Decreased Aerobic Capacity in ANO5-Muscular Dystrophy

Peer reviewe

Dominant Distal Myopathy 3 (MPD3) Caused by a Deletion in the HNRNPA1 Gene

Background and Objectives To determine the genetic cause of the disease in the previously reported family with adult-onset autosomal dominant distal myopathy (myopathy, distal, 3; MPD3). Methods Continued clinical evaluation including muscle MRI and muscle pathology. A linkage analysis with single nucleotide polymorphism arrays and genome sequencing were used to identify the genetic defect, which was verified by Sanger sequencing. RNA sequencing was used to investigate the transcriptional effects of the identified genetic defect. Results Small hand muscles (intrinsic, thenar, and hypothenar) were first involved with spread to the lower legs and later proximal muscles. Dystrophic changes with rimmed vacuoles and cytoplasmic inclusions were observed in muscle biopsies at advanced stage. A single nucleotide polymorphism array confirmed the previous microsatellite-based linkage to 8p22-q11 and 12q13-q22. Genome sequencing of three affected family members combined with structural variant calling revealed a small heterozygous deletion of 160 base pairs spanning the second last exon 10 of the heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) gene, which is in the linked region on chromosome 12. Segregation of the mutation with the disease was confirmed by Sanger sequencing. RNA sequencing showed that the mutant allele produces a shorter mutant mRNA transcript compared with the wild-type allele Immunofluorescence studies on muscle biopsies revealed small p62 and larger TDP-43 inclusions. Discussion A small exon 10 deletion in the gene HNRNPA1 was identified as the cause of MPD3 in this family. The new HNRNPA1-related phenotype, upper limb presenting distal myopathy, was thus confirmed, and the family displays the complexities of gene identification.Peer reviewe

A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy

Axial myopathy is a rare neuromuscular disease that is characterized by paraspinal muscle atrophy and abnormal posture, most notably camptocormia (also known as bent spine). The genetic cause of familial axial myopathy is unknown. Described here are the clinical features and cause of late-onset predominant axial myopathy and encephalopathy. A 73-year-old woman presented with a 10-year history of severe paraspinal muscle atrophy and cerebellar ataxia. Her 84-year-old sister also developed late-onset paraspinal muscle atrophy and generalized seizures with encephalopathy. Computed tomography showed severe atrophy and fatty degeneration of their paraspinal muscles. Their mother and maternal aunt also developed bent spines. The existence of many ragged-red fibers and cytochrome c oxidase-negative fibers in the biceps brachii muscle of the proband indicated a mitochondrial abnormality. No significant abnormalities were observed in the respiratory chain enzyme activities; however, the activities of complexes I and IV were relatively low compared with the activities of other complexes. Sequence analysis of the mitochondrial DNA from the muscle revealed a novel heteroplasmic mutation (m.602C>T) in the mitochondrial tRNAPhe gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease

Upregulated IL-1β in dysferlin-deficient muscle attenuates regeneration by blunting the response to pro-inflammatory macrophages.

BACKGROUND: Loss-of-function mutations in the dysferlin gene (DYSF) result in a family of muscle disorders known collectively as the dysferlinopathies. Dysferlin-deficient muscle is characterized by inflammatory foci and macrophage infiltration with subsequent decline in muscle function. Whereas macrophages function to remove necrotic tissue in acute injury, their prevalence in chronic myopathy is thought to inhibit resolution of muscle regeneration. Two major classes of macrophages, classical (M1) and alternative (M2a), play distinct roles during the acute injury process. However, their individual roles in chronic myopathy remain unclear and were explored in this study. METHODS: To test the roles of the two macrophage phenotypes on regeneration in dysferlin-deficient muscle, we developed an in vitro co-culture model of macrophages and muscle cells. We assayed the co-cultures using ELISA and cytokine arrays to identify secreted factors and performed transcriptome analysis of molecular networks induced in the myoblasts. RESULTS: Dysferlin-deficient muscle contained an excess of M1 macrophage markers, compared with WT, and regenerated poorly in response to toxin injury. Co-culturing macrophages with muscle cells showed that M1 macrophages inhibit muscle regeneration whereas M2a macrophages promote it, especially in dysferlin-deficient muscle cells. Examination of soluble factors released in the co-cultures and transcriptome analysis implicated two soluble factors in mediating the effects: IL-1β and IL-4, which during acute injury are secreted from M1 and M2a macrophages, respectively. To test the roles of these two factors in dysferlin-deficient muscle, myoblasts were treated with IL-4, which improved muscle differentiation, or IL-1β, which inhibited it. Importantly, blockade of IL-1β signaling significantly improved differentiation of dysferlin-deficient cells. CONCLUSIONS: We propose that the inhibitory effects of M1 macrophages on myogenesis are mediated by IL-1β signals and suppression of the M1-mediated immune response may improve muscle regeneration in dysferlin deficiency. Our studies identify a potential therapeutic approach to promote muscle regeneration in dystrophic muscle

Kustannus-hyötyanalyysimalli julkisten palveluiden tilaratkaisumuutoksille

Tämä tutkimus suoritetaan osana Liikelaitos Oulun Tilakeskuksen johtamaa hankesuunnitelmaa, jonka tarkoituksena on Myllytullin alueen museoiden ja tiedekeskuksen yhteisen organisaation toiminnan puitteiden tutkiminen ja esittäminen. Tutkimuksen tarkoituksena on selvittää kasvavan trendin, kulttuuri-instituutioiden yhdistymiseen, liittyvän tilaratkaisuvaihtoehtojen kustannus-hyötyanalyysin käyttöä ja toteuttamista. Lisäksi tutkimuksen tarkoituksena on luoda Oulun kaupungille kustannus-hyötyanalyysimalli, jota Liikelaitos Oulun Tilakeskus voi käyttää jatkossa hankkeissaan eri hankevaihtoehtojen kannattavuuksia vertaillessa. Tutkimuksen teoriaosiossa käsitellään kustannus-hyötyanalyysiä kirjallisuuskatsauksena eri artikkeleiden, tieteellisten kirjajulkaisuiden ja Internet-lähteiden pohjalta. Se pyrkii kattamaan kustannus-hyötyanalyysin keskeisimmät asiat, kuten kustannus-hyötyanalyysin määritelmän, vaiheet, ajoittamisen ja käyttäjäperspektiivit. Lisäksi tutkimusta varten selvennettiin herkkyysanalyysi, diskonttaus ja diskonttokoron valinta. Muita tutkimuksessa käsiteltyjä relevantteja aiheita ovat kulttuuripalveluiden kustannusten ja hyötyjen määrittäminen sekä kulttuuri-instituutioiden fuusioituminen. Empiriaosiossa etsitään informaatiota kulttuuri-instituutioiden tilaratkaisuvaihtoehtojen kustannus-hyötyanalyysille eri museotiedusteluilla, haastatteluilla ja aivoriihikokouksilla hankkeen sidosryhmien jäsenten kanssa. Empiriaosassa käsitellään kustannus-hyötyanalyysiä tapausesimerkin avulla, jossa huomioidaan tehtävänannon mukaan museoiden ja tiedekeskuksen toiminnalliset synergia- ja prosessihyödyt verrattuna tilojen määrän kasvun aiheuttamaan lisäkustannukseen. Viimeisessä osiossa vastataan tutkimuskysymyksiin, tarkastellaan tutkimusta kriittisesti ja pohditaan aiheita jatkotutkimuksille. Tutkimustulokset selvittävät työn tilaajalle, mitä asioita on tärkeä huomioida kustannus-hyötyanalyysissä kulttuuri-instituutioille. Tuloksissa selvitetään mitkä ovat ne tekijät, jotka vaikuttavat eniten julkisten tilaratkaisuhankkeiden vaihtoehtovalintaan kustannus-hyötyanalyysia tehtäessä. Lisäksi pohditaan miten kustannuksia ja hyötyjä tulee kerätä ja arvioida tapausesimerkin tyyppisissä hankkeissa.This study is performed as a part of the project plan leaded by Liikelaitos Oulun Tilakeskus. The project aims to studying and presenting the unification possibilities of the Myllytulli’s area museums’ and science center’s joint organization. The purpose of the study is to find out the use and implementation of cost-benefit analysis in the increasing trend of cultural institution mergers and their space-related solutions. In addition, this study aims to establish a cost-benefit model for the City of Oulu, which the city may use in comparing the profitability of various project alternatives in their future purposes. The theoretical section deals with cost-benefit analysis as a literature review through different articles, scientific publications and Internet sources. It aims to cover the key issues of cost-benefit analysis, such as the definition, steps and user perspectives of cost-benefit analysis. In addition, the research clarifies the sensitivity analysis, discounting and the selection of the discount rate. Other relevant topics dealt are the determination of the costs and benefits of cultural services and cultural institution mergers. The empirical section sought information about space-related solutions in cost-benefit analysis through different requests for information, interviews and brainstorming sessions with the stakeholders of the project. The empirical section deals with the cost-benefit analysis through a case example that takes into account the assignment of the museums and science center operational synergy and process benefits compared to the additional cost entailed via the growth of facilities. In the last section of this study, research questions are answered, this study is critically examined and topics for further research are discussed. The results clarify to the client what matters are important to the cost-benefit analysis of cultural institutions. The results explain what are the factors that mostly affect the cost-benefit analysis of public space-related projects. It will also address how the costs and benefits need to be collected and evaluated in projects similar to the case study

Concurrent Paraspinous Myopathy and Myasthenia Gravis.

Paraspinous myopathy is a rare neuromuscular disorder characterized by selective involvement of the cervical, thoracic, or lumbar muscles. Leading clinical features include a bent spine or dropped head (antecollis). In myasthenia gravis (MG), patients may have camptocormia secondary to neuromuscular junction dysfunction of the paraspinal muscles, and this condition usually responds to acetylcholinesterase inhibitors or immunosuppressive treatments. However, concomitant MG and paraspinous myopathy with histologic and electrophysiologic evidence of myopathic changes of the paraspinal muscles has only been reported twice in the literature. In this case series, 5 patients with MG with paraspinous myopathy are reported. While neck and extension truncal weakness is not uncommon in MG, most often the weakness is due to neuromuscular junction dysfunction. Coexisting paraspinous myopathy and MG is under-recognized, is often resistant to mainstay treatments, and should be considered in patients presenting with neck or trunk extensor weakness