Paula R Clemens

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Are you Paula R Clemens?

Claim your profile

Publications (99)558.52 Total impact

  • P. Clemens · L. Morgenroth · K. Clinard · R. Bendixen

    No preview · Article · Oct 2015 · Neuromuscular Disorders

  • No preview · Article · Oct 2015 · Neuromuscular Disorders
  • [Show abstract] [Hide abstract]
    ABSTRACT: An opt-out newborn screening (NBS) program for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) was implemented at 2 hospitals in Pittsburgh, Pennsylvania between 1987 and 1995. For patients and their parents in families that received a diagnosis of DMD or BMD, either by NBS or by traditional diagnostics after symptom onset, attitudes toward NBS for DMD and BMD were assessed. All patients and most parents supported NBS for DMD and BMD. In contrast to the NBS parent cohort, the non-NBS cohort felt that diagnosis by NBS would cause anxiety. There was strong support of NBS for DMD and BMD in both patients and their parents in families who received a diagnosis through NBS or through traditional diagnostics. No negative psychosocial impacts of NBS were identified among those families who received a diagnosis through NBS. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Aug 2015 · Muscle & Nerve
  • [Show abstract] [Hide abstract]
    ABSTRACT: Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.
    No preview · Article · May 2015 · Proceedings of the National Academy of Sciences
  • [Show abstract] [Hide abstract]
    ABSTRACT: In Duchenne muscular dystrophy (DMD) patients and the mdx mouse model of DMD, chronic activation of the classical nuclear factor κB (NF-κB) pathway contributes to the pathogenesis that causes degeneration of muscle fibers, inflammation and fibrosis. Prior studies demonstrate that inhibition of IKK-mediated NF-κB activation using L-isomer NF-κB essential modulator (NEMO) binding domain (NBD) peptide-based approaches reduce muscle pathology in the mdx mouse. For our studies, the NBD peptide is synthesized as a fusion peptide with an eight lysine (8K) protein transduction domain to facilitate intra-cellular delivery. We hypothesized that D-isoform peptide could have a greater effect than the naturally occurring L-isoform peptide due to longer persistence of the D-isoform peptide in vivo. In this study, we compared systemic treatment with low (1mg/kg) and high (10mg/kg) doses of L- and D-isomer 8K-wild type-NBD peptide in mdx mice. Treatment with both L- or D-isoform 8K-wild type-NBD peptide resulted in decreased activation of NF-κB and improved histology in skeletal muscle of the mdx mouse. However, we observed kidney toxicity, characterized by proteinuria, increased serum creatinine, activation of NF-κB and pathological changes in kidney cortex, that was most severe with treatment with the D-isoform of 8K-wild type-NBD peptide. The observed toxicity was also seen in normal mice.
    No preview · Article · May 2015 · Molecular Medicine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac disease is a major cause of death in patients with muscular dystrophies. The use of feasible and reproducible echocardiographic measures of cardiac function is critical to advance the field of therapeutics for dystrophic cardiomyopathy. Participants aged 8 to 18 years with genetically confirmed Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, or limb-girdle muscular dystrophy were enrolled at five centers, and standardized echocardiographic examinations were performed. Measures of systolic and diastolic function and speckle-tracking echocardiography-derived cardiac strain were reviewed independently by two central readers. Furthermore, echocardiographic measures from participants with DMD were compared with those from retrospective age-matched control subjects from a single site to assess measures of myocardial function. Forty-eight participants (mean age, 13.3 ± 2.7 years) were enrolled. Shortening fraction had a greater interobserver correlation (intraclass correlation coefficient [ICC] = 0.63) compared with ejection fraction (ICC = 0.49). One reader could measure ejection fraction in only 53% of participants. Myocardial performance index measured by pulse-wave Doppler and Doppler tissue imaging showed similar ICCs (0.55 and 0.54). Speckle-tracking echocardiography showed a high ICC (0.96). Focusing on participants with DMD (n = 33), significantly increased mitral A-wave velocities, lower E/A ratios, and lower Doppler tissue imaging mitral lateral E' velocities were observed compared with age-matched control subjects. Speckle-tracking echocardiography demonstrated subclinical myocardial dysfunction with decreased average circumferential and longitudinal strain in three distinct subgroups: participants with DMD with normal shortening fractions, participants with DMD aged < 13 years, and participants with DMD with myocardial performance index scores < 0.40 compared with control subjects. In a muscular dystrophy cohort, assessment of cardiac function is feasible and reproducible using shortening fraction, diastolic measures, and myocardial performance index. Cardiac strain measures identified early myocardial disease in patients with DMD. Copyright © 2015 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography
  • [Show abstract] [Hide abstract]
    ABSTRACT: Infantile FSHD is uncommon. We aim to describe the clinical features and secondary conditions in early onset FSHD. This study was conducted at participating Cooperative International Neuromuscular Research Group (CINRG) sites. The diagnosis was based on onset of symptoms involving the facial or shoulder girdle muscles and contraction of the D4Z4 repeat array (<38 kb) in the 4q35 subtelomeric region. In addition, participants were identified based on onset of facial and shoulder weakness <10 years of age. Clinical assessments included cognitive, hearing, eye, speech, and motor function evaluations. Descriptive statistics were used to summarize the baseline characteristics. Spearman correlation was used to determine the association between EcoR1 fragment size and degree of muscle involvement. To date, 20 participants (10 males and 10 females, median age = 16.7 (IQR 13.1–25.4) years) were recruited. The median EcoR1 fragment size was 15 (IQR 12–18.5) kb. 12/16 (75%) had <4 D4Z4 repeats and 8 (50%) had no family history of FSHD. The median age at onset of facial and shoulder weakness was 4 (IQR 1–6) and 7 (IQR 5–8) years respectively. Four (24%) participants were dependent on wheelchair for all mobility, 6 (46%) had noticeable speech impairment, and 15 (88%) had moderate to severe facial and scapular weakness. Extramuscular manifestations included 1 (6%) with intellectual disability, 3 (17%) with visual concerns, 4 (24%) with developmental delay, 6 (38%) with hearing loss, and 9 (53%) with chronic pain. The EcoR1 fragment size had a strong negative correlation with Brooke scale (r = −0.80), Vignos scale (r = −0.67), and FSHD clinical severity scale (r = −0.72 for facial, −0.64 for shoulder, and −0.60 for pelvic muscle weakness). Infantile FSHD causes severe weakness and early loss of independent ambulation. Smaller EcoR1 fragment size was associated with great disease severity. Additional longitudinal studies will help determine the rate of decline in motor function over time.
    No preview · Article · Oct 2014 · Neuromuscular Disorders
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD). Methods: This investigation was a cross-sectional cross-sectional analysis of clinical data from the multi-institutional Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study of 340 DMD patients aged 2-28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%. Results: Two hundred thirty-one participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47 of 174), and it was associated significantly with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P > 0.68). In patients with cardiomyopathy, 57% (27 of 47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15 of 127) of patients without cardiomyopathy. Conclusions: We found that echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort.
    Full-text · Article · Aug 2014 · Muscle & Nerve
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Disease inclusion in the newborn screening (NBS) panel should consider the opinions of those most affected by the outcome of screening. We assessed the level and factors that affect parent attitudes regarding NBS panel inclusion of Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and spinal muscular atrophy (SMA). Methods: The attitudes toward NBS for DMD, BMD, and SMA were surveyed and compared for 2 categories of parents, those with children affected with DMD, BMD, or SMA and expectant parents unselected for known family medical history. Results: The level of support for NBS for DMD, BMD, and SMA was 95.9% among parents of children with DMD, BMD, or SMA and 92.6% among expectant parents. Conclusions: There was strong support for NBS for DMD, BMD, and SMA in both groups of parents. Given advances in diagnostics and promising therapeutic approaches, discussion of inclusion in NBS should continue.
    No preview · Article · Jun 2014 · Muscle & Nerve
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gene correction is attractive for single gene mutation disorders, such as Duchenne muscular dystrophy (DMD). The mdx mouse model of DMD is dystrophin deficient due to a premature chain-terminating point mutation in exon 23 of the dystrophin gene. Gene editing of genomic DNA using single-stranded oligodeoxynucleotides (ssODNs) offers the potential to change the DNA sequence to alter mRNA and protein expression in defined ways. When applied to fetal skeletal muscle of mdx mice in utero, this technology leads to restoration of dystrophin protein expression, thus providing a valid gene-based therapeutic application at the earliest developmental stage. Here, we describe detailed methods for gene editing using muscle delivery of ssODNs to the fetal mdx mouse in utero at embryonic day 16 and to test correction of dystrophin deficiency at different ages after birth.
    No preview · Article · Feb 2014 · Methods in molecular biology (Clifton, N.J.)

  • No preview · Article · Oct 2013 · Neuromuscular Disorders
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have previously shown that i.m. administration of bacterially expressed murine histidyl-tRNA synthetase (HRS) triggers florid muscle inflammation (relative to appropriate control proteins) in various congenic strains of mice. Because severe disease develops even in the absence of adaptive immune responses to HRS, we sought to identify innate immune signaling components contributing to our model of HRS-induced myositis. In vitro stimulation assays demonstrated HRS-mediated activation of HEK293 cells transfected with either TLR2 or TLR4, revealing an excitatory capacity exceeding that of other bacterially expressed fusion proteins. Corresponding to this apparent functional redundancy of TLR signaling pathways, HRS immunization of B6.TLR2(-/-) and B6.TLR4(-/-) single-knockout mice yielded significant lymphocytic infiltration of muscle tissue comparable to that produced in C57BL/6 wild-type mice. In contrast, concomitant elimination of TLR2 and TLR4 signaling in B6.TLR2(-/-).TLR4(-/-) double-knockout mice markedly reduced the severity of HRS-induced muscle inflammation. Complementary subfragment analysis demonstrated that aa 60-90 of HRS were absolutely required for in vitro as well as in vivo signaling via these MyD88-dependent TLR pathways-effects mediated, in part, through preferential binding of exogenous ligands capable of activating specific TLRs. Collectively, these experiments indicate that multiple MyD88-dependent signaling cascades contribute to this model of HRS-induced myositis, underscoring the antigenic versatility of HRS and confirming the importance of innate immunity in this system.
    Full-text · Article · Jul 2013 · The Journal of Immunology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Unlabelled: introduction: Glucocorticoid (GC) therapy in Duchenne muscular dystrophy (DMD) has altered disease progression, necessitating contemporary natural history studies. Methods: The Cooperative Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 DMD males, ages 2-28 years. A comprehensive battery of measures was obtained. Results: A novel composite functional "milestone" scale scale showed clinically meaningful mobility and upper limb abilities were significantly preserved in GC-treated adolescents/young adults. Manual muscle test (MMT)-based calculations of global strength showed that those patients <10 years of age treated with steroids declined by 0.4 ± 0.39 MMT unit/year, compared with -0.4 ± 0.39 MMT unit/year in historical steroid-naive subjects. Pulmonary function tests (PFTs) were relatively preserved in steroid-treated adolescents. The linearity and magnitude of decline in measures were affected by maturational changes and functional status. Conclusions: In DMD, long-term use of GCs showed reduced strength loss and preserved functional capabilities and PFTs compared with previous natural history studies performed prior to the widespread use of GC therapy.
    Full-text · Article · Jul 2013 · Muscle & Nerve
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials. Methods The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2–28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/health-related quality-of-life instruments. ResultsGlucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years). Conclusions Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics. Muscle Nerve, 2013
    Full-text · Article · Jul 2013 · Muscle & Nerve
  • [Show abstract] [Hide abstract]
    ABSTRACT: Duchenne muscular dystrophy is a genetic muscle disease caused by absence of a functional dystrophin protein. Lack of dystrophin protein disrupts the dystrophin-glycoprotein complex causing muscle membrane instability and degeneration. One of the secondary manifestations resulting from lack of functional dystrophin in muscle tissue is increased level of cytokines that recruit inflammatory cells, leading to chronic up-regulation of the nuclear factor κB (NF-κB). Negative regulators of the classical NF-κB pathway improve muscle health in the mdx mouse model for DMD. We have previously shown in vitro that a negative regulator of the NF-κB pathway, A20, plays a role in muscle regeneration. Here, we show that over-expression of A20 using a muscle-specific promoter delivered with an adeno-associated virus serotype 8 vector to the mdx mouse decreases activation of the NF-κB pathway in skeletal muscle. Recombinant A20 expression resulted in a reduction in number of fibers with centrally placed nuclei and a reduction in the number of T-cells infiltrating muscle transduced with AAV8-A20 vector. Taken together, we conclude that over-expression of A20 in mdx skeletal muscle provides improved muscle health by reduction of chronic inflammation and muscle degeneration. These results suggest A20 is a potential therapeutic target to ameliorate symptoms of DMD.
    No preview · Article · Nov 2012 · Molecular Medicine
  • Nanette C Joyce · Lauren P Hache · Paula R Clemens
    [Show abstract] [Hide abstract]
    ABSTRACT: This article reviews the recent literature regarding bone health as it relates to the patient living with neuromuscular disease (NMD). Studies defining the scope of bone-related disease in NMD are scant. The available evidence is discussed, focusing on abnormal calcium metabolism, increased fracture risk, and the prevalence of both scoliosis and hypovitaminosis D in Duchenne muscular dystrophy, amyotrophic lateral sclerosis, and spinal muscular atrophy. Future directions are discussed, including the urgent need for studies both to determine the nature and extent of poor bone health, and to evaluate the therapeutic effect of available osteoporosis treatments in patients with NMD.
    No preview · Article · Nov 2012 · Physical Medicine and Rehabilitation Clinics of North America
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Late-onset Pompe disease is a progressive, debilitating, and often fatal neuromuscular disorder resulting from the deficiency of a lysosomal enzyme, acid α-glucosidase. This extension study was conducted to determine the durability of the efficacy and safety of alglucosidase alfa observed over a period of 78 weeks in the Late-Onset Treatment Study (LOTS). Methods: Patients who completed the LOTS study were eligible for this open-label extension study and received alglucosidase alfa 20mg/kg biweekly for an additional 26 weeks. The primary efficacy assessments were the distance walked during a 6-minute walk test and the percentage of predicted forced vital capacity in the upright position. Data are reported as change from patient's original LOTS baseline for each measure. Results: The benefit of alglucosidase alfa treatment observed in LOTS at Week 78 was, in general, maintained at Week 104. The mean increase in distance walked measured 28.2 ± 66.5m from LOTS baseline to Week 78 and 21.3 ± 78.0m from LOTS baseline to Week 104. The mean change from baseline in percentage of predicted forced vital capacity was 1.3% ± 5.7% from LOTS baseline to Week 78 and 0.8% ± 6.7% from LOTS baseline to Week 104. Treatment-related adverse events were mainly infusion-associated reactions observed in 35% of patients. No deaths or anaphylactic reactions were observed during the extension study. Conclusions: The LOTS Extension study showed that patients treated with alglucosidase alfa for up to 104 weeks maintained the improved walking distance and stabilization in pulmonary function observed in the first 78 weeks of alglucosidase alfa therapy.
    No preview · Article · Sep 2012 · Molecular Genetics and Metabolism
  • Hoda Abdel-Hamid · Paula R Clemens
    [Show abstract] [Hide abstract]
    ABSTRACT: The study reviews recent advances in pharmacological management of muscular dystrophies. Similarities and differences among the pathophysiology of different forms of muscular dystrophy lead to a broad array of approaches to provide new treatments. In this review, we include only those muscular dystrophies for which advances have been published in the past year. This represents the 'advancing edge' of a large body of research over more than 20 years. This runs the gamut of new discoveries in symptomatic management to mutation-specific strategies that attempt to correct the root cause of the disorder. The field of pharmacological therapies for the muscular dystrophies continues to steadily advance. It is encouraging that research into new therapies is increasingly exploring pharmacological strategies with the potential to ameliorate disease pathology to a clinically significant degree.
    No preview · Article · Aug 2012 · Current opinion in neurology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.
    Full-text · Article · Jun 2012 · The Journal of clinical investigation
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Therapeutic gene replacement of a dystrophin cDNA into dystrophic muscle can provide functional dystrophin protein to the tissue. However, vector-mediated gene transfer is limited by anti-vector and anti-transgene host immunity that causes rejection of the therapeutic protein. We hypothesized that rapamycin (RAPA) would diminish immunity due to vector-delivered recombinant dystrophin in the adult mdx mouse model for DMD. To test this hypothesis, we injected limb muscle of mdx mice with RAPA-containing, poly-lactic-co-glycolic acid (PLGA) microparticles prior to dystrophin gene transfer and analyzed treated tissue after 6 weeks. RAPA decreased host immunity against vector-mediated dystrophin protein, as demonstrated by decreased cellular infiltrates and decreased anti-dystrophin antibody production. The interpretation of the effect of RAPA on recombinant dystrophin expression was complex because of an effect of PLGA microparticles.
    Full-text · Article · May 2012 · Scientific Reports

Publication Stats

4k Citations
558.52 Total Impact Points


  • 1996-2015
    • University of Pittsburgh
      • • Department of Pediatrics
      • • Department of Neurology
      Pittsburgh, Pennsylvania, United States
  • 2012
    • University of Miami
      • Department of Neurology
      Coral Gables, FL, United States
  • 2011
    • Spokane VA Medical Center
      Spokane, Washington, United States
  • 2008
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2005
    • U.S. Department of Veterans Affairs
      Washington, Washington, D.C., United States
  • 2001
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 1991-1995
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, Texas, United States
  • 1994
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States