A Phase 2 Study of AMO-02 (tideglusib) in Congenital and Childhood Onset Myotonic Dystrophy Type 1 (DM1)

Background: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in Type 1 myotonic dystrophy (DM1), a rare neuromuscular disorder that manifests at any age. AMO-02 (tideglusib) inhibits GSK3β activity in preclinical models of DM1 and promotes cellular maturation as well as normalizing aberrant molecular and behavioral phenotypes. This Phase 2 study assessed the pharmacokinetics, safety and tolerability, and preliminary efficacy, of AMO-02 in adolescents and adults with Congenital and Childhood-onset DM1. Methods: Sixteen subjects (aged 13 to 34) with Congenital and Childhood-onset DM1 received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n=8) or 1000 mg (n=8) of AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and ECGs, as well as efficacy assessments of syndromal, cognitive and muscular functioning, were obtained. Results: AMO-02 plasma concentrations conformed to a two-compartment model with first-order absorption and elimination, and dose-dependent increases in exposure (area-under-the-curve, or AUC) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events nor dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their CNS and neuromuscular symptoms after 12 weeks of treatment compared to the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative AUC) was significantly correlated (p<0.01) with change from baseline on several key efficacy assessments. Conclusion: AMO-02 has favorable pharmacokinetic and clinical risk/benefit profiles meriting further study as a potential treatment for Congenital and Childhood-onset DM1

A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders

\ua9 2024 The AuthorsMitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre

Queixas musculoesqueléticas em uma Unidade Básica de Saúde: implicações para o planejamento das ações em saúde e fisioterapia

OBJETIVO: O objetivo deste estudo foi analisar a prevalência de queixas musculoesqueléticas em adultos em uma Unidade Básica de Saúde. MÉTODO: Foram avaliados os usuários atendidos na recepção espontânea no período de março de 2010 a maio de 2011. Ao todo, foram estudados 1.023 indivíduos. A caracterização das queixas foi realizada por meio de questionário com dados sociodemográficos e motivo da procura por atendimento. RESULTADOS: Os dados mostraram que a maioria dos usuários pertence ao sexo feminino (71,2%), está na faixa etária de 31 a 60 anos (50,0%), é solteira (31,6%), aposentada (14,2%) e apresenta queixas em vários sistemas (77,1%). O sistema musculoesquelético é o mais acometido (14,4%), representando o segundo motivo de procura por atendimento (31,0%). Analisando as razões de chance de ocorrência de queixas musculoesqueléticas com relação às variáveis estudadas, verificou-se que pessoas com idade entre 40 e 59 anos apresentaram 3,49 (IC95% 2,17-5,57) vezes mais chances de associação com essas dores do que as demais. Não houve associação entre outros sistemas e variáveis. CONCLUSÃO: A alta prevalência de queixas musculoesqueléticas requer um novo olhar de gestores em saúde para o atendimento destas demandas, pensando em incluir o fisioterapeuta na atenção básica para tratamento de dores de menor complexidade

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Search for the neutral Higgs bosons of the minimal supersymmetric standard model in pp collisions at root s=7 TeV with the ATLAS detector

A search for neutral Higgs bosons of the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is based on a sample of proton-proton collisions at a centre-of-mass energy of 7TeV recorded with the ATLAS detector at the Large Hadron Collider. The data were recorded in 2011 and correspond to an integrated luminosity of 4.7 fb-1 to 4.8 fb-1. Higgs boson decays into oppositely-charged muon or τ lepton pairs are considered for final states requiring either the presence or absence of b-jets. No statistically significant excess over the expected background is observed and exclusion limits at the 95% confidence level are derived. The exclusion limits are for the production cross-section of a generic neutral Higgs boson, φ, as a function of the Higgs boson mass and for h/A/H production in the MSSM as a function of the parameters mA and tan β in the mhmax scenario for mA in the range of 90GeV to 500 GeV. Copyright CERN

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques