lllin000_PaperForge/audit/2AGGSMVQ/block_trace.csv

38 KiB
Raw Blame History

1pageblock_idraw_labelcontent_previewbboxrolerole_confidenceevidenceseed_roleseed_confidencezonestyle_familymarker_typerender_defaultindex_default
210doc_titleA Pulsing Electric Field (PEF) Increases Human Chondrocyte Proliferation through a Transduction Pathway Involving Nitric Oxide Signaling[66.0, 64.0, 1077.0, 139.0]paper_title0.8["page-1 zone title_zone: A Pulsing Electric Field (PEF) Increases Human Chondrocyte P"]paper_title0.8frontmatter_main_zonesupport_likenoneTrueTrue
311textRobert J. Fitzsimmons, $ ^{1} $ Stephen L. Gordon, $ ^{2} $ James Kronberg, $ ^{2} $ Timothy Ganey, $ ^{3} $ Arthur A. Pilla $ ^{4} $[67.0, 170.0, 833.0, 195.0]frontmatter_noise0.7["keyword-like block: Robert J. Fitzsimmons, $ ^{1} $ Stephen L. Gordon, $ ^{2} $ "]frontmatter_noise0.7body_zonereference_likecitation_lineFalseFalse
412text $ ^{1} $The Technical Basis LLC, 24769 Redlands Blvd, Suite E, Loma Linda, California 92354, $ ^{2} $Healthonics, Inc., Atlanta, Georgia, $ ^{3} $Department of Orthopedic Surgery, Atlanta Medical C[66.0, 207.0, 1079.0, 269.0]affiliation0.8["page-1 zone affiliation_zone: $ ^{1} $The Technical Basis LLC, 24769 Redlands Blvd, Suite "]affiliation0.8frontmatter_main_zonesupport_likeaffiliation_markerTrueTrue
513textReceived 12 June 2007; accepted 18 October 2007[66.0, 278.0, 416.0, 298.0]frontmatter_noise0.8["page-1 zone journal_furniture_zone: Received 12 June 2007; accepted 18 October 2007"]frontmatter_noise0.8frontmatter_main_zonesupport_likenoneFalseFalse
614textPublished online 31 January 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jor.20590[66.0, 298.0, 839.0, 318.0]frontmatter_noise0.7["frontmatter noise text: Published online 31 January 2008 in Wiley InterScience (www."]frontmatter_noise0.7frontmatter_main_zonesupport_likenoneFalseFalse
715abstractABSTRACT: A potential treatment modality for joint pain due to cartilage degradation is electromagnetic fields (EMF) that can be delivered, noninvasively, to chondrocytes buried within cartilage. A pu[67.0, 333.0, 1080.0, 614.0]abstract_body0.85["abstract label from Paddle OCR"]abstract_body0.85frontmatter_main_zonesupport_likenoneTrueTrue
816textKeywords: pulsing electric field; chondrocytes; DNA content; nitric oxide; cGMP[67.0, 628.0, 686.0, 650.0]frontmatter_noise0.7["frontmatter noise text: Keywords: pulsing electric field; chondrocytes; DNA content;"]frontmatter_noise0.7frontmatter_main_zonesupport_likenoneFalseFalse
917textTo provide patients with more treatment options for pain management, especially as the population ages, there is a growing need for new methods, drugs, and devices. $ ^{1} $ Joint pain due to injury, [66.0, 691.0, 558.0, 828.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
1018textCartilage tissue has limited capacity for repair following injury. Untreated defects in the cartilage layer of a joint heal poorly or do not heal at all. The tissue degradation that ensues leads inevi[65.0, 829.0, 559.0, 1034.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
1119textNoninvasive electromagnetic fields have been shown to reduce musculoskeletal pain and edema with no known side effects. $ ^{5} $ Recently, a capacitively coupled pulsing electric field (PEF) signal ha[65.0, 1034.0, 559.0, 1309.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
12110textIt is well known that PEMF signals of the type produced by BGS devices can have a physiologically significant effect on tissue growth and repair in animal studies $ ^{7} $ and human clinical trials. $[65.0, 1310.0, 560.0, 1381.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
13111textstudies7 and human clinical trials.8 Based on these reports it was hypothesized that PEF signals may be able to modulate chondrocyte proliferation. It is thus the primary intent of this study to test [583.0, 688.0, 1079.0, 805.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
14112textIt was considered equally important to determine a possible biological pathway by which the PEF signal could exert its action on chondrocytes. This would help establish a set of criteria by which prop[583.0, 806.0, 1080.0, 1105.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
15113paragraph_titleMATERIALS AND METHODS[586.0, 1126.0, 864.0, 1148.0]section_heading0.9["explicit scholarly heading: MATERIALS AND METHODS"]section_heading0.9body_zoneheading_likecanonical_section_nameTrueTrue
16114textMajority of reagents were purchased from Sigma (St. Louis, MO) such as culture media (DMEM, #MT10013CV), calf serum (#B14-401F), and L-NAME (#72760) for inhibition of nitric oxide synthase, LY82583 (#[583.0, 1150.0, 1078.0, 1341.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
17115paragraph_titleCell Culture[585.0, 1363.0, 691.0, 1383.0]section_heading0.5["unnumbered paragraph_title on page 1 outside title zone: Cell Culture"]section_heading0.5body_zonebody_likeshort_fragmentTrueTrue
18116textNormal human chondrocytes (#CC2550) were obtained from Clonetics subdivision of Lonza (Walkersville, MD). Chondrocytes were grown for expansion in 100-mm culture dishes using DMEM supplemented with 5%[583.0, 1384.0, 1079.0, 1471.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
19117footnoteCorrespondence to: R.J. Fitzsimmons (T: 909-478-9085; F: 909-478-9015; E-mail: biocore1@aol.com)[66.0, 1406.0, 558.0, 1446.0]frontmatter_support0.75["page-1 correspondence footnote: Correspondence to: R.J. Fitzsimmons (T: 909-478-9085; F: 909"]frontmatter_support0.75body_zonebody_likenoneTrueTrue
20118footnote© 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.[68.0, 1449.0, 559.0, 1471.0]frontmatter_noise0.8["page-1 zone journal_furniture_zone: \u00a9 2008 Orthopaedic Research Society. Published by Wiley Peri"]frontmatter_noise0.8body_zonebody_likenoneFalseFalse
21119number854[69.0, 1478.0, 105.0, 1497.0]noise0.9["page number label"]noise0.9body_zonebody_likeshort_fragmentFalseFalse
22120footerJOURNAL OF ORTHOPAEDIC RESEARCH JUNE 2008[131.0, 1479.0, 472.0, 1500.0]noise0.9["footer label"]noise0.9body_zonebody_likenoneFalseFalse
2320headerPULSING ELECTRIC FIELD INCREASES CHONDROCYTE PROLIFERATION[444.0, 68.0, 1056.0, 88.0]noise0.9["header label"]noise0.9body_zonebody_likenoneFalseFalse
2421number855[1083.0, 68.0, 1118.0, 87.0]noise0.9["page number label"]noise0.9frontmatter_side_zonesupport_likeshort_fragmentFalseFalse
2522textcalf serum). For experiments, chondrocytes were detached using trypsin, pooled into a single aliquot, counted, and then separated into culture wells using DMEM containing 0.1% calf serum. The use of 0[106.0, 117.0, 601.0, 496.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
2623paragraph_titleCell Proliferation[108.0, 514.0, 252.0, 534.0]unknown_structural0.6["unnumbered paragraph_title, inferred level subsection_heading: Cell Proliferation"]subsection_heading0.6frontmatter_side_zonesupport_likeshort_fragmentFalseTrue
2724textDNA content of cell layer was used as an index of cell number, and an increase in cell number was used as an indication of increased cell proliferation. The culture media was removed and the cell laye[107.0, 535.0, 602.0, 685.0]unknown_structural0.8["page-1 zone author_zone: DNA content of cell layer was used as an index of cell numbe"]authors0.8body_zonebody_likenoneFalseTrue
2825paragraph_titleNitric Oxide Measurement[108.0, 706.0, 329.0, 727.0]subsection_heading0.6["unnumbered paragraph_title, inferred level subsection_heading: Nitric Oxide Measurement"]subsection_heading0.6frontmatter_side_zonesupport_likenoneTrueTrue
2926textNitrite in culture media was measured as an index of nitric oxide levels using the Griess reaction. $ ^{12} $ An aliquot (250 $ \mu $L) of conditioned culture media was collected and measured for nit[107.0, 728.0, 600.0, 834.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
3027paragraph_titlecGMP Measurement[108.0, 854.0, 278.0, 873.0]unknown_structural0.6["unnumbered paragraph_title, inferred level subsection_heading: cGMP Measurement"]subsection_heading0.6frontmatter_side_zonesupport_likeshort_fragmentFalseTrue
3128textThe level of cGMP in the cell layer was measured using cGMP Enzyme Immunoassay Kit from Sigma (#CG200-1kt). The culture media was removed and the cell layer rinsed with PBS at 4°C. The cell layer was [107.0, 873.0, 601.0, 1002.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
3229paragraph_titlePEF Signal[108.0, 1023.0, 198.0, 1044.0]subsection_heading0.6["unnumbered paragraph_title, inferred level subsection_heading: PEF Signal"]subsection_heading0.6body_zonebody_likeshort_fragmentTrueTrue
33210textThe PEF signal (MedRelief® model SE55, Healthonics Inc, Atlanta, GA) is characterized by a pulse-burst waveform with a primary signal of asymmetrical biphasic rectangular pulses, 210/30 $ \mu $s in e[106.0, 1045.0, 601.0, 1318.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
34211paragraph_titleApplication of PEF Signal to Cell Culture[109.0, 1342.0, 436.0, 1363.0]subsection_heading0.6["unnumbered paragraph_title, inferred level subsection_heading: Application of PEF Signal to Cell Culture"]subsection_heading0.6body_zonebody_likenoneTrueTrue
35212textThe PEF signal was delivered by capacitive coupling to chondrocytes using a novel replacement for traditional salt bridges. $ ^{13} $ In this new system, niobium wire jumpers were used instead of salt[107.0, 1362.0, 602.0, 1470.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
36213textis closely controllable. The resulting vivid, nonfading light interference colors are used in jewelry, and jewelers niobium is manufactured in standard colors. Importantly for this application, the h[625.0, 117.0, 1121.0, 325.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
37214textNiobium wire is cut and bent to form bridges between culture wells and the PEF signal passes through these bridges capacitively. Multiple wells are joined together in series. The wire is formed to fit[625.0, 326.0, 1120.0, 493.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
38215textPreliminary studies found no indication of cytotoxicity when the PEF signal was delivered to either osteoblasts or chondrocytes via the niobium bridge. No changes in temperature or pH were detected in[625.0, 494.0, 1121.0, 641.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
39216paragraph_titleStatistics[627.0, 660.0, 706.0, 680.0]sub_subsection_heading0.6["unnumbered paragraph_title, inferred level sub_subsection_heading: Statistics"]sub_subsection_heading0.6frontmatter_side_zonesupport_likeshort_fragmentTrueTrue
40217textFor all measures the average value and standard deviation are reported. Number of samples per group was six. Data is expressed as percent of control values. Multiple control bars in a graph indicate c[624.0, 682.0, 1122.0, 1061.0]frontmatter_noise0.8["page-1 zone journal_furniture_zone: For all measures the average value and standard deviation ar"]frontmatter_noise0.8body_zonebody_likenoneFalseFalse
41218paragraph_titleRESULTS[628.0, 1081.0, 720.0, 1104.0]section_heading0.9["explicit scholarly heading: RESULTS"]section_heading0.9body_zoneheading_likecanonical_section_nameTrueTrue
42219textThe experimental design was to first investigate whether PEF had an effect on chondrocyte DNA content measured 72 h after PEF treatment. The experimental design then focused on changes in second messe[625.0, 1105.0, 1120.0, 1292.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
43220paragraph_titleEffect of Stimuli on Chondrocytes after 72 Hours[627.0, 1309.0, 1043.0, 1331.0]subsection_heading0.6["unnumbered paragraph_title, inferred level subsection_heading: Effect of Stimuli on Chondrocytes after 72 Hours"]subsection_heading0.6body_zoneheading_likenoneTrueTrue
44221textA single 30-min treatment period to PEF with an amplitude producing 2.7 microamperes across culture media and an electric field of 0.2 mV/cm significantly increased DNA content by $ 133 \pm 10\% $ (p[625.0, 1332.0, 1120.0, 1471.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
45222footerJOURNAL OF ORTHOPAEDIC RESEARCH JUNE 2008[781.0, 1496.0, 1119.0, 1515.0]noise0.9["footer label"]noise0.9body_zonebody_likenoneFalseFalse
4630number856[68.0, 68.0, 105.0, 87.0]noise0.9["page number label"]noise0.9body_zonebody_likeshort_fragmentFalseFalse
4731headerFITZSIMMONS ET AL.[135.0, 67.0, 316.0, 88.0]noise0.9["header label"]noise0.9body_zonebody_likeshort_fragmentFalseFalse
4832chart[80.0, 116.0, 546.0, 434.0]figure_asset0.85["media label: chart"]media_asset0.85body_zoneunknown_likeemptyTrueTrue
4933figure_titleFigure 1. Effect on DNA content after 72 h. Normal human chondrocytes were plated in DMEM containing 0.1% calf serum and allowed to attach and equilibrate for 24 h. In the graph above, PEF signal was [66.0, 446.0, 559.0, 628.0]figure_caption0.92["figure_title label: Figure 1. Effect on DNA content after 72 h. Normal human cho"]figure_caption0.92display_zonelegend_likefigure_numberTrueTrue
5034textInsulin-like growth factor 1 and added calf serum (increases calf serum from 0.1 to 1.0%) also increased DNA content, as shown in Figure 1. A dose response to IGF1 showed higher concentrations (up to [66.0, 644.0, 558.0, 783.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
5135paragraph_titleEffect of PEF Treatment on Short-Term NO Release[67.0, 806.0, 500.0, 827.0]subsection_heading0.6["unnumbered paragraph_title, inferred level subsection_heading: Effect of PEF Treatment on Short-Term NO Release"]subsection_heading0.6body_zoneheading_likenoneTrueTrue
5236textIn preliminary studies it was found that PEF could increase NO content transiently within 30 min of initiation of PEF treatment and the elevated NO levels would typically return to control levels shor[65.0, 826.0, 559.0, 988.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
5337textTo determine pathways involved in response to PEF treatment, chondrocytes were PEF treated in experiments with and without inhibitors. As shown in Figure 2, PEF treatment increased NO levels when meas[65.0, 988.0, 559.0, 1217.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
5438textIn another series of experiments adding either 0.5 mM $ CaCl_{2} $ to the culture media or the calcium ionophore A23187 to 1 mM and measuring NO content of culture media 30 min later showed an increa[65.0, 1218.0, 559.0, 1379.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
5539textEffect of PEF Treatment on Short-Term cGMP Generation Nitric oxide acts as a second messenger for the activation of guanylate cyclase (15). Therefore, cGMP was[66.0, 1401.0, 559.0, 1472.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
56310chart[598.0, 114.0, 1063.0, 493.0]media_asset0.85["media label: chart"]media_asset0.85body_zoneunknown_likeemptyTrueTrue
57311figure_titleFigure 2. PEF signal and short-term (30 min) NO release. Normal human chondrocytes were plated in DMEM containing 0.1% calf serum and allowed to attach and equilibrate for 24 h. In one experiment (lig[584.0, 503.0, 1079.0, 744.0]figure_caption0.92["figure_title label: Figure 2. PEF signal and short-term (30 min) NO release. Nor"]figure_caption0.92display_zonelegend_likefigure_numberTrueTrue
58312textmeasured in the cell layer after PEF treatment. As shown in Figure 3, PEF treatment increased cGMP within the 30-min treatment period. This effect was blocked by either W7 or by L-NAME, as expected if[583.0, 772.0, 1081.0, 865.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
59313chart[598.0, 887.0, 1063.0, 1262.0]figure_asset0.85["media label: chart"]media_asset0.85body_zoneunknown_likeemptyTrueTrue
60314figure_titleFigure 3. PEF signal increases short-term (30 min) cGMP generation. Normal human chondrocytes were plated in DMEM containing 0.1% calf-serum and allowed to attach and equilibrate for 24 h. In one expe[584.0, 1274.0, 1079.0, 1470.0]figure_caption0.92["figure_title label: Figure 3. PEF signal increases short-term (30 min) cGMP gene"]figure_caption0.92display_zonelegend_likefigure_numberTrueTrue
61315footerJOURNAL OF ORTHOPAEDIC RESEARCH JUNE 2008[68.0, 1498.0, 406.0, 1517.0]noise0.9["footer label"]noise0.9body_zonebody_likenoneFalseFalse
6240headerPULSING ELECTRIC FIELD INCREASES CHONDROCYTE PROLIFERATION[445.0, 67.0, 1056.0, 88.0]noise0.9["header label"]noise0.9body_zonebody_likenoneFalseFalse
6341number857[1083.0, 68.0, 1118.0, 87.0]noise0.9["page number label"]noise0.9body_zonebody_likeshort_fragmentFalseFalse
6442chart[122.0, 115.0, 585.0, 442.0]figure_asset0.85["media label: chart"]media_asset0.85body_zoneunknown_likeemptyTrueTrue
6543figure_titleFigure 4. PEF signal and SNP increase short-term (30 min) cGMP generation. Normal human chondrocytes were plated in DMEM containing 0.1% calf serum and allowed to attach and equilibrate for 24 h. The [107.0, 455.0, 601.0, 650.0]figure_caption0.92["figure_title label: Figure 4. PEF signal and SNP increase short-term (30 min) cG"]figure_caption0.92display_zonelegend_likefigure_numberTrueTrue
6644textcGMP was increased in a cascade from calmodulin to nitric oxide synthase to cGMP.[107.0, 713.0, 600.0, 758.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
6745textIn Figure 4, both PEF and a nitric oxide donor (SNP) increased cGMP content of the cell layer within 30 min of treatment. The guanylate cyclase inhibitor (LY83583) blocked both PEF treatment and SNP f[107.0, 759.0, 601.0, 967.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
6846paragraph_titleEffect of Inhibitors on Ability of PEF Treatment to Increase DNA Content at 72 Hours[108.0, 991.0, 527.0, 1034.0]subsection_heading0.6["unnumbered paragraph_title, inferred level subsection_heading: Effect of Inhibitors on Ability of PEF Treatment to Increase"]subsection_heading0.6body_zoneheading_likenoneTrueTrue
6947textIn Figure 5, PEF treatment, when applied one time for 30 min, increased chondrocyte proliferation as observed in previous experiments. When L-NAME was added prior to PEF treatment the increase in chon[107.0, 1035.0, 600.0, 1195.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
7048textEffect of SNP on Chondrocyte Proliferation at 72 Hours In Figure 6, SNP was added to a final concentration of 150 $ \mu $M, which increased nitric oxide content in culture media to 752 ± 74% of contr[106.0, 1217.0, 602.0, 1470.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
7149chart[640.0, 117.0, 1106.0, 476.0]media_asset0.85["media label: chart"]media_asset0.85body_zoneunknown_likeemptyTrueTrue
72410figure_titleFigure 5. PEF signal and increased DNA content at 72 h. Normal human chondrocytes were plated in DMEM containing 0.1% calf serum and allowed to attach and equilibrate for 24 h. In one experiment (ligh[627.0, 486.0, 1121.0, 687.0]figure_caption0.92["figure_title label: Figure 5. PEF signal and increased DNA content at 72 h. Norm"]figure_caption0.92display_zonelegend_likefigure_numberTrueTrue
73411textcontent when present for 30 min, which is similar to the profile of NO release with PEF alone.[626.0, 713.0, 1120.0, 760.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
74412paragraph_titleDISCUSSION[629.0, 781.0, 762.0, 803.0]section_heading0.9["explicit scholarly heading: DISCUSSION"]section_heading0.9body_zoneheading_likecanonical_section_nameTrueTrue
75413textNormal tissue regeneration proceeds through a series of phases starting with inflammation $ ^{16} $ and culminating in the deposition and organization of new tissue. In the[626.0, 805.0, 1122.0, 875.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
76414chart[639.0, 895.0, 1105.0, 1259.0]figure_asset0.85["media label: chart"]media_asset0.85body_zoneunknown_likeemptyTrueTrue
77415figure_titleFigure 6. SNP and PEF effects on DNA. Normal human chondrocytes were plated in DMEM containing 0.1% calf serum and allowed to attach and equilibrate for 24 h. Cultures were treated to SNP (an NO donor[625.0, 1274.0, 1120.0, 1469.0]figure_caption0.92["figure_title label: Figure 6. SNP and PEF effects on DNA. Normal human chondrocy"]figure_caption0.92display_zonelegend_likefigure_numberTrueTrue
78416footerJOURNAL OF ORTHOPAEDIC RESEARCH JUNE 2008[782.0, 1497.0, 1119.0, 1515.0]noise0.9["footer label"]noise0.9body_zonebody_likenoneFalseFalse
7950number858[69.0, 68.0, 104.0, 87.0]noise0.9["page number label"]noise0.9body_zonebody_likeshort_fragmentFalseFalse
8051headerFITZSIMMONS ET AL.[135.0, 68.0, 317.0, 88.0]noise0.9["header label"]noise0.9body_zonebody_likeshort_fragmentFalseFalse
8152textcase of chronic joint pain, whether due to a prior injury or osteoarthritis, tissue regeneration stalls indefinitely in the inflammation phase. This leads to progressive degeneration of cartilage, irr[65.0, 117.0, 559.0, 255.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
8253textCartilage degradation in itself does not translate as a sensory perception directly from the cartilage; joint pain is the symptom that causes patients to seek treatment. Unfortunately, treatments aime[65.0, 256.0, 559.0, 622.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
8354textThis study utilized a PEF signal adapted from the signal used in bone growth stimulators, employed successfully for recalcitrant bone fractures. $ ^{17} $ There are a number of similarities between th[66.0, 622.0, 558.0, 1034.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
8455textThe results of this study also suggest that release of NO is part of the biologic pathway involved in increased DNA content of chondrocyte cultures following PEF treatment. NO increased within the 30-[65.0, 1035.0, 559.0, 1287.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6tail_nonref_hold_zoneunknown_likenoneTrueTrue
8556textNitric oxide has many influences, $ ^{16,21} $ of which one can be activation of guanylate cyclase, which produces cGMP. $ ^{15} $ This study showed that the PEF signal increased cGMP within the 30-mi[65.0, 1286.0, 559.0, 1471.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6tail_nonref_hold_zoneunknown_likenoneTrueTrue
8657textcultures following PEF signal treatment was blocked by LY83583, thereby indicating cGMP is involved in the pathway of PEF-stimulated DNA content of chondrocyte cultures. I h i i i id l ld b[583.0, 117.0, 1079.0, 209.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
8758textIn these experiments nitric oxide release could be increased with added calcium or a calcium ionophore, which is consistent with reports that NOS can be regulated by calcium. $ ^{23} $ When the calmod[583.0, 210.0, 1079.0, 415.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
8859textTaken together, the data indicates this PEF signal stimulates chondrocyte proliferation through a biological pathway that involves calcium/ calmodulin, nitric oxide synthase, nitric oxide, and cGMP. T[583.0, 415.0, 1079.0, 759.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
89510textWhether this PEF signal can impart beneficial action to cartilage in human patients, of course, remains to be tested. One limitation of this study is the use of chondrocytes in cell culture, and the o[583.0, 759.0, 1080.0, 1013.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
90511paragraph_titleACKNOWLEDGMENTS[587.0, 1037.0, 811.0, 1059.0]section_heading0.6["unnumbered paragraph_title, inferred level section_heading: ACKNOWLEDGMENTS"]section_heading0.6body_zoneheading_likeshort_fragmentTrueTrue
91512textThis study was partially funded, and the PEF generators were supplied, by Healthonics Inc., Altanta, GA.[584.0, 1061.0, 1077.0, 1105.0]body_paragraph0.6["default body_paragraph for text label"]body_paragraph0.6body_zonebody_likenoneTrueTrue
92513paragraph_titleREFERENCES[588.0, 1124.0, 714.0, 1146.0]reference_heading0.9["references heading: REFERENCES"]reference_heading0.9reference_zoneheading_likeshort_fragmentTrueTrue
93514reference_content1. Felson D, Zhang Y. 1998. An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum 41:13431355.[600.0, 1150.0, 1077.0, 1208.0]reference_item0.85["reference content label: 1. Felson D, Zhang Y. 1998. An update on the epidemiology of"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
94515reference_content2. Department of Health and Human Services. 1991. Aging America: trends and projections. DHHS publication number FC:AJp-28001. Washington, DC: DHHS.[599.0, 1210.0, 1076.0, 1267.0]reference_item0.85["reference content label: 2. Department of Health and Human Services. 1991. Aging Amer"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
95516reference_content3. Manek N, Lane N. 2000. Osteoarthritis: current concepts in diagnosis and management. Am Fam Phys 61:17951804.[600.0, 1270.0, 1075.0, 1308.0]reference_item0.85["reference content label: 3. Manek N, Lane N. 2000. Osteoarthritis: current concepts i"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
96517reference_content4. Rubin B. 2005. Management of osteoarthritic knee pain. J Am Osteopath Assoc 105(Suppl):S23S28.[599.0, 1309.0, 1076.0, 1347.0]reference_item0.85["reference content label: 4. Rubin B. 2005. Management of osteoarthritic knee pain. J "]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
97518reference_content5. Zizic T, Hoffman K, Holt P, et al. 1995. The treatment of osteoarthritis of the knee with pulsed electrical stimulation. J Rheumatol 22:17571761.[600.0, 1349.0, 1077.0, 1407.0]reference_item0.85["reference content label: 5. Zizic T, Hoffman K, Holt P, et al. 1995. The treatment of"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
98519reference_content6. Basset C, Pawluk R, Pilla A. 1974. Augmentation of bone repair by inductively coupled electromagnetic fields. Science 184:575577.[600.0, 1410.0, 1077.0, 1466.0]reference_item0.85["reference content label: 6. Basset C, Pawluk R, Pilla A. 1974. Augmentation of bone r"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
99520footerJOURNAL OF ORTHOPAEDIC RESEARCH JUNE 2008[67.0, 1498.0, 406.0, 1517.0]noise0.9["footer label"]noise0.9tail_nonref_hold_zoneunknown_likenoneFalseFalse
10060headerPULSING ELECTRIC FIELD INCREASES CHONDROCYTE PROLIFERATION[445.0, 69.0, 1055.0, 88.0]noise0.9["header label"]noise0.9unknown_likenoneFalseFalse
10161number859[1083.0, 69.0, 1118.0, 87.0]noise0.9["page number label"]noise0.9unknown_likeshort_fragmentFalseFalse
10262reference_content7. Fredericks D, Nepola J, Baker J, et al. 2000. Effect of pulsed electromagnetic fields on bone healing in a rabbit tibial osteotomy model. J Orthop Trauma 14:93100.[123.0, 122.0, 599.0, 180.0]reference_item0.85["reference content label: 7. Fredericks D, Nepola J, Baker J, et al. 2000. Effect of p"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
10363reference_content8. Akai M, Hayashi K. 2002. Effect of electrical stimulation on musculoskeletal systems: a meta-analysis of controlled clinical trials. Bioelectromagnetics 23:132143.[123.0, 182.0, 598.0, 239.0]reference_item0.85["reference content label: 8. Akai M, Hayashi K. 2002. Effect of electrical stimulation"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
10464reference_content9. Diniz P, Soejima K, Ito G. 2002. Nitric oxide mediates the effects of pulsed electromagnetic field stimulation on the osteoblast proliferation and differentiation. Nitric Oxide 7:1823.[121.0, 242.0, 599.0, 299.0]reference_item0.85["reference content label: 9. Diniz P, Soejima K, Ito G. 2002. Nitric oxide mediates th"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
10565reference_content10. Cheng J, Zhang C, Han JS, et al. 2007. TENS stimulates constitutive nitric oxide release via opiate signaling in invertebrate neural tissues. Med Sci Monit 13:163167.[115.0, 301.0, 599.0, 358.0]reference_item0.85["reference content label: 10. Cheng J, Zhang C, Han JS, et al. 2007. TENS stimulates c"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
10666reference_content11. Van Susante JL, Buma P, Van Beuningen HM, et al. 2000. Responsiveness of bovine chondrocytes to growth factors in medium with different serum concentrations. J Orthop Res 18:6877.[115.0, 361.0, 598.0, 438.0]reference_item0.85["reference content label: 11. Van Susante JL, Buma P, Van Beuningen HM, et al. 2000. R"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
10767reference_content12. Guevara I, Iwanejko J, Dembinska-Kiec A, et al. 1998. Determination of nitrite/nitrate in human biological material by the simple Griess reaction. Clin Chim Acta 274:177188.[115.0, 442.0, 598.0, 517.0]reference_item0.85["reference content label: 12. Guevara I, Iwanejko J, Dembinska-Kiec A, et al. 1998. De"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
10868reference_content13. Kronberg J, Ganey T, Fitzsimmons R. 2006. A novel niobium salt bridge for in vitro PEMF studies. 28th annual meeting, Bioelectromagnetics Society, abstract 115.[114.0, 521.0, 598.0, 578.0]reference_item0.85["reference content label: 13. Kronberg J, Ganey T, Fitzsimmons R. 2006. A novel niobiu"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
10969reference_content14. Ganey T. Personal communication, May 2006.[116.0, 579.0, 491.0, 598.0]reference_item0.85["reference content label: 14. Ganey T. Personal communication, May 2006."]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
110610reference_content15. Knowles R, Palacios M, Palmer R, et al. 1989 Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase. Pro[116.0, 601.0, 599.0, 678.0]reference_item0.85["reference content label: 15. Knowles R, Palacios M, Palmer R, et al. 1989 Formation o"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
111611reference_content16. Brooks P. 2003. Inflammation as an important feature of osteoarthritis. Bull World Health Organ 81:689690.[115.0, 680.0, 599.0, 718.0]reference_item0.85["reference content label: 16. Brooks P. 2003. Inflammation as an important feature of "]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
112612reference_content17. Pilla A. 2006. Mechanisms and therapeutic applications of time varying and static magnetic fields. In: Barnes F, Greenebaum B, editors. Biological and medical aspects of electromagnetic fields. Bo[115.0, 721.0, 599.0, 798.0]reference_item0.85["reference content label: 17. Pilla A. 2006. Mechanisms and therapeutic applications o"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
113613reference_content18. DeMattei M, Caruso A, Pezzetti F, et al. 2001. Effects of pulsed electromagnetic fields on human articular chondrocyte proliferation. Connect Tissue Res 42:111.[634.0, 122.0, 1119.0, 180.0]reference_item0.85["reference content label: 18. DeMattei M, Caruso A, Pezzetti F, et al. 2001. Effects o"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
114614reference_content19. Fioravanti A, Nerucci F, Collodel G, et al. 2002. Biochemical and morphological study of human articular chondrocytes cultivated in the presence of pulsed signal therapy. Ann Rheum Dis 61:1032103[635.0, 182.0, 1118.0, 259.0]reference_item0.85["reference content label: 19. Fioravanti A, Nerucci F, Collodel G, et al. 2002. Bioche"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
115615reference_content20. Kim S, Shin H, Eom D, et al. 2002. Enhanced expression of neuronal nitric oxide synthase and phospholipase C- $ \gamma $1 in regenerating murine neuronal cells by pulsed electromagnetic field. Exp[633.0, 262.0, 1118.0, 338.0]reference_item0.85["reference content label: 20. Kim S, Shin H, Eom D, et al. 2002. Enhanced expression o"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
116616reference_content21. Schwentker A, Vodovotz Y, Weller R, et al. 2002. Nitric oxide and wound repair: role of cytokines. Nitric Oxide 7:110.[632.0, 341.0, 1117.0, 379.0]reference_item0.85["reference content label: 21. Schwentker A, Vodovotz Y, Weller R, et al. 2002. Nitric "]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
117617reference_content22. Miura M, Takayama K, Okada J. 1993. Increase in nitric oxide and cyclic GMP of rat cerebellum by radio frequency burst-type electromagnetic field radiation. J Physiol 461:513524.[633.0, 381.0, 1118.0, 439.0]reference_item0.85["reference content label: 22. Miura M, Takayama K, Okada J. 1993. Increase in nitric o"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
118618reference_content23. Knudsen G, Nishida C, Mooney S, et al. 2003. Nitric oxide synthase (NOS) reductase domain models suggest a new control element in endothelial NOS that attenuates calmodulin-dependent activity. J B[633.0, 442.0, 1119.0, 537.0]reference_item0.85["reference content label: 23. Knudsen G, Nishida C, Mooney S, et al. 2003. Nitric oxid"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
119619reference_content24. Pilla A, Muehsam D, Markov M. 1999. EMF signals and ion/ligand binding kinetics: prediction of bioeffective waveform parameters. Bioelectrochem Bioenerg 48:2734.[633.0, 541.0, 1118.0, 598.0]reference_item0.85["reference content label: 24. Pilla A, Muehsam D, Markov M. 1999. EMF signals and ion/"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
120620reference_content25. Markov MS, Pilla AA. 1997. Weak static magnetic field modulation of myosin phosphorylation in a cell-free preparation: calcium dependence. Bioelectrochem Bioenergetics 43:235240.[633.0, 601.0, 1118.0, 676.0]reference_item0.85["reference content label: 25. Markov MS, Pilla AA. 1997. Weak static magnetic field mo"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
121621reference_content26. Brighton C, Wang W, Seldes R, et al. 2001. Signal transduction in electrically stimulated bone cells. J Bone Joint Surg 83-A:15141523.[633.0, 681.0, 1118.0, 737.0]reference_item0.85["reference content label: 26. Brighton C, Wang W, Seldes R, et al. 2001. Signal transd"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
122622reference_content27. Ciombor DM, Lester G, Aaron RK, et al. 2002. Low frequency EMF regulates chondrocyte differentiation and expression of matrix proteins. J Orthop Res 20:4050.[632.0, 741.0, 1120.0, 798.0]reference_item0.85["reference content label: 27. Ciombor DM, Lester G, Aaron RK, et al. 2002. Low frequen"]reference_item0.85reference_zonereference_likereference_numeric_dotTrueTrue
123623footerJOURNAL OF ORTHOPAEDIC RESEARCH JUNE 2008[781.0, 1497.0, 1118.0, 1515.0]noise0.9["footer label"]noise0.9unknown_likenoneFalseFalse