stains for amyloid precursor protein (APP), glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba1), ED1, and rat IgG. Multifocal axonal degeneration, as evidenced by staining with amino cupric silver, was present in all blast-exposed rats at all time points. Deep cerebellar and brainstem white matter tracts were most heavily stained with amino cupric silver, with the morphologic staining patterns suggesting a process of diffuse axonal injury. Silver-stained sections revealed mild multifocal neuronal death at 24 h and 72 h. GFAP, ED1, and Iba1 staining were not prominently increased, although small numbers of reactive microglia were seen within areas of neuronal death. Increased blood-brain barrier permeability (as measured by IgG staining) was seen at 24 h and primarily affected the contralateral cortex. Axonal injury was the most prominent feature during the initial 2 weeks following blast exposure, although degeneration of other neuronal processes was also present. Strikingly, silver staining revealed otherwise undetected abnormalities, and therefore represents a recommended outcome measure in future studies of blast TBI. © 2011, Mary Ann Liebert, Inc.
Erwin A.,Georgetown University |
Gudesblatt M.,South Shore Neurologic Associates |
Bethoux F.,Cleveland Clinic |
Bennett S.E.,State University of New York at Buffalo |
And 7 more authors.
Multiple Sclerosis Journal | Year: 2011
The majority of patients with multiple sclerosis (MS) have symptoms of spasticity that increasingly impair function as the disease progresses. With appropriate treatment, however, quality of life can be improved. Oral antispasticity medications are useful in managing mild spasticity but are frequently ineffective in controlling moderate to severe spasticity, because patients often cannot tolerate the adverse effects of increasing doses. Intrathecal baclofen (ITB) therapy can be an effective alternative to oral medications in patients who have a suboptimal response to oral medications or who cannot tolerate dose escalation or multidrug oral regimens. ITB therapy may be underutilized in the MS population because clinicians (a) are more focused on disease-modifying therapies rather than symptom control, (b) underestimate the impact of spasticity on quality of life, and (c) have concerns about the cost and safety of ITB therapy. Delivery of ITB therapy requires expertly trained staff and proper facilities for pump management. This article summarizes the findings and recommendations of an expert panel on the use of ITB therapy in the MS population and the role of the physician and comprehensive care team in patient selection, screening, and management. © 2011 The Author(s).
Dave K.D.,The Michael J Fox Foundation For Parkinsons Research |
De Silva S.,The Michael J Fox Foundation For Parkinsons Research |
Sheth N.P.,The Michael J Fox Foundation For Parkinsons Research |
Ramboz S.,Psychogenics, Inc. |
And 18 more authors.
Neurobiology of Disease | Year: 2014
Recessively inherited loss-of-function mutations in the PTEN-induced putative kinase 1(Pink1), DJ-1 (Park7) and Parkin (Park2) genes are linked to familial cases of early-onset Parkinson's disease (PD). As part of its strategy to provide more tools for the research community, The Michael J. Fox Foundation for Parkinson's Research (MJFF) funded the generation of novel rat models with targeted disruption ofPink1, DJ-1 or Parkin genes and determined if the loss of these proteins would result in a progressive PD-like phenotype. Pathological, neurochemical and behavioral outcome measures were collected at 4, 6 and 8. months of age in homozygous KO rats and compared to wild-type (WT) rats. Both Pink1 and DJ-1 KO rats showed progressive nigral neurodegeneration with about 50% dopaminergic cell loss observed at 8 months of age. ThePink1 KO and DJ-1 KO rats also showed a two to three fold increase in striatal dopamine and serotonin content at 8 months of age. Both Pink1 KO and DJ-1 KO rats exhibited significant motor deficits starting at 4. months of age. However, Parkin KO rats displayed normal behaviors with no neurochemical or pathological changes. These results demonstrate that inactivation of the Pink1 or DJ-1 genes in the rat produces progressive neurodegeneration and early behavioral deficits, suggesting that these recessive genes may be essential for the survival of dopaminergic neurons in the substantia nigra (SN). These MJFF-generated novel rat models will assist the research community to elucidate the mechanisms by which these recessive genes produce PD pathology and potentially aid in therapeutic development. © 2014.
Wiley C.A.,University of Pittsburgh |
Bissel S.J.,University of Pittsburgh |
Lesniak A.,University of Pittsburgh |
Dixon C.E.,Pittsburgh Healthcare System and Safar Center for Resuscitation Research |
And 9 more authors.
Journal of Neurotrauma | Year: 2016
We used controlled cortical impact in mice to model human traumatic brain injury (TBI). Local injury was accompanied by distal diaschisis lesions that developed within brain regions anatomically connected to the injured cortex. At 7 days after injury, histochemistry documented broadly distributed lesions, particularly in the contralateral cortex and ipsilateral thalamus and striatum. Reactive astrocytosis and microgliosis were noted in multiple neural pathways that also showed silver-stained cell processes and bodies. Wisteria floribunda agglutinin (WFA) staining, a marker of perineuronal nets, was substantially diminished in the ipsilateral, but less so in the contralateral cortex. Contralateral cortical silver positive diaschisis lesions showed loss of both phosphorylated and unphosphorylated neurofilament staining, but overall preservation of microtubule-associated protein (MAP)-2 staining. Thalamic lesions showed substantial loss of MAP-2 and unphosphorylated neurofilaments in addition to moderate loss of phosphorylated neurofilament. One animal demonstrated contralateral cerebellar degeneration at 7 days post-injury. After 21 days, the gliosis had quelled, however persistent silver staining was noted. Using a novel serial section technique, we were able to perform electron microscopy on regions fully characterized at the light microscopy level. Cell bodies and processes that were silver positive at the light microscopy level showed hydropic disintegration consisting of: loss of nuclear heterochromatin; dilated somal and neuritic processes with a paucity of filaments, tubules, and mitochondria; and increased numbers of electron-dense membranous structures. Importantly the cell membrane itself was still intact 3 weeks after injury. Although the full biochemical nature of these lesions remains to be deciphered, the morphological preservation of damaged neurons and processes raises the question of whether this is a reversible process. © 2016, Mary Ann Liebert, Inc.
Skotak M.,University of Nebraska - Lincoln |
Wang F.,University of Nebraska - Lincoln |
Alai A.,University of Nebraska - Lincoln |
Holmberg A.,University of Nebraska - Lincoln |
And 3 more authors.
Journal of Neurotrauma | Year: 2013
We evaluated the acute (up to 24 h) pathophysiological response to primary blast using a rat model and helium driven shock tube. The shock tube generates animal loadings with controlled pure primary blast parameters over a wide range and field-relevant conditions. We studied the biomechanical loading with a set of pressure gauges mounted on the surface of the nose, in the cranial space, and in the thoracic cavity of cadaver rats. Anesthetized rats were exposed to a single blast at precisely controlled five peak overpressures over a wide range (130, 190, 230, 250, and 290 kPa). We observed 0% mortality rates in 130 and 230 kPa groups, and 30%, 24%, and 100% mortality rates in 190, 250, and 290 kPa groups, respectively. The body weight loss was statistically significant in 190 and 250 kPa groups 24 h after exposure. The data analysis showed the magnitude of peak-to-peak amplitude of intracranial pressure (ICP) fluctuations correlates well with mortality rates. The ICP oscillations recorded for 190, 250, and 290 kPa are characterized by higher frequency (10-20 kHz) than in other two groups (7-8 kHz). We noted acute bradycardia and lung hemorrhage in all groups of rats subjected to the blast. We established the onset of both corresponds to 110 kPa peak overpressure. The immunostaining against immunoglobulin G (IgG) of brain sections of rats sacrificed 24-h post-exposure indicated the diffuse blood-brain barrier breakdown in the brain parenchyma. At high blast intensities (peak overpressure of 190 kPa or more), the IgG uptake by neurons was evident, but there was no evidence of neurodegeneration after 24 h post-exposure, as indicated by cupric silver staining. We observed that the acute response as well as mortality is a non-linear function over the peak overpressure and impulse ranges explored in this work. © 2013 Mary Ann Liebert, Inc.
Sargent L.M.,U.S. National Institute for Occupational Safety and Health |
Hubbs A.F.,U.S. National Institute for Occupational Safety and Health |
Young S.-H.,U.S. National Institute for Occupational Safety and Health |
Kashon M.L.,U.S. National Institute for Occupational Safety and Health |
And 15 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2012
Carbon nanotubes were among the earliest products of nanotechnology and have many potential applications in medicine, electronics, and manufacturing. The low density, small size, and biological persistence of carbon nanotubes create challenges for exposure control and monitoring and make respiratory exposures to workers likely. We have previously shown mitotic spindle aberrations in cultured primary and immortalized human airway epithelial cells exposed to 24, 48 and 96μg/cm 2 single-walled carbon nanotubes (SWCNT). To investigate mitotic spindle aberrations at concentrations anticipated in exposed workers, primary and immortalized human airway epithelial cells were exposed to SWCNT for 24-72h at doses equivalent to 20 weeks of exposure at the Permissible Exposure Limit for particulates not otherwise regulated. We have now demonstrated fragmented centrosomes, disrupted mitotic spindles and aneuploid chromosome number at those doses. The data further demonstrated multipolar mitotic spindles comprised 95% of the disrupted mitoses. The increased multipolar mitotic spindles were associated with an increased number of cells in the G2 phase of mitosis, indicating a mitotic checkpoint response. Nanotubes were observed in association with mitotic spindle microtubules, the centrosomes and condensed chromatin in cells exposed to 0.024, 0.24, 2.4 and 24μg/cm 2 SWCNT. Three-dimensional reconstructions showed carbon nanotubes within the centrosome structure. The lower doses did not cause cytotoxicity or reduction in colony formation after 24h; however, after three days, significant cytotoxicity was observed in the SWCNT-exposed cells. Colony formation assays showed an increased proliferation seven days after exposure. Our results show significant disruption of the mitotic spindle by SWCNT at occupationally relevant doses. The increased proliferation that was observed in carbon nanotube-exposed cells indicates a greater potential to pass the genetic damage to daughter cells. Disruption of the centrosome is common in many solid tumors including lung cancer. The resulting aneuploidy is an early event in the progression of many cancers, suggesting that it may play a role in both tumorigenesis and tumor progression. These results suggest caution should be used in the handling and processing of carbon nanotubes. © 2012.
Seifert H.A.,University of South Florida |
Collier L.A.,University of South Florida |
Chapman C.B.,University of South Florida |
Benkovic S.A.,NeuroScience Associates |
And 2 more authors.
Journal of Neuroimmune Pharmacology | Year: 2014
The delayed immune response to stroke is responsible for the increased neural injury that continues to occur after the initial ischemic event. This delayed immune response has been linked to the spleen, as splenectomy prior to middle cerebral artery occlusion (MCAO) is neuroprotective. Interferon gamma (IFNγ) is linked to the splenic response, which enhances neural injury following MCAO. IFNγ activates the expression of the inflammatory chemokine interferon-inducible protein 10 (IP-10). This study was designed to determine the role of IFNγ signaling in the inflammatory response following MCAO. Expression of IP-10 increased in the brain and the spleen following MCAO. Splenectomy inhibited the increase of IP-10 in the brain post-MCAO, while recombinant IFNγ administration to splenectomized rats returned IP-10 levels in the brain to levels found in rats after MCAO only. Systemic administration of an IFNγ neutralizing antibody to MCAO-treated rats reduced infarct volume and IP-10 levels in the brain. T cell infiltration was reduced in the MCAO-damaged brains of IFNγ antibody-treated animals relative to those that received isotype control antibodies. Additionally, inhibiting IFNγ signaling with splenectomy or an IFNγ neutralizing antibody blocked the induction of IP-10 expression and decreased neurodegeneration following MCAO. Targeting this pro-inflammatory pathway following stroke could be a promising stroke therapeutic. © 2014, Springer Science+Business Media New York.
Ludvig N.,NYU Langone Medical Center |
Switzer III R.C.,NeuroScience Associates |
Tang H.M.,NYU Langone Medical Center |
Kuzniecky R.I.,NYU Langone Medical Center
Brain Research | Year: 2012
Electrophysiological and behavioral studies have demonstrated that muscimol administered through the cranial meninges can prevent focal neocortical seizures. It was proposed that transmeningeal muscimol delivery can be used for the treatment of intractable focal neocortical epilepsy. However, it has not been proved that muscimol administered via the transmeningeal route can penetrate into the neocortex. The purpose of the present study was to solve this problem by using combined autoradiography-histology methods. Four rats were implanted with epidural cups over the parietal cortices. A 50 μL mixture of [3H] muscimol and unlabeled muscimol with a final concentration of 1.0 mM was delivered through each cup on the dura mater. After a 1-hour exposure, the muscimol solution was removed and replaced with formalin to trap the transmeningeally diffused molecules. Then the whole brain was fixed transcardially, sectioned, with the sections subjected to autoradiography and thionine counterstaining. Results showed that (1) [3H] muscimol diffused through the meninges into the cortical tissue underlying the epidural cup in all rats. (2) [3H] muscimol-related autoradiography grains were distributed in all six neocortical layers. (3) [3H] muscimol-related autoradiography grains were localized to the cortical area underneath the epidural delivery site and were absent in the cerebral cortical white matter and other brain structures. This study provided evidence that muscimol can be delivered via the transmeningeal route into the neocortical tissue in a spatially controlled manner. The finding further supports the rationale of using transmeningeal muscimol for the treatment of intractable focal neocortical epilepsy. © 2011 Elsevier B.V. All rights reserved.
Seifert H.A.,University of South Florida |
Leonardo C.C.,University of South Florida |
Hall A.A.,University of South Florida |
Rowe D.D.,University of South Florida |
And 4 more authors.
Metabolic Brain Disease | Year: 2012
Delayed neuronal death associated with stroke has been increasingly linked to the immune response to the injury. Splenectomy prior to middle cerebral artery occlusion (MCAO) is neuroprotective and significantly reduces neuroinflammation. The present study investigated whether splenic signaling occurs through interferon gamma (IFNγ). IFNγ was elevated early in spleens but later in the brains of rats followingMCAO. Splenectomy decreased the amount of IFNγ in the infarct post-MCAO. Systemic administration of recombinant IFNγ abolished the protective effects of splenectomy with a concurrent increase in INFγ expression in the brain. These results suggest a role for spleen-derived IFNγ in stroke pathology. © Springer Science+Business Media, LLC 2012.
Switzer 3rd. R.C.,NeuroScience Associates
Toxicologic pathology | Year: 2011
Adequate tissue sampling is known to reduce the likelihood that the toxicity of novel biomolecules, chemicals, and drugs might go undetected. Each organ, and often specific structurally and functionally distinct regions within it, must be assessed to detect potential site-specific toxicity. Adequate sampling of the brain requires particular consideration because of the many major substructures and more than 600 subpopulations of generally irreplaceable cells with unique functions and vulnerabilities. All known neurotoxicants affect specific subpopulations (usually neurons) rather than damaging a certain percentage of cells throughout the brain; thus, all populations should be independently assessed for lesions. Historically, the affected neural cell subpopulation has not been predictable, but it is now clear that sampling selected populations (e.g., cerebral cortex, hippocampus, cerebellar folia) cannot forecast the health of other populations. This article reviews the neuroanatomical domains affected by several model neurotoxicants to illustrate the need for more comprehensive neurohistological evaluation during nonclinical development of novel compounds. The article also describes an easily executed, cost-effective method that uses a set number of evenly spaced coronal (cross) sections to accomplish this comprehensive brain assessment during nonclinical safety studies performed in rodents, dogs, and nonhuman primates.