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Ioannis N Mammas, Demetrios A Spandidos
According to Professor Basil T. Darras, Professor of Neurology (Pediatrics) at Harvard Medical School and Director of the Spinal Muscular Atrophy (SMA) Program at Boston Children's Hospital in Boston (MA, USA), the diagnosis of SMA type I is clinical and is based on detailed general physical and neurological examinations. SMA type I remains the most common genetic disease resulting in death in infancy and is really devastating for the child, the parents, as well as the medical professionals with the privilege of caring for patients with SMA and their parents...
April 2018: Experimental and Therapeutic Medicine
Aziza Alrafiah, Evangelia Karyka, Ian Coldicott, Kayleigh Iremonger, Katherin E Lewis, Ke Ning, Mimoun Azzouz
Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease. SMA is caused by mutations in the survival motor neuron gene ( SMN1 ), leading to reduced levels of SMN protein in the CNS. The actin-binding protein plastin 3 (PLS3) has been reported as a modifier for SMA, making it a potential therapeutic target. Here, we show reduced levels of PLS3 protein in the brain and spinal cord of a mouse model of SMA. Our study also revealed that lentiviral-mediated PLS3 expression restored axonal length in cultured Smn-deficient motor neurons...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Michela Ferrucci, Gloria Lazzeri, Marina Flaibani, Francesca Biagioni, Federica Cantini, Michele Madonna, Domenico Bucci, Fiona Limanaqi, Paola Soldani, Francesco Fornai
Counting motor neurons within the spinal cord and brainstem represents a seminal step to comprehend the anatomy and physiology of the final common pathway sourcing from the CNS. Motor neuron loss allows to assess the severity of motor neuron disorders while providing a tool to assess disease modifying effects. Counting motor neurons at first implies gold standard identification methods. In fact, motor neurons may occur within mixed nuclei housing a considerable amount of neurons other than motor neurons. In the present review, we analyse various approaches to count motor neurons emphasizing both the benefits and bias of each protocol...
March 14, 2018: Histology and Histopathology
Masaki Kobayashi, Douglas W Zochodne
Diabetic polyneuropathy (DPN) continues to be generally considered as a "microvascular" complication of diabetes mellitus alongside nephropathy and retinopathy. The microvascular hypothesis, however, may be tempered by the concept that diabetes directly targets dorsal root ganglion sensory neurons. This neuron specific concept, supported by accumulating evidence, might account for important features of DPN, such as its early sensory neuron degeneration. Diabetic sensory neurons develop neuronal atrophy alongside a series of mRNA changes related to declines in structural proteins, increases in heat shock protein (HSP), increases in the receptor for advanced glycation endproducts (RAGE), declines in growth factor signaling and other changes...
March 13, 2018: Journal of Diabetes Investigation
Frank Curmi, Ruben J Cauchi
Gemin3, also known as DDX20 or DP103, is a DEAD-box RNA helicase which is involved in more than one cellular process. Though RNA unwinding has been determined in vitro , it is surprisingly not required for all of its activities in cellular metabolism. Gemin3 is an essential gene, present in Amoeba and Metazoa. The highly conserved N-terminus hosts the helicase core, formed of the helicase- and DEAD-domains, which, based on crystal structure determination, have key roles in RNA binding. The C-terminus of Gemin3 is highly divergent between species and serves as the interaction site for several accessory factors that could recruit Gemin3 to its target substrates and/or modulate its function...
March 9, 2018: Biochemical Society Transactions
Jeong-Ki Kim, Umrao R Monani
Spinal muscular atrophy (SMA) is a common and oft-fatal pediatric neuromuscular disorder caused by insufficient SMN protein. Now, two clinical trials (Mendell et al., 2017; Finkel et al., 2017) demonstrate that restoring the protein is therapeutic, offering new treatment options and renewed hope to SMA patients.
March 7, 2018: Neuron
Luke W Thompson, Kim D Morrison, Sally L Shirran, Ewout J N Groen, Tom H Gillingwater, Catherine H Botting, Judith E Sleeman
Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative condition caused by reduction in functional Survival Motor Neurones Protein (SMN). SMN has been implicated in transport of mRNA in neural cells for local translation. We previously identified microtubule-dependant mobile vesicles rich in SMN and SmB, a member of the Sm family of snRNP-associated proteins, in neural cells. By comparing the interactomes of SmB and SmN, a neural-specific Sm protein, we now show that the essential neural protein neurochondrin (NCDN) interacts with Sm proteins and SMN in the context of mobile vesicles in neurites...
March 5, 2018: Journal of Cell Science
Mukesh Kumar, Shilpi Modi, Poonam Rana, Pawan Kumar, Ratnesh Kanwar, Tarun Sekhri, Maria D'souza, Subash Khushu
Subclinical hypothyroidism (SCH) is characterized by mild elevation of thyroid stimulating hormone (TSH) (range 5-10 μIU/ml) and normal free triiodothyronine (FT3) and free thyroxine (FT4). The cognitive function impairment is well known in thyroid disorders such as hypothyroidism and hyperthyroidism, but little is known about deficits in brain functions in SCH subjects. Also, whether hormone-replacement treatment is necessary or not in SCH subjects is still debatable. In order to have an insight into the cognition of SCH subjects, intrinsic and extrinsic functional connectivity (FC) of the resting state networks (RSNs) was studied...
March 5, 2018: Journal of Neuroendocrinology
S Radovic, G Dubsky De Wittenau, N Mandl, E Betto, F Curcio, M Morgante, I R Lonigro
A comparison of the individual genomes within a species demonstrates that structural variation, including copy number variation (CNV), is a major contributor to phenotypic diversity and evolutionary adaptation. CNVs lead to the under/over-expression of a gene, according to the changes in the gene dosage, which account for the development of a number of genomic disorders. Thus, the development of efficient, rapid and accurate CNV screening is of fundamental importance. We report a method that enables the simultaneous determination of the copy numbers of several different targets as well as the discrimination among highly similar/almost identical targets that differ by only one single nucleotide variant, which establishes their copy numbers...
January 2018: Journal of Biological Regulators and Homeostatic Agents
Jessika Nystedt, Peter Mannfolk, Petra Nilsson, Anders Bengtsson, Andreas Jönsen, Pia C Sundgren, Olof Strandberg
PURPOSE: To investigate resting state functional connectivity of lupus-patients and associated subgroups according to the ACR NPSLE case definitions (ACR ad Hoc 1999). Additionally, we investigated whether or not the observed alterations correlated with disease duration, SLE-disease activity index-2000 (SLEDAI-2k) and Systemic Lupus International Collaborating Clinical/ACR organ damage index (SDI)-scores. MATERIAL AND METHOD: Anatomical 3T MRI and resting state-fMRI (rs-fMRI) were performed in 61 female lupus-patients (mean age = 37...
March 2, 2018: Brain Connectivity
Rahimeh Rahimi, Jamshid Karimi, Iraj Khodadadi, Heidar Tayebinia, Nejat Kheiripour, Mohammad Hashemnia, Fatemeh Goli
Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD). Urotensin II ((U-II)) and its receptor (UTR) are involved in the progression of CVD through enhancement in the production of reactive oxygen species (ROS). Since silymarin (SMN) is a natural agent with anti-diabetic effects, this study aimed to investigate the antioxidant potency of SMN on the expression of (U-II)/UTR system and oxidative stress status in the heart of type 2 diabetic rats. Thirty-six male Wistar rats were randomly divided into six groups (n = 6)...
February 26, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Carolyn J Kushner, Wei-Ting Hwang, Shiyu Wang, Lawrence J Solin, Neha Vapiwala
PURPOSE: Women with ductal carcinoma in situ (DCIS) or early-stage breast cancer have an excellent prognosis, but their risk of developing second malignant neoplasms (SMNs) is not well established. We analyzed SMNs in a large cohort with long follow-up after breast conservation therapy. METHODS: The study population comprised 755 women with DCIS (n = 135) or stage I-II breast carcinoma (n = 620). Subjects were aged 25-89 (median 55) years when they underwent breast-conserving surgery followed by radiotherapy to the entire breast (60-68Gray) between 1992 and 2001...
February 27, 2018: Breast Cancer Research and Treatment
Eveline S Arnold, Kenneth H Fischbeck
Autosomal-recessive proximal spinal muscular atrophy (Werdnig-Hoffmann, Kugelberg-Welander) is caused by mutation of the SMN1 gene, and the clinical severity correlates with the number of copies of a nearly identical gene, SMN2. The SMN protein plays a critical role in spliceosome assembly and may have other cellular functions, such as mRNA transport. Cell culture and animal models have helped to define the disease mechanism and to identify targets for therapeutic intervention. The main focus for developing treatment has been to increase SMN levels, and accomplishing this with small molecules, oligonucleotides, and gene replacement has been quite...
2018: Handbook of Clinical Neurology
Hongyu Yang, Chao Zhang, Chang Liu, Tao Yu, Guojun Zhang, Nan Chen, Kuncheng Li
The aims of this study were to investigate the brain network alternation in patients with temporal lobe epilepsy (TLE) with and without cognitive impairment (CI) using functional magnetic resonance imaging (fMRI) and to further explore the potential mechanisms of epilepsy-induced CI. Forty patients with TLE and nineteen healthy controls (HCs) were recruited for this study. All participants received the Montreal Cognitive Assessment (MoCA) test, and the patients were divided into CI (n=21) and cognitive nonimpairment (CNI) groups (n=19) according to MoCA performance...
February 20, 2018: Epilepsy & Behavior: E&B
Gillian K Maxwell, Eva Szunyogova, Hannah K Shorrock, Thomas H Gillingwater, Simon H Parson
Spinal muscular atrophy (SMA), an autosomal recessive disease caused by a decrease in levels of the survival motor neuron (SMN) protein, is the most common genetic cause of infant mortality. Although neuromuscular pathology is the most severe feature of SMA, other organs and tissues, including the heart, are also known to be affected in both patients and animal models. Here, we provide new insights into changes occurring in the heart, predominantly at pre- and early symptomatic ages, in the Taiwanese mouse model of severe SMA...
February 22, 2018: Journal of Anatomy
Chun Liang Hsu, John R Best, Michelle W Voss, Todd C Handy, Olivier Beauchet, Chris Lim, Teresa Liu-Ambrose
Background: Subtle, but observable, changes in mobility often exist among older adults with mild cognitive impairment (MCI). Notably, these changes are not inconsequential. Therefore, there is a strong interest to better understand the underlying neural correlates of gait slowing among older adults with MCI. In this study, we aimed to characterize patterns of functional connectivity associated with slower gait speed in older adults with MCI. Methods: 49 participants ≥ 60 years with MCI were included in the cross-sectional study...
February 17, 2018: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Christine E Beattie, Stephen J Kolb
Spinal muscular atrophy is caused by deletions or mutations in the SMN1 gene that result in reduced expression of the SMN protein. The SMN protein is an essential molecular chaperone that is required for the biogenesis of multiple ribonucleoprotein (RNP) complexes including spliceosomal small nuclear RNPs (snRNPs). Reductions in SMN expression result in a reduced abundance of snRNPs and to downstream RNA splicing alterations. SMN is also present in axons and dendrites and appears to have important roles in the formation of neuronal mRNA-protein complexes during development or neuronal repair...
February 17, 2018: Brain Research
Valeria Parente, Stefania Corti
Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families...
2018: Therapeutic Advances in Neurological Disorders
Ewout J N Groen, Kevin Talbot, Thomas H Gillingwater
Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease-modifying therapy for SMA by US and European authorities - the antisense oligonucleotide nusinersen...
February 9, 2018: Nature Reviews. Neurology
Yu Wang, Yi-Xin He, Tian-Tian Diao, Shi-Yao Wei, Wen-Rui Qi, Cen-Cen Wang, Shu-Min Song, Min Bi, Chun-Mei Li, Cai-Xia Zhang, Yan-Pei Hou, Qiu-Ju Wei, Bing Li
Since urine samples more directly reflect kidney alterations and damage than blood samples, we investigated whether urine anti-PLA2 R antibody (uPLA2 R-Ab) could be utilized similarly to serum anti-PLA2 R antibody (sPLA2 R-Ab) as a noninvasive biomarker of idiopathic membranous nephropathy (IMN). In this study, we performed a qualitative analysis using an indirect immunofluorescence test (IIFT) and measured uPLA2 R-Ab and sPLA2 R-Ab concentrations using an enzyme-linked immunosorbent assay (ELISA) in 28 patients with biopsy-proven IMN and 12 patients with secondary membranous nephropathy (SMN)...
January 2, 2018: Oncotarget
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