Publications by authors named "Julia Button"

12 Publications

  • Page 1 of 1

Chronic Fatigue After Thyroidectomy: A Patient-Centered Survey.

Am Surg 2021 Jan 31:3134821989054. Epub 2021 Jan 31.

Department of Surgery, 2332University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Fatigue after thyroidectomy is common, but there is a paucity of data regarding its prevalence and duration. We hypothesized that total thyroidectomy (TT) patients would have more long-term fatigue than thyroid lobectomy (TL) patients.

Methods: Statewide survey of thyroidectomy patients (2004-2017) was carried out.

Results: 281 patients completed the survey. 216 respondents (77%) had TT and 65 (23%) had TL. Within one year of surgery, 172 (61%) respondents recalled being troubled by new fatigue all, most, or some of the time. Total thyroidectomy patients were more likely to report new fatigue (69% vs. 44%, aOR 2.72, 95% CI 1.44 to 5.18). Of patients ( = 172) reporting new fatigue, 67 (39%) reported at least moderate improvement. Nineteen (28%) saw improvement within 1 year, 35 (52%) saw improvement in 1-2 years, and 11 (16%) saw improvement after 2 years.

Conclusion: Long-term fatigue after TT can be debilitating, long-lasting, and less prevalent after TL.
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http://dx.doi.org/10.1177/0003134821989054DOI Listing
January 2021

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Brain 2020 04;143(4):1127-1142

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
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http://dx.doi.org/10.1093/brain/awaa062DOI Listing
April 2020

Progressive Multiple Sclerosis Is Associated with Faster and Specific Retinal Layer Atrophy.

Ann Neurol 2020 06 28;87(6):885-896. Epub 2020 Apr 28.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objective: Therapeutic development in progressive multiple sclerosis (PMS) has been hampered by a lack of reliable biomarkers to monitor neurodegeneration. Optical coherence tomography (OCT)-derived retinal measures have been proposed as promising biomarkers to fulfill this role. However, it is unclear whether retinal atrophy persists in PMS, exceeds normal aging, or can be distinguished from relapsing-remitting multiple sclerosis (RRMS).

Methods: 178 RRMS, 186 PMS, and 66 control participants were followed with serial OCT for a median follow-up of 3.7 years.

Results: The estimated proportion of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell + inner plexiform layer (GCIPL) thinning in multiple sclerosis (MS) attributable to normal aging increased from 42.7% and 16.7% respectively at age 25 years, to 83.7% and 81.1% at age 65 years. However, independent of age, PMS was associated with faster pRNFL (-0.34 ± 0.09%/yr, p < 0.001) and GCIPL (-0.27 ± 0.07%/yr, p < 0.001) thinning, as compared to RRMS. In both MS and controls, higher baseline age was associated with faster inner nuclear layer (INL) and outer nuclear layer (ONL) thinning. INL and ONL thinning were independently faster in PMS, as compared to controls (INL:-0.09 ± 0.04%/yr, p = 0.03; ONL:-0.12 ± 0.06%/yr, p = 0.04), and RRMS (INL:-0.10 ± 0.04%/yr, p = 0.01; ONL:-0.13 ± 0.05%/yr, p = 0.01), whereas they were similar in RRMS and controls. Unlike RRMS, disease-modifying therapies (DMTs) did not impact rates of retinal layer atrophy in PMS.

Interpretation: PMS is associated with faster retinal atrophy independent of age. INL and ONL measures may be novel biomarkers of neurodegeneration in PMS that appear to be unaffected by conventional DMTs. The effects of aging on rates of retinal layer atrophy should be considered in clinical trials incorporating OCT outcomes. ANN NEUROL 2020;87:885-896.
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http://dx.doi.org/10.1002/ana.25738DOI Listing
June 2020

Retinal measurements predict 10-year disability in multiple sclerosis.

Ann Clin Transl Neurol 2019 02 19;6(2):222-232. Epub 2019 Jan 19.

Department of Neurology Johns Hopkins University Baltimore Maryland.

Objective: Optical coherence tomography (OCT)-derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long-term disability is unknown. We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later.

Methods: Between 2006 and 2008, 172 people with MS underwent Stratus time domain-OCT imaging [160 with measurement of total macular volume (TMV)] and high and low-contrast letter acuity (LCLA) testing ( = 150; 87%). All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10-year follow-up. We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10-year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status.

Results: In multivariable models, lower baseline TMV was associated with higher 10-year EDSS scores (mean increase in EDSS of 0.75 per 1 mm loss in TMV (mean difference = 0.75; 95% CI: 0.11-1.39;  = 0.02). In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.86 higher EDSS scores at 10 years (mean difference = 0.86; 95% CI: 0.23-1.48) and had over 3.5-fold increased odds of clinically significant EDSS worsening relative to those in the highest tertile of baseline TMV (OR: 3.58; 95% CI: 1.30-9.82; = 0.008). pRNFL and LCLA predicted the 10-year EDSS scores only in univariate models.

Interpretation: Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status.
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http://dx.doi.org/10.1002/acn3.674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389740PMC
February 2019

Characteristics of morphologic macular abnormalities in neuroimmunology practice.

Mult Scler 2019 03 10;25(3):361-371. Epub 2017 Nov 10.

Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, USA.

Background: Morphologic macular abnormalities (MMAs) are frequently seen on macular optical coherence tomography (OCT) imaging in neuroimmunology practice, yet studies pragmatically assessing prevalence and risk factors of MMAs to date are limited.

Objective: To describe the characteristics of MMAs in a neuroimmunology-based academic practice.

Methods: Cross-sectional study of 1450 patients (2900 eyes) who underwent spectral-domain macular OCT between June 2010 and June 2012. The association between MMAs and demographic variables was analyzed using mixed-effects logistic regression. Odds ratios (ORs) were calculated per 5-year age increments.

Results: MMAs were observed in 338/2872 eyes (11.7%) of 232/1445 participants (16.1%). The most common abnormalities identified, included drusen (6.0%), epiretinal membrane (ERM; 5.5%), and microcystoid macular pathology (MMP; 1.9%). Overall, patients with MMAs were older (OR: 1.79, p = 5 × 10) and more likely to be males (OR: 2.45, p = 0.014). In particular, advancing age was associated with higher risk of drusen and ERM (OR: 1.80 and 4.26, p = 2 × 10 and 7 × 10, respectively). MMP prevalence declined with age (OR: 0.73, p = 0.015) and was associated with African-American ethnicity (OR: 15.0, p = 5 × 10).

Conclusion: Unexpected or incidental MMAs are common in patients assessed with OCT in neuroimmunology practice, emphasizing the importance of comprehensive OCT image review for risk stratification and appropriate ophthalmology referral.
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http://dx.doi.org/10.1177/1352458517741206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929206PMC
March 2019

Longitudinal multiple sclerosis lesion segmentation data resource.

Data Brief 2017 Jun 8;12:346-350. Epub 2017 Apr 8.

CNRM, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20892, USA.

The data presented in this article is related to the research article entitled "Longitudinal multiple sclerosis lesion segmentation: Resource and challenge" (Carass et al., 2017) [1]. In conjunction with the 2015 International Symposium on Biomedical Imaging, we organized a longitudinal multiple sclerosis (MS) lesion segmentation challenge providing training and test data to registered participants. The training data consists of five subjects with a mean of 4.4 (±0.55) time-points, and test data of fourteen subjects with a mean of 4.4 (±0.67) time-points. All 82 data sets had the white matter lesions associated with multiple sclerosis delineated by two human expert raters. The training data including multi-modal scans and manually delineated lesion masks is available for download. In addition, the testing data is also being made available in conjunction with a website for evaluating the automated analysis of the testing data.
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http://dx.doi.org/10.1016/j.dib.2017.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412004PMC
June 2017

Retrograde trans-synaptic visual pathway degeneration in multiple sclerosis: A case series.

Mult Scler 2017 Jun 7;23(7):1035-1039. Epub 2017 Apr 7.

The Division of Neuroimmunology and Neurological Infections, Department of Neurology, The Johns Hopkins hospital, Baltimore, MD, USA.

Background: Trans-synaptic degeneration (TSD) describes the propagation of neuronal injury through synaptic pathways in the human nervous system and may be linked to the accelerated retinal atrophy seen in multiple sclerosis (MS).

Results: We report six cases where homonymous, hemi-macular ganglion cell + inner plexiform (GCIP) thickness reduction was seen in conjunction with posterior visual pathway lesions. Macular microcystoid changes of the inner nuclear layer (INL) were seen in a subset of three subjects.

Conclusion: Our findings highlight the utility of assessing regional GCIP changes to identify potential retrograde TSD in MS and demonstrate that INL changes may be an accompaniment in such instances.
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http://dx.doi.org/10.1177/1352458516679035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451303PMC
June 2017

Longitudinal multiple sclerosis lesion segmentation: Resource and challenge.

Neuroimage 2017 03 11;148:77-102. Epub 2017 Jan 11.

Institute of Medical Informatics, University of Lübeck, 23538 Lübeck, Germany.

In conjunction with the ISBI 2015 conference, we organized a longitudinal lesion segmentation challenge providing training and test data to registered participants. The training data consisted of five subjects with a mean of 4.4 time-points, and test data of fourteen subjects with a mean of 4.4 time-points. All 82 data sets had the white matter lesions associated with multiple sclerosis delineated by two human expert raters. Eleven teams submitted results using state-of-the-art lesion segmentation algorithms to the challenge, with ten teams presenting their results at the conference. We present a quantitative evaluation comparing the consistency of the two raters as well as exploring the performance of the eleven submitted results in addition to three other lesion segmentation algorithms. The challenge presented three unique opportunities: (1) the sharing of a rich data set; (2) collaboration and comparison of the various avenues of research being pursued in the community; and (3) a review and refinement of the evaluation metrics currently in use. We report on the performance of the challenge participants, as well as the construction and evaluation of a consensus delineation. The image data and manual delineations will continue to be available for download, through an evaluation website as a resource for future researchers in the area. This data resource provides a platform to compare existing methods in a fair and consistent manner to each other and multiple manual raters.
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http://dx.doi.org/10.1016/j.neuroimage.2016.12.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344762PMC
March 2017

Disease-modifying therapies modulate retinal atrophy in multiple sclerosis: A retrospective study.

Neurology 2017 02 11;88(6):525-532. Epub 2017 Jan 11.

From the Departments of Neurology (J.B., O.A.-L., P.B., S.D.N., P.A.C., S.S.) and Electrical and Computer Engineering (A.L., J.P.), Johns Hopkins University, Baltimore, MD; Department of Internal Medicine (O.A.-L.), North Shore Medical Center, Salem, MA; Department of Neurology and Ophthalmology (T.F., E.M.F.), University of Texas Southwestern, Dallas; and Department of Neurology (L.J.B.), New York University Langone Medical Center, New York.

Objective: To retrospectively investigate whether disease-modifying therapies (DMTs) exert differential effects on rates of retinal atrophy in relapsing-remitting multiple sclerosis (RRMS), as assessed using optical coherence tomography (OCT).

Methods: A total of 402 patients with RRMS followed at the Johns Hopkins MS Center who underwent Cirrus-HD OCT were assessed for eligibility. Inclusion criteria included at least 1 year of OCT follow-up and adherence to a single DMT during the period of follow-up. Combined thickness of the ganglion cell + inner plexiform (GCIP) and other retinal layers was computed utilizing automated macular segmentation. Retinal thickness changes were analyzed using mixed-effects linear regression.

Results: The effects of glatiramer acetate (GA; n = 48), natalizumab (NAT; n = 46), and interferon-β-1a subcutaneously (IFN; n = 35) and intramuscularly (IFN; n = 28) were assessed. Baseline analyses revealed no significant differences between groups in terms of age, sex, optic neuritis history, or follow-up duration. During follow-up, relative to NAT-treated patients, IFN- and GA-treated patients exhibited 0.37 μm/y (p < 0.001) and 0.14 μm/y (p = 0.035) faster rates of GCIP thinning, respectively, adjusting for the interval between initiation of DMT and OCT monitoring (gap time), age, sex, relapses, and disease duration. In the IFN group, GCIP thinning was 1.53 μm/y faster during the first year of therapy vs during the time interval afterwards (p < 0.001).

Conclusions: Rates of GCIP atrophy in patients with RRMS vary according to DMT utilization. Our findings support OCT for monitoring neurodegenerative treatment effects in the retina, an easily accessible tissue, and as a practical outcome measure in RRMS clinical trials.
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http://dx.doi.org/10.1212/WNL.0000000000003582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304463PMC
February 2017

Retinal degeneration in primary-progressive multiple sclerosis: A role for cortical lesions?

Mult Scler 2017 01 11;23(1):43-50. Epub 2016 Jul 11.

Departments of Neurology, Radiology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA/Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Perinatal Sciences, University of Genoa, Genoa, Italy.

Background: Retinal atrophy in multiple sclerosis (MS) is secondary to optic nerve focal inflammation and to injury of the posterior visual pathway.

Objectives: To investigate the contribution of cortical lesions (CLs) to retinal pathology in primary-progressive multiple sclerosis (PPMS).

Methods: We performed a cross-sectional evaluation of 25 patients and 20 controls, relating magnetic resonance imaging (MRI) metrics of visual pathway integrity with parameters derived from spectral-domain optical coherence tomography (peripapillary retinal nerve fiber layer (RNFL) thickness, ganglion cell + inner plexiform layer (GCIPL) thickness, and macular volume (MV)).

Results: Mean RNFL, GCIPL thickness, and MV were significantly reduced in patients compared to controls. MV and GCIPL thickness were significantly correlated with visual acuity. RNFL thinning was associated with thalamus and visual cortex volume (respectively, p = 0.01 and p < 0.05). In addition to thalamic volume, GCIPL thinning was associated with CLs and intracortical lesion number and volume, leucocortical lesion volume (all p ⩽ 0.05) while MV decrease was associated with CLs volume ( p = 0.05) and intracortical lesion number and volume ( p < 0.05).

Conclusion: Our results suggest that RNFL thinning and GCIPL thinning/MV decrease may be explained by alternative mechanisms including retrograde trans-synaptic degeneration and/or a common pathophysiologic process affecting both the brain with CLs and the retina with neuronal loss.
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http://dx.doi.org/10.1177/1352458516637679DOI Listing
January 2017

Alternative transcription initiation leads to expression of a novel ALK isoform in cancer.

Nature 2015 Oct 7;526(7573):453-7. Epub 2015 Oct 7.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.

Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ∼11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK(ATI). In ALK(ATI)-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signalling pathways, drives growth-factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
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http://dx.doi.org/10.1038/nature15258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807020PMC
October 2015

Dynamic modulation of innate immune response by varying dosages of lipopolysaccharide (LPS) in human monocytic cells.

J Biol Chem 2014 Aug 26;289(31):21584-90. Epub 2014 Jun 26.

From the Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061 and the Virginia Tech Carillion School of Medicine, Roanoke, Virginia 24016

Innate monocytes and macrophages can be dynamically programmed into distinct states depending upon the strength of external stimuli. Innate programming may bear significant relevance to the pathogenesis and resolution of human inflammatory diseases. However, systems analyses with regard to the dynamic programming of innate leukocytes are lacking. In this study, we focused on the dynamic responses of human promonocytic THP-1 cells to lipopolysaccharide (LPS). We observed that varying dosages of LPS differentially modulate the expression of selected pro- and anti- inflammatory mediators such as IL-6 and IL-33. Super-low dosages of LPS preferentially induced the pro-inflammatory mediator IL-6, while higher dosages of LPS induced both IL-6 and IL-33. Mechanistically, we demonstrated that super-low and high doses of LPS cause differential activation of GSK3 and Akt, as well as the transcription factors FoxO1 and CREB. Inhibition of GSK3 enabled THP-1 cells to express IL-33 when challenged with super-low dose LPS. On the other hand, activation of CREB with adenosine suppressed IL-6 expression. Taken together, our study reveals a dynamic modulation of monocytic cells in response to varying dosages of endotoxin, and may shed light on our understanding of the dynamic balance that controls pathogenesis and resolution of inflammatory diseases.
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http://dx.doi.org/10.1074/jbc.M114.583518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118118PMC
August 2014