Dubbioso R.,University of Naples Federico II |
Moretta P.,Scientific Institute of Telese Terme BN |
Manganelli F.,University of Naples Federico II |
Fiorillo C.,Molecular Medicine |
And 3 more authors.
Journal of Neurology | Year: 2012
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disorder caused by a small expansion of a short polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). It presents with adult onset of progressive eyelid drooping, swallowing difficulties and proximal limb weakness, usually without involvement of central nervous system (CNS). However, cognitive decline with relevant behavioural and psychological symptoms has been recently described in homozygous patients. In this study, we performed for the first time an extensive neuropsychological and neuropsychiatric evaluation on 11 OPMD heterozygote patients. We found that they were less efficient than a matched control sample on several tests, particularly those tapping executive functions. Moreover, the presence of negative correlation between GCN expansion size and some neuropsychological scores raises the issue that CNS involvement might be linked to the genetic defect, being worse in patients with larger expansion. Our results might be consistent with the toxic gain-of-function theory in the pathogenesis of OPMD and hint at a possible direct role of PABPN1 in the CNS also in heterozygote patients. © Springer-Verlag 2011.
Liu Y.-F.,Institutes of Basic Medical science |
Lei H.-Y.,Microbiology and Immunology |
Teng C.-H.,Molecular Medicine |
Wang M.-C.,Clinical Pharmacy |
And 4 more authors.
Infection and Immunity | Year: 2012
Outer membrane proteins (OMPs) serve as the permeability channels for nutrients, toxins, and antibiotics. In Escherichia coli, OmpA has been shown to be involved in bacterial virulence, and OmpC is related to multidrug resistance. However, it is unclear whether OmpC also has a role in the virulence of E. coli. The aims of this study were to characterize the role of OmpC in antimicrobial resistance and bacterial virulence in E. coli. The ompC deletion mutant showed significantly decreased susceptibility to carbapenems and cefepime. To investigate the survival of E. coli exposed to the innate immune system, a human blood bactericidal assay showed that the ompC mutant increased survival in blood and serum but not in complement-inactivated serum. These effects were also demonstrated in the natural selection of OmpC mutants. Also, C1q interacted with E. coli through a complex of antibodies bound to OmpC as a major target. Bacterial survival was increased in the wild-type strain in a dose-dependent manner by adding free recombinant OmpC protein or anti-C1q antibody to human serum. These results demonstrated that the interaction of OmpC-specific antibody and C1q was the key step in initiating the antibody-dependent classical pathway for the clearance of OmpC-expressing E. coli. Anti-OmpC antibody was detected in human sera, indicating that OmpC is an immunogen. These data indicate that the loss of OmpC in E. coli is resistant to not only antibiotics, but also the serum bactericidal effect, which is mediated from the C1q and anti-OmpC antibody-dependent classical pathway. © 2012, American Society for Microbiology.
Building on wireless technology that has the potential to interfere with pain, scientists have developed flexible, implantable devices that can activate — and, in theory, block — pain signals in the body and spinal cord before those signals reach the brain. The researchers, at Washington University School of Medicine in St. Louis and the University of Illinois at Urbana-Champaign, said the implants one day may be used in different parts of the body to fight pain that doesn’t respond to other therapies. “Our eventual goal is to use this technology to treat pain in very specific locations by providing a kind of ‘switch’ to turn off the pain signals long before they reach the brain,” said co-senior investigator Robert W. Gereau IV, Ph.D., the Dr. Seymour and Rose T. Brown Professor of Anesthesiology and director of the Washington University Pain Center. The study is published online Nov. 9 in the journal Nature Biotechnology. Because the devices are soft and stretchable, they can be implanted into parts of the body that move, Gereau explained. The devices previously developed by the scientists had to be anchored to bone. “But when we’re studying neurons in the spinal cord or in other areas outside of the central nervous system, we need stretchable implants that don’t require anchoring,” he said. The new devices are held in place with sutures. Like the previous models, they contain microLED lights that can activate specific nerve cells. Gereau said he hopes to use the implants to blunt pain signals in patients who have pain that cannot be managed with standard therapies. The researchers experimented with mice that were genetically engineered to have light-sensitive proteins on some of their nerve cells. To demonstrate that the implants could influence the pain pathway in nerve cells, the researchers activated a pain response with light. When the mice walked through a specific area in a maze, the implanted devices lit up and caused the mice to feel discomfort. Upon leaving that part of the maze, the devices turned off, and the discomfort dissipated. As a result, the animals quickly learned to avoid that part of the maze. The experiment would have been very difficult with older optogenetic devices, which are tethered to a power source and can inhibit the movement of the mice. Because the new, smaller, devices are flexible and can be held in place with sutures, they also may have potential uses in or around the bladder, stomach, intestines, heart or other organs, according to co-principal investigator John A. Rogers, Ph.D., professor of materials science and engineering at the University of Illinois. “They provide unique, biocompatible platforms for wireless delivery of light to virtually any targeted organ in the body,” he said. Rogers and Gereau designed the implants with an eye toward manufacturing processes that would allow for mass production so the devices could be available to other researchers. Gereau, Rogers and Michael R. Bruchas, Ph.D., associate professor of anesthesiology at Washington University, have launched a company called NeuroLux to aid in that goal. Funding for this research comes from a National Institutes of Health (NIH) Director’s Transformative Research Award, as well as the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, an NIH Ruth I Kirschstein Predoctoral Fellowship, a Howard Hughes Medical Institute Medical Research Fellowship, and a W.M. Keck Fellowship in Molecular Medicine.
System allows pathology labs and others to match patients' test results to personalized cancer treatments, including clinical trials and experimental drugs, in real-time. MolecularMatch, a personalized cancer treatment company that works with labs, hospitals, genomic cores and physicians to connect cancer patients to treatment options, launched its MM LAB software today at The Molecular Medicine Tri-Conference. MM LAB, which is available through an online portal, allows pathology labs and others to match patients’ test results to personalized cancer treatments, including clinical trials and experimental drugs, in real-time. It is based on the already available, public-facing MolecularMatch cancer treatment search engine. “We’ve taken a time-consuming, manual task that usually happens after lab results are returned, and automated it with an intelligent, science-based, Google-like search,” said MolecularMatch CEO Kevin Coker. “With MM LAB, oncologists and patients get test results and easily understandable treatment options all at once, rather than having to wait even longer to find and begin a course of treatment.” After test results are matched to treatments in MM LAB, the options are curated by the client laboratory's staff and included in the reports sent back to physicians and patients. “MolecularMatch provides a powerful resource for molecular pathologists,” said Christopher Corless, MD, PhD., Chief Medical Officer of OHSU Knight Diagnostic Laboratories. “Identifying treatment options — particularly trials — is a time-consuming task. The MolecularMatch platform allows our team to efficiently match complex genomic test data to appropriate treatment options in much less time.”
Racis L.,University of Sassari |
Tessa A.,Molecular Medicine |
Storti E.,Molecular Medicine |
Santorelli F.M.,Molecular Medicine
European Journal of Paediatric Neurology | Year: 2014
Background Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare, early-onset autosomal recessive motor neuron disease associated with mutations in ALS2. Aim We studied a 17-year-old boy who had features of IAHSP. We also reviewed the current literature on ALS2-related syndromes. Methods Clinical and neuroimaging studies were performed. Blood DNA analyses were combined with mRNA studies in cultured skin fibroblasts. Results Like previously described cases, the patient presented with severe spastic paraparesis and showed rapid progression of paresis to the upper limbs. He also developed bulbar involvement and severe scoliosis during childhood. In blood DNA we identified a novel splice-site homozygous mutation in ALS2 (c.3836+1G > T), producing exon skipping in fibroblast mRNA and predicting premature protein truncation. Conclusions This case adds to the allelic heterogeneity of IAHSP. Review of the pertinent literature indicates a fairly homogeneous clinical picture in IAHSP that should facilitate molecular confirmation and prevention of long-term complications. © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.