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https://www.readbyqxmd.com/read/28644430/the-clinical-landscape-for-sma-in-a-new-therapeutic-era
#1
REVIEW
K Talbot, E F Tizzano
Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy, due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy...
June 23, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28637335/astrocyte-produced-mir-146a-as-a-mediator-of-motor-neuron-loss-in-spinal-muscular-atrophy
#2
Samantha L Sison, Teresa N Patitucci, Emily R Seminary, Eric Villalon, Christian L Lorson, Allison D Ebert
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology...
June 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28631749/causes-of-death-after-traumatic-spinal-cord-injury-a-70-year-british-study
#3
G Savic, M J DeVivo, H L Frankel, M A Jamous, B M Soni, S Charlifue
DESIGN: Retrospective and prospective observational. OBJECTIVE: Analyse causes of death after traumatic spinal cord injury (tSCI) in persons surviving the first year post injury, and establish any trend over time. SETTING: Two spinal centres in Great Britain. METHODS: The sample consisted of 5483 patients with tSCI admitted to Stoke Mandeville and Southport spinal centres who were injured between 1943 and 2010, survived first year post injury, had residual neurological deficit on discharge and were British residents...
June 20, 2017: Spinal Cord
https://www.readbyqxmd.com/read/28626021/acute-segmental-poliomyelitis-like-flaccid-paralysis-in-an-adult-in-the-uk-associated-with-enterovirus-d68
#4
Sybil R L Stacpoole, Adam Molyneux, Dirk Bäumer
Enterovirus D68 has been associated with a poliomyelitis-like illness, notably during an outbreak in 2014, and particularly affecting children in the USA. We report a case of acute segmental flaccid paralysis with respiratory involvement in an adult in the UK, with enterovirus D68 detected in a sputum sample. MR imaging of cervical spinal cord showed a longitudinally extensive T2 hyperintensity in the anterior cord. Cerebrospinal fluid showed an elevated white cell count, predominantly lymphocytic, with otherwise normal constituents and negative viral PCRs...
June 16, 2017: Practical Neurology
https://www.readbyqxmd.com/read/28616022/therapeutic-opportunities-and-challenges-of-induced-pluripotent-stem-cells-derived-motor-neurons-for-treatment-of-amyotrophic-lateral-sclerosis-and-motor-neuron-disease
#5
REVIEW
Manoj Kumar Jaiswal
Amyotrophic lateral sclerosis (ALS) and motor neuron diseases (MNDs) are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs), muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3-5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients...
May 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28615436/hospital-safety-among-neurologic-patients-a-population-based-cohort-study-of-adverse-events
#6
Khara M Sauro, Hude Quan, Khokan C Sikdar, Peter Faris, Nathalie Jette
OBJECTIVE: To examine the frequency and type of adverse events (AEs) experienced by neurologic patients in hospital. METHODS: This population-based, retrospective cohort study used hospital discharge abstract data for children and adults admitted to hospital from 2009 to 2015 with 1 of 9 neurologic conditions (Alzheimer disease and related dementia, brain tumor, epilepsy, motor neuron disease, multiple sclerosis, parkinsonism/Parkinson disease, spinal cord injury, traumatic brain injury, and stroke)...
June 14, 2017: Neurology
https://www.readbyqxmd.com/read/28615341/high-frequency-epidural-stimulation-across-the-respiratory-cycle-evokes-phrenic-short-term-potentiation-after-incomplete-cervical-spinal-cord-injury
#7
Elisa J Gonzalez-Rothi, Kristi A Streeter, Marie H Hanna, Anna C Stamas, Paul J Reier, David M Baekey, David D Fuller
C2 spinal hemilesion (C2Hx) paralyzes the ipsilateral diaphragm, but recovery is possible through activation of "crossed spinal" synaptic inputs to ipsilateral phrenic motoneurons. We tested the hypothesis that high frequency epidural stimulation (HF-ES) would potentiate ipsilateral phrenic output after subacute and chronic C2Hx. HF-ES (300 Hz) was applied to the ventrolateral C4 or T2 spinal cord ipsilateral to C2Hx in anesthetized and mechanically ventilated adult rats. Stimulus duration was 60-sec and currents ranged from 100-1000 µA...
June 14, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28601952/an-in-vitro-experimental-model-for-analysis-of-central-control-of-sympathetic-nerve-activity
#8
Yuji Oyama, Kamon Iigaya, Yoshino Minoura, Toshitaka Okabe, Masahiko Izumizaki, Hiroshi Onimaru
Newborn rat brainstem-spinal cord preparations are useful for in vitro analysis of various brainstem functions including respiratory activity. When studying the central control of sympathetic nerve activity (SNA), it is important to record peripheral outputs of the SNA. We developed an in vitro preparation in which neuronal connections between the cardiovascular center in the medulla and SNA peripheral outputs are preserved. Zero- to 1-day-old rats were deeply anesthetized with isoflurane, and the brainstem and spinal cord were isolated with a partial right thoracic cage to record sympathetic nerve discharge from the right thoracic sympathetic nerve trunk (T9-T11)...
June 10, 2017: Journal of Physiological Sciences: JPS
https://www.readbyqxmd.com/read/28592693/non-genomic-actions-of-17-%C3%AE-estradiol-restore-respiratory-neuroplasticity-in-young-ovariectomized-female-rats
#9
Brendan J Dougherty, Elizabeth S Kopp, Jyoti J Watters
Gonadal steroids modulate CNS plasticity, including phrenic long-term facilitation (pLTF), a form of spinal respiratory neuroplasticity resulting in increased phrenic nerve motor output following exposure to acute intermittent hypoxia (aIH; three 5 min episodes, 10.5% O2). Despite the importance of respiratory system neuroplasticity, and its dependence on estrogen in males, little is known about pLTF expression or mechanisms of estrogen signaling in females. Here, we tested the hypotheses that: 1) pLTF expression in young, gonadally intact female rats would be expressed during estrous cycle stages in which 17β-estradiol (E2) is naturally high (e...
June 7, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28571527/assessment-and-management-of-acute-spinal-cord-injury-from-point-of-injury-to-rehabilitation
#10
Laureen D Hachem, Christopher S Ahuja, Michael G Fehlings
CONTEXT: Spinal cord injury (SCI) is a devastating condition that can lead to significant neurological impairment and reduced quality of life. Despite advancements in our understanding of the pathophysiology and secondary injury mechanisms involved in SCI, there are currently very few effective treatments for this condition. The field, however, is rapidly changing as new treatments are developed and key discoveries are made. METHODS: In this review, we outline the pathophysiology, management, and long-term rehabilitation of individuals with traumatic SCI...
June 1, 2017: Journal of Spinal Cord Medicine
https://www.readbyqxmd.com/read/28570440/successful-reinnervation-of-the-diaphragm-after-intercostal-to-phrenic-nerve-neurotization-in-patients-with-high-spinal-cord-injury
#11
Kulvir S Nandra, Martin Harari, Thea P Price, Patrick J Greaney, Michael S Weinstein
OBJECTIVE: Our objective in this study was to extend diaphragmatic pacing therapy to include paraplegic patients with high cervical spinal cord injuries between C3 and C5. INTRODUCTION: Diaphragmatic pacing has been used in patients experiencing ventilator-dependent respiratory failure due to spinal cord injury as a means to reduce or eliminate the need for mechanical ventilation. However, this technique relies on intact phrenic nerve function. Recently, phrenic nerve reconstruction with intercostal nerve grafting has expanded the indications for diaphragmatic pacing...
May 31, 2017: Annals of Plastic Surgery
https://www.readbyqxmd.com/read/28566610/an-autopsy-case-of-respiratory-failure-induced-by-repetitive-cervical-spinal-cord-damage-due-to-abnormal-movement-of-the-neck-in-athetoid-cerebral-palsy
#12
Yo-Ichi Takei, Hiroshi Koshihara, Kenya Oguchi, Kiyomitsu Oyanagi, Shinji Ohara
We herein report the clinical and autopsy findings of a 48-year-old right-handed man with athetoid cerebral palsy who suffered from cervical myelopathy due to abnormal neck movement, and who died of respiratory failure. Pathologically, the external appearance of the ventral surface of the cervical spinal cord revealed a linear indentation running obliquely at the level between the C4 and C5 segments. In the most severely compressed lesion, the gray matter was predominantly affected and severely atrophic. Microscopically, clusters of oligodendrocytes associated with thinly myelinated axons were also observed in the lateral funiculus...
2017: Internal Medicine
https://www.readbyqxmd.com/read/28554833/optimization-of-mitochondrial-isolation-techniques-for-intraspinal-transplantation-procedures
#13
Jenna L Gollihue, Samir P Patel, Charlie Mashburn, Khalid C Eldahan, Patrick G Sullivan, Alexander G Rabchevsky
BACKGROUND: Proper mitochondrial function is essential to maintain normal cellular bioenergetics and ionic homeostasis. In instances of severe tissue damage, such as traumatic brain and spinal cord injury, mitochondria become damaged and unregulated leading to cell death. The relatively unexplored field of mitochondrial transplantation following neurotrauma is based on the theory that replacing damaged mitochondria with exogenous respiratory-competent mitochondria can restore overall tissue bioenergetics...
May 26, 2017: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/28548606/anatomical-recruitment-of-spinal-v2a-interneurons-into-phrenic-motor-circuitry-after-high-cervical-spinal-cord-injury
#14
Lyandysha Viktorovna Zholudeva, Jordyn Karliner, Kimberly J Dougherty, Michael Lane
More than half of all spinal cord injuries (SCIs) occur at the cervical level, often resulting in impaired respiration. Despite this devastating outcome, there is substantial evidence for endogenous neuroplasticity after cervical SCI. Spinal interneurons are widely recognized as being an essential anatomical component of this plasticity by contributing to novel neuronal pathways that can result in functional improvement. The identity of spinal interneurons involved with respiratory plasticity post-SCI, however, has remained largely unknown...
May 26, 2017: Journal of Neurotrauma
https://www.readbyqxmd.com/read/28548204/endovascular-treatment-for-ruptured-abdominal-aortic-aneurysm
#15
REVIEW
Stephen Badger, Rachel Forster, Paul H Blair, Peter Ellis, Frank Kee, Denis W Harkin
BACKGROUND: An abdominal aortic aneurysm (AAA) (pathological enlargement of the aorta) is a condition that can occur as a person ages. It is most commonly seen in men older than 65 years of age. Progressive aneurysm enlargement can lead to rupture and massive internal bleeding, which is fatal unless timely repair can be achieved. Despite improvements in perioperative care, mortality remains high (approximately 50%) after conventional open surgical repair. Endovascular aneurysm repair (EVAR), a minimally invasive technique, has been shown to reduce early morbidity and mortality as compared to conventional open surgery for planned AAA repair...
May 26, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28533325/physiologic-regulation-of-heart-rate-and-blood-pressure-involves-connexin-36-containing-gap-junctions
#16
Varinder K Lall, Gareth Bruce, Larysa Voytenko, Mark Drinkhill, Kerstin Wellershaus, Klaus Willecke, Jim Deuchars, Susan A Deuchars
Chronically elevated sympathetic nervous activity underlies many cardiovascular diseases. Elucidating the mechanisms contributing to sympathetic nervous system output may reveal new avenues of treatment. The contribution of the gap junctional protein connexin 36 (Cx36) to the regulation of sympathetic activity and thus blood pressure and heart rate was determined using a mouse with specific genetic deletion of Cx36. Ablation of the Cx36 protein was confirmed in sympathetic preganglionic neurons of Cx36 knockout (KO) mice...
May 22, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28526145/alpha-2-agonists
#17
REVIEW
Viet Nguyen, Dawn Tiemann, Edward Park, Ali Salehi
Alpha-2 adrenergic receptors are spread throughout the central and peripheral nervous system, specifically in the pontine locus coeruleus, medullospinal tracts, rostral ventrolateral medulla, and the dorsal horn of the spinal cord. Alpha-2 agonist agents cause neuromodulation in these centers, leading to sedation, analgesia, vasodilatation, and bradycardia with little effect on the respiratory drive, which accounts for their good safety profile. The 2 major drugs in this group are clonidine and dexmedetomidine...
June 2017: Anesthesiology Clinics
https://www.readbyqxmd.com/read/28524214/-possible-treatments-for-infantile-spinal-atrophy
#18
S I Pascual-Pascual, M Garcia-Romero
The new treatments of spinal muscular atrophy (SMA) due by SMN1 gene deletions are reviewed. There are several ways to increase the protein SMN, its activity and persistence in the tissues. Neuroprotective drugs as olesoxime or riluzole, and drugs acting by epigenetic mechanisms, as histone deacetylase inhibitors, have shown positive effects in preclinical studies but no clear efficacy in clinical trials. They might give in the future added benefits when used associated to other genetic modifying drugs. The best improvements in murine models of SMA and in clinical trials have been reached with antisense oligonucleotides, drugs that modify the splicing of SMN2, and they are expected to get better in the near future...
May 17, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/28511992/rna-seq-analyses-reveal-that-cervical-spinal-cords-and-anterior-motor-neurons-from-amyotrophic-lateral-sclerosis-subjects-show-reduced-expression-of-mitochondrial-dna-encoded-respiratory-genes-and-rhtfam-may-correct-this-respiratory-deficiency
#19
Amy C Ladd, David G Brohawn, Ravindar R Thomas, Paula M Keeney, Stuart S Berr, Shaharyar M Khan, Francisco R Portell, Meiram Zh Shakenov, Patrick F Antkowiak, Bijoy Kundu, Nicholas Tustison, James P Bennett
Amyotrophic lateral sclerosis (ALS) is a generally fatal neurodegenerative disease of adults that produces weakness and atrophy due to dysfunction and death of upper and lower motor neurons. We used RNA-sequencing (RNA-seq) to analyze expression of all mitochondrial DNA (mtDNA)-encoded respiratory genes in ALS and CTL human cervical spinal cords (hCSC) and isolated motor neurons. We analyzed with RNA-seq mtDNA gene expression in human neural stem cells (hNSC) exposed to recombinant human mitochondrial transcription factor A (rhTFAM), visualized in 3-dimensions clustered gene networks activated by rhTFAM, quantitated their interactions with other genes and determined their gene ontology (GO) families...
May 13, 2017: Brain Research
https://www.readbyqxmd.com/read/28503328/phrenic-pacing-compared-with-mechanical-ventilation
#20
Morten Packert Andersen, Michael Laub, Fin Biering-Sørensen
STUDY DESIGN: Comparable case series. OBJECTIVES: High-cervical spinal cord injury (SCI) may disrupt the ability to breathe sufficiently. To restore respiration a phrenic nerve pacer can be implanted. The aims of this study were to describe the use of phrenic nerve pacing in tetraplegics in Denmark and compare the users with a population of ventilator dependent tetraplegics. SETTING: Clinics for Spinal Cord Injuries, and Respiratory Centre East, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark...
2017: Spinal Cord Series and Cases
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