Intraocular Pressure-Lowering Effect of Latanoprost Is Hampered by Defective Cervical Lymphatic Drainage
Identifieur interne : 004413 ( Pmc/Corpus ); précédent : 004412; suivant : 004414Intraocular Pressure-Lowering Effect of Latanoprost Is Hampered by Defective Cervical Lymphatic Drainage
Auteurs : Young Kook Kim ; Kyeong Ik Na ; Jin Wook Jeoung ; Ki Ho ParkSource :
- PLoS ONE [ 1932-6203 ] ; 2017.
Abstract
To evaluate whether defects in cervical lymphatic drainage influence the intraocular pressure (IOP)-lowering effect of latanoprost in patients with primary open-angle glaucoma (POAG) who have undergone unilateral radical neck dissection (uRND).
We enrolled (1) bilateral POAG patients who had started (bilateral) latanoprost (0.005%) monotherapy prior to their uRND and (2) treatment-naïve, bilateral glaucoma suspects (GSs) who had undergone the same surgery. We compared the eyes ipsilateral to the uRND with their fellow eyes in terms of the changes in IOP between the baseline (prior to the uRND) and the follow-up visits (1, 3, and 6 months after the uRND).
The study involved 22 eyes of 11 POAG patients and 14 eyes of 7 GSs. In the POAG patients, IOP had increased significantly after surgery in the eyes ipsilateral to the uRND (from 14.7±1.4mmHg to 17.1±2.2mmHg; P = 0.007). Interestingly, in the eyes contralateral to the uRND, IOP had not changed significantly after surgery (from 14.2±1.8mmHg to 14.4±2.0mmHg; P = 0.826). In GSs, the eyes ipsilateral to the uRND did not differ significantly from their fellow eyes in terms of post-operative IOP change (ipsilateral value: 0.3±0.5mmHg, fellow eyes: -0.1±0.7mmHg; P = 0.242).
In the POAG patients, IOP had increased significantly in the eyes ipsilateral to the uRND. However, it had not changed significantly in the eyes contralateral to the surgery or in the eyes of the GSs. These findings suggest that, latanoprost works, at least in part, by enhancing outflow from the aqueous humor via the uveolymphatic pathway.
Url:
DOI: 10.1371/journal.pone.0169683
PubMed: 28081184
PubMed Central: 5231387
Links to Exploration step
PMC:5231387Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Intraocular Pressure-Lowering Effect of Latanoprost Is Hampered by Defective Cervical Lymphatic Drainage</title><author><name sortKey="Kim, Young Kook" sort="Kim, Young Kook" uniqKey="Kim Y" first="Young Kook" last="Kim">Young Kook Kim</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Na, Kyeong Ik" sort="Na, Kyeong Ik" uniqKey="Na K" first="Kyeong Ik" last="Na">Kyeong Ik Na</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jeoung, Jin Wook" sort="Jeoung, Jin Wook" uniqKey="Jeoung J" first="Jin Wook" last="Jeoung">Jin Wook Jeoung</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Park, Ki Ho" sort="Park, Ki Ho" uniqKey="Park K" first="Ki Ho" last="Park">Ki Ho Park</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28081184</idno><idno type="pmc">5231387</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231387</idno><idno type="RBID">PMC:5231387</idno><idno type="doi">10.1371/journal.pone.0169683</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">004413</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004413</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Intraocular Pressure-Lowering Effect of Latanoprost Is Hampered by Defective Cervical Lymphatic Drainage</title><author><name sortKey="Kim, Young Kook" sort="Kim, Young Kook" uniqKey="Kim Y" first="Young Kook" last="Kim">Young Kook Kim</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Na, Kyeong Ik" sort="Na, Kyeong Ik" uniqKey="Na K" first="Kyeong Ik" last="Na">Kyeong Ik Na</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jeoung, Jin Wook" sort="Jeoung, Jin Wook" uniqKey="Jeoung J" first="Jin Wook" last="Jeoung">Jin Wook Jeoung</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Park, Ki Ho" sort="Park, Ki Ho" uniqKey="Park K" first="Ki Ho" last="Park">Ki Ho Park</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Purpose</title><p>To evaluate whether defects in cervical lymphatic drainage influence the intraocular pressure (IOP)-lowering effect of latanoprost in patients with primary open-angle glaucoma (POAG) who have undergone unilateral radical neck dissection (uRND).</p></sec><sec id="sec002"><title>Methods</title><p>We enrolled (1) bilateral POAG patients who had started (bilateral) latanoprost (0.005%) monotherapy prior to their uRND and (2) treatment-naïve, bilateral glaucoma suspects (GSs) who had undergone the same surgery. We compared the eyes ipsilateral to the uRND with their fellow eyes in terms of the changes in IOP between the baseline (prior to the uRND) and the follow-up visits (1, 3, and 6 months after the uRND).</p></sec><sec id="sec003"><title>Results</title><p>The study involved 22 eyes of 11 POAG patients and 14 eyes of 7 GSs. In the POAG patients, IOP had increased significantly after surgery in the eyes ipsilateral to the uRND (from 14.7±1.4mmHg to 17.1±2.2mmHg; P = 0.007). Interestingly, in the eyes contralateral to the uRND, IOP had not changed significantly after surgery (from 14.2±1.8mmHg to 14.4±2.0mmHg; P = 0.826). In GSs, the eyes ipsilateral to the uRND did not differ significantly from their fellow eyes in terms of post-operative IOP change (ipsilateral value: 0.3±0.5mmHg, fellow eyes: -0.1±0.7mmHg; P = 0.242).</p></sec><sec id="sec004"><title>Conclusion</title><p>In the POAG patients, IOP had increased significantly in the eyes ipsilateral to the uRND. However, it had not changed significantly in the eyes contralateral to the surgery or in the eyes of the GSs. These findings suggest that, latanoprost works, at least in part, by enhancing outflow from the aqueous humor via the uveolymphatic pathway.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Heijl, A" uniqKey="Heijl A">A Heijl</name></author><author><name sortKey="Leske, Mc" uniqKey="Leske M">MC Leske</name></author><author><name sortKey="Bengtsson, B" uniqKey="Bengtsson B">B Bengtsson</name></author><author><name sortKey="Hyman, L" uniqKey="Hyman L">L Hyman</name></author><author><name sortKey="Bengtsson, B" uniqKey="Bengtsson B">B Bengtsson</name></author><author><name sortKey="Hussein, M" uniqKey="Hussein M">M Hussein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leske, Mc" uniqKey="Leske M">MC Leske</name></author><author><name sortKey="Heijl, A" uniqKey="Heijl A">A Heijl</name></author><author><name sortKey="Hussein, M" uniqKey="Hussein M">M Hussein</name></author><author><name sortKey="Bengtsson, B" uniqKey="Bengtsson B">B Bengtsson</name></author><author><name sortKey="Hyman, L" uniqKey="Hyman L">L Hyman</name></author><author><name sortKey="Komaroff, E" uniqKey="Komaroff E">E Komaroff</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goel, M" uniqKey="Goel M">M Goel</name></author><author><name sortKey="Picciani, Rg" uniqKey="Picciani R">RG Picciani</name></author><author><name sortKey="Lee, Rk" uniqKey="Lee R">RK Lee</name></author><author><name sortKey="Bhattacharya, Sk" uniqKey="Bhattacharya S">SK Bhattacharya</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yucel, Yh" uniqKey="Yucel Y">YH Yucel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yucel, Yh" uniqKey="Yucel Y">YH Yucel</name></author><author><name sortKey="Johnston, Mg" uniqKey="Johnston M">MG Johnston</name></author><author><name sortKey="Ly, T" uniqKey="Ly T">T Ly</name></author><author><name sortKey="Patel, M" uniqKey="Patel M">M Patel</name></author><author><name sortKey="Drake, B" uniqKey="Drake B">B Drake</name></author><author><name sortKey="Gumus, E" uniqKey="Gumus E">E Gumus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tam, Al" uniqKey="Tam A">AL Tam</name></author><author><name sortKey="Gupta, N" uniqKey="Gupta N">N Gupta</name></author><author><name sortKey="Zhang, Z" uniqKey="Zhang Z">Z Zhang</name></author><author><name sortKey="Yucel, Yh" uniqKey="Yucel Y">YH Yucel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hollo, G" uniqKey="Hollo G">G Hollo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Poyer, Jf" uniqKey="Poyer J">JF Poyer</name></author><author><name sortKey="Millar, C" uniqKey="Millar C">C Millar</name></author><author><name sortKey="Kaufman, Pl" uniqKey="Kaufman P">PL Kaufman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thieme, H" uniqKey="Thieme H">H Thieme</name></author><author><name sortKey="Schimmat, C" uniqKey="Schimmat C">C Schimmat</name></author><author><name sortKey="Munzer, G" uniqKey="Munzer G">G Munzer</name></author><author><name sortKey="Boxberger, M" uniqKey="Boxberger M">M Boxberger</name></author><author><name sortKey="Fromm, M" uniqKey="Fromm M">M Fromm</name></author><author><name sortKey="Pfeiffer, N" uniqKey="Pfeiffer N">N Pfeiffer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lutjen Drecoll, E" uniqKey="Lutjen Drecoll E">E Lutjen-Drecoll</name></author><author><name sortKey="Tamm, E" uniqKey="Tamm E">E Tamm</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Richter, M" uniqKey="Richter M">M Richter</name></author><author><name sortKey="Krauss, Ah" uniqKey="Krauss A">AH Krauss</name></author><author><name sortKey="Woodward, Df" uniqKey="Woodward D">DF Woodward</name></author><author><name sortKey="Lutjen Drecoll, E" uniqKey="Lutjen Drecoll E">E Lutjen-Drecoll</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crawford, K" uniqKey="Crawford K">K Crawford</name></author><author><name sortKey="Kaufman, Pl" uniqKey="Kaufman P">PL Kaufman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nilsson, Sf" uniqKey="Nilsson S">SF Nilsson</name></author><author><name sortKey="Sperber, Go" uniqKey="Sperber G">GO Sperber</name></author><author><name sortKey="Bill, A" uniqKey="Bill A">A Bill</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnston, Mg" uniqKey="Johnston M">MG Johnston</name></author><author><name sortKey="Gordon, Jl" uniqKey="Gordon J">JL Gordon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ohhashi, T" uniqKey="Ohhashi T">T Ohhashi</name></author><author><name sortKey="Mizuno, R" uniqKey="Mizuno R">R Mizuno</name></author><author><name sortKey="Ikomi, F" uniqKey="Ikomi F">F Ikomi</name></author><author><name sortKey="Kawai, Y" uniqKey="Kawai Y">Y Kawai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tam, Al" uniqKey="Tam A">AL Tam</name></author><author><name sortKey="Gupta, N" uniqKey="Gupta N">N Gupta</name></author><author><name sortKey="Zhang, Z" uniqKey="Zhang Z">Z Zhang</name></author><author><name sortKey="Yucel, Yh" uniqKey="Yucel Y">YH Yucel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Camras, Cb" uniqKey="Camras C">CB Camras</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alm, A" uniqKey="Alm A">A Alm</name></author><author><name sortKey="Stjernschantz, J" uniqKey="Stjernschantz J">J Stjernschantz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scherer, Wj" uniqKey="Scherer W">WJ Scherer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Swartz, Ma" uniqKey="Swartz M">MA Swartz</name></author><author><name sortKey="Skobe, M" uniqKey="Skobe M">M Skobe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Swartz, Ma" uniqKey="Swartz M">MA Swartz</name></author><author><name sortKey="Hubbell, Ja" uniqKey="Hubbell J">JA Hubbell</name></author><author><name sortKey="Reddy, St" uniqKey="Reddy S">ST Reddy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Swartz, Ma" uniqKey="Swartz M">MA Swartz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wiig, H" uniqKey="Wiig H">H Wiig</name></author><author><name sortKey="Swartz, Ma" uniqKey="Swartz M">MA Swartz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bradbury, Mw" uniqKey="Bradbury M">MW Bradbury</name></author><author><name sortKey="Cole, Df" uniqKey="Cole D">DF Cole</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Krohn, J" uniqKey="Krohn J">J Krohn</name></author><author><name sortKey="Rodahl, E" uniqKey="Rodahl E">E Rodahl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Foldi, M" uniqKey="Foldi M">M Foldi</name></author><author><name sortKey="Csanda, E" uniqKey="Csanda E">E Csanda</name></author><author><name sortKey="Simon, M" uniqKey="Simon M">M Simon</name></author><author><name sortKey="Obal, F" uniqKey="Obal F">F Obal</name></author><author><name sortKey="Schneider, I" uniqKey="Schneider I">I Schneider</name></author><author><name sortKey="Dobranovics, I" uniqKey="Dobranovics I">I Dobranovics</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Casley Smith, Jr" uniqKey="Casley Smith J">JR Casley-Smith</name></author><author><name sortKey="Clodius, L" uniqKey="Clodius L">L Clodius</name></author><author><name sortKey="Foldi Borcsok, E" uniqKey="Foldi Borcsok E">E Foldi-Borcsok</name></author><author><name sortKey="Gruntzig, J" uniqKey="Gruntzig J">J Gruntzig</name></author><author><name sortKey="Foldi, M" uniqKey="Foldi M">M Foldi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yucel, Y" uniqKey="Yucel Y">Y Yucel</name></author><author><name sortKey="Gupta, N" uniqKey="Gupta N">N Gupta</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Unthank, Jl" uniqKey="Unthank J">JL Unthank</name></author><author><name sortKey="Hogan, Rd" uniqKey="Hogan R">RD Hogan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Amann Vesti, Br" uniqKey="Amann Vesti B">BR Amann-Vesti</name></author><author><name sortKey="Gitzelmann, G" uniqKey="Gitzelmann G">G Gitzelmann</name></author><author><name sortKey="Koppensteiner, R" uniqKey="Koppensteiner R">R Koppensteiner</name></author><author><name sortKey="Franzeck, Uk" uniqKey="Franzeck U">UK Franzeck</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Franzeck, Uk" uniqKey="Franzeck U">UK Franzeck</name></author><author><name sortKey="Spiegel, I" uniqKey="Spiegel I">I Spiegel</name></author><author><name sortKey="Fischer, M" uniqKey="Fischer M">M Fischer</name></author><author><name sortKey="Bortzler, C" uniqKey="Bortzler C">C Bortzler</name></author><author><name sortKey="Stahel, Hu" uniqKey="Stahel H">HU Stahel</name></author><author><name sortKey="Bollinger, A" uniqKey="Bollinger A">A Bollinger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shayan, R" uniqKey="Shayan R">R Shayan</name></author><author><name sortKey="Achen, Mg" uniqKey="Achen M">MG Achen</name></author><author><name sortKey="Stacker, Sa" uniqKey="Stacker S">SA Stacker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ohhashi, T" uniqKey="Ohhashi T">T Ohhashi</name></author><author><name sortKey="Olschowka, Ja" uniqKey="Olschowka J">JA Olschowka</name></author><author><name sortKey="Jacobowitz, Dm" uniqKey="Jacobowitz D">DM Jacobowitz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Harisinghani, Mg" uniqKey="Harisinghani M">MG Harisinghani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Foldi, M" uniqKey="Foldi M">M Foldi</name></author><author><name sortKey="Csanda, E" uniqKey="Csanda E">E Csanda</name></author><author><name sortKey="Zoltan, Ot" uniqKey="Zoltan O">OT Zoltan</name></author><author><name sortKey="Dobranovics, I" uniqKey="Dobranovics I">I Dobranovics</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hollo, G" uniqKey="Hollo G">G Hollo</name></author><author><name sortKey="Pap, G" uniqKey="Pap G">G Pap</name></author><author><name sortKey="Bagi, Zt" uniqKey="Bagi Z">ZT Bagi</name></author><author><name sortKey="Kovacsovics, B" uniqKey="Kovacsovics B">B Kovacsovics</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cross, Jm" uniqKey="Cross J">JM Cross</name></author><author><name sortKey="Girkin, Ca" uniqKey="Girkin C">CA Girkin</name></author><author><name sortKey="Owsley, C" uniqKey="Owsley C">C Owsley</name></author><author><name sortKey="Mcgwin, G" uniqKey="Mcgwin G">G McGwin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Parekh, As" uniqKey="Parekh A">AS Parekh</name></author><author><name sortKey="Mansouri, K" uniqKey="Mansouri K">K Mansouri</name></author><author><name sortKey="Weinreb, Rn" uniqKey="Weinreb R">RN Weinreb</name></author><author><name sortKey="Tafreshi, A" uniqKey="Tafreshi A">A Tafreshi</name></author><author><name sortKey="Korn, Bs" uniqKey="Korn B">BS Korn</name></author><author><name sortKey="Kikkawa, Do" uniqKey="Kikkawa D">DO Kikkawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Krupin, T" uniqKey="Krupin T">T Krupin</name></author><author><name sortKey="Jacobs, Ls" uniqKey="Jacobs L">LS Jacobs</name></author><author><name sortKey="Podos, Sm" uniqKey="Podos S">SM Podos</name></author><author><name sortKey="Becker, B" uniqKey="Becker B">B Becker</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28081184</article-id><article-id pub-id-type="pmc">5231387</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0169683</article-id><article-id pub-id-type="publisher-id">PONE-D-16-33852</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Head</subject><subj-group><subject>Eyes</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Head</subject><subj-group><subject>Eyes</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Ocular System</subject><subj-group><subject>Eyes</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Ocular System</subject><subj-group><subject>Eyes</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Ophthalmology</subject><subj-group><subject>Eye Diseases</subject><subj-group><subject>Glaucoma</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Surgical and Invasive Medical Procedures</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Endocrine System</subject><subj-group><subject>Thyroid</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Endocrine System</subject><subj-group><subject>Thyroid</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Oncology</subject><subj-group><subject>Cancers and Neoplasms</subject><subj-group><subject>Breast Tumors</subject><subj-group><subject>Papillary Carcinomas</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Oncology</subject><subj-group><subject>Cancers and Neoplasms</subject><subj-group><subject>Carcinomas</subject><subj-group><subject>Papillary Carcinomas</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Surgical and Invasive Medical Procedures</subject><subj-group><subject>Ophthalmic Procedures</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Surgical and Invasive Medical Procedures</subject><subj-group><subject>Radical Surgery</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Neuroscience</subject><subj-group><subject>Sensory Perception</subject><subj-group><subject>Vision</subject><subj-group><subject>Visual Acuity</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Psychology</subject><subj-group><subject>Sensory Perception</subject><subj-group><subject>Vision</subject><subj-group><subject>Visual Acuity</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Social Sciences</subject><subj-group><subject>Psychology</subject><subj-group><subject>Sensory Perception</subject><subj-group><subject>Vision</subject><subj-group><subject>Visual Acuity</subject></subj-group></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Intraocular Pressure-Lowering Effect of Latanoprost Is Hampered by Defective Cervical Lymphatic Drainage</article-title><alt-title alt-title-type="running-head">Effect of Lymphatic Drainage Defect on IOP</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Young Kook</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Na</surname><given-names>Kyeong Ik</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jeoung</surname><given-names>Jin Wook</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Ki Ho</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Acott</surname><given-names>Ted S</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Oregon Health and Science University, UNITED STATES</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p><list list-type="simple"><list-item><p><bold>Conceptualization:</bold> YKK KIN JWJ KHP.</p></list-item><list-item><p><bold>Data curation:</bold> YKK KIN JWJ KHP.</p></list-item><list-item><p><bold>Formal analysis:</bold> YKK KIN JWJ KHP.</p></list-item><list-item><p><bold>Funding acquisition:</bold> KHP.</p></list-item><list-item><p><bold>Investigation:</bold> YKK KIN JWJ KHP.</p></list-item><list-item><p><bold>Methodology:</bold> YKK KIN JWJ KHP.</p></list-item><list-item><p><bold>Project administration:</bold> KHP.</p></list-item><list-item><p><bold>Resources:</bold> YKK KIN JWJ KHP.</p></list-item><list-item><p><bold>Software:</bold> YKK KIN JWJ KHP.</p></list-item><list-item><p><bold>Supervision:</bold> KHP.</p></list-item><list-item><p><bold>Validation:</bold> YKK KIN JWJ KHP.</p></list-item><list-item><p><bold>Visualization:</bold> YKK KIN JWJ KHP.</p></list-item><list-item><p><bold>Writing – original draft:</bold> YKK KIN JWJ KHP.</p></list-item><list-item><p><bold>Writing – review & editing:</bold> YKK KIN JWJ KHP.</p></list-item></list></p></fn><corresp id="cor001">* E-mail: <email>kihopark@snu.ac.kr</email></corresp></author-notes><pub-date pub-type="epub"><day>12</day><month>1</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>12</volume><issue>1</issue><elocation-id>e0169683</elocation-id><history><date date-type="received"><day>24</day><month>8</month><year>2016</year></date><date date-type="accepted"><day>19</day><month>12</month><year>2016</year></date></history><permissions><copyright-statement>© 2017 Kim et al</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>Kim et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0169683.pdf"></self-uri><abstract><sec id="sec001"><title>Purpose</title><p>To evaluate whether defects in cervical lymphatic drainage influence the intraocular pressure (IOP)-lowering effect of latanoprost in patients with primary open-angle glaucoma (POAG) who have undergone unilateral radical neck dissection (uRND).</p></sec><sec id="sec002"><title>Methods</title><p>We enrolled (1) bilateral POAG patients who had started (bilateral) latanoprost (0.005%) monotherapy prior to their uRND and (2) treatment-naïve, bilateral glaucoma suspects (GSs) who had undergone the same surgery. We compared the eyes ipsilateral to the uRND with their fellow eyes in terms of the changes in IOP between the baseline (prior to the uRND) and the follow-up visits (1, 3, and 6 months after the uRND).</p></sec><sec id="sec003"><title>Results</title><p>The study involved 22 eyes of 11 POAG patients and 14 eyes of 7 GSs. In the POAG patients, IOP had increased significantly after surgery in the eyes ipsilateral to the uRND (from 14.7±1.4mmHg to 17.1±2.2mmHg; P = 0.007). Interestingly, in the eyes contralateral to the uRND, IOP had not changed significantly after surgery (from 14.2±1.8mmHg to 14.4±2.0mmHg; P = 0.826). In GSs, the eyes ipsilateral to the uRND did not differ significantly from their fellow eyes in terms of post-operative IOP change (ipsilateral value: 0.3±0.5mmHg, fellow eyes: -0.1±0.7mmHg; P = 0.242).</p></sec><sec id="sec004"><title>Conclusion</title><p>In the POAG patients, IOP had increased significantly in the eyes ipsilateral to the uRND. However, it had not changed significantly in the eyes contralateral to the surgery or in the eyes of the GSs. These findings suggest that, latanoprost works, at least in part, by enhancing outflow from the aqueous humor via the uveolymphatic pathway.</p></sec></abstract><funding-group><funding-statement>The author(s) received no specific funding for this work.</funding-statement></funding-group><counts><fig-count count="1"></fig-count><table-count count="5"></table-count><page-count count="12"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>Data are available from the Seoul National University Hospital Institutional Review Board for researchers who meet the criteria for access to confidential data. An institutional contact name and email address for interested readers to access our minimal dataset from the Seoul National University Hospital: Name: Data Manager of Seoul National University Hospital Institutional Review Board; Email <email>02361@snuh.org</email>.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>Data are available from the Seoul National University Hospital Institutional Review Board for researchers who meet the criteria for access to confidential data. An institutional contact name and email address for interested readers to access our minimal dataset from the Seoul National University Hospital: Name: Data Manager of Seoul National University Hospital Institutional Review Board; Email <email>02361@snuh.org</email>.</p></notes></front><body><sec sec-type="intro" id="sec005"><title>Introduction</title><p>Glaucoma is a chronic progressive disease characterized by optic nerve damage and visual field loss. To preserve sight in glaucoma patients, it is crucial to lower intraocular pressure (IOP).[<xref rid="pone.0169683.ref001" ref-type="bibr">1</xref>, <xref rid="pone.0169683.ref002" ref-type="bibr">2</xref>] For this reason, investigators have mainly focused on improving fluid drainage from the eye using both pharmaceutical and surgical methods. Typically, aqueous humor is thought to drain from the eye via the trabecular meshwork and/or uveoscleral outflow pathways.[<xref rid="pone.0169683.ref003" ref-type="bibr">3</xref>] Recently, however, lymphatic vessels have been discovered in the human uvea itself, and animal studies have shown lymphatic fluid outflow through these vessels.[<xref rid="pone.0169683.ref004" ref-type="bibr">4</xref>–<xref rid="pone.0169683.ref006" ref-type="bibr">6</xref>] Additionally, there has been a report to the effect that regional lymphatic stasis and the absence of collateral drainage to the contralateral side significantly reduce the aqueous humour outflow and lead to bilateral, secondary IOP elevation.[<xref rid="pone.0169683.ref007" ref-type="bibr">7</xref>]</p><p>The prostaglandin (PG) F2a analogue such as latanoprost is one of the most widely prescribed topical eye medications for glaucoma. It lowers IOP by (1) stimulating the PG F2a receptors in the ciliary muscle, thereby increasing outflow,[<xref rid="pone.0169683.ref008" ref-type="bibr">8</xref>, <xref rid="pone.0169683.ref009" ref-type="bibr">9</xref>] (2) widening connective tissue spaces,[<xref rid="pone.0169683.ref010" ref-type="bibr">10</xref>, <xref rid="pone.0169683.ref011" ref-type="bibr">11</xref>] and (3) increasing uveoscleral outflow.[<xref rid="pone.0169683.ref012" ref-type="bibr">12</xref>, <xref rid="pone.0169683.ref013" ref-type="bibr">13</xref>] However, PG F2a analogues are known to contract lymphatic vessels as well.[<xref rid="pone.0169683.ref014" ref-type="bibr">14</xref>, <xref rid="pone.0169683.ref015" ref-type="bibr">15</xref>] In a study, the lymphatic drainage rate from the anterior chamber into the submandibular lymph node was found to be greater in latanoprost-treated mice than in controls.[<xref rid="pone.0169683.ref016" ref-type="bibr">16</xref>] Hence, it is thought that latanoprost might work, in part, by acting on the lymphatic channels in the eye.</p><p>Regardless of the mechanism, topical latanoprost effectively controls IOP.[<xref rid="pone.0169683.ref017" ref-type="bibr">17</xref>, <xref rid="pone.0169683.ref018" ref-type="bibr">18</xref>] However, a subgroup of patients with glaucoma are unresponsive or poorly-responsive to latanoprost monotherapy. In one study, 25% of patients using latanoprost did not exhibit a “clinically meaningful” reduction in IOP.[<xref rid="pone.0169683.ref019" ref-type="bibr">19</xref>] We have hypothesized that the response to latanoprost monotherapy is affected by the drainage function of the lymphatic system. In the present study, therefore, we retrospectively investigated IOP in (1) latanoprost-treated patients with bilateral primary open-angle glaucoma (POAG) and (2) non-treated, bilateral glaucoma suspects (GSs), all of whom had subsequently undergone unilateral radical neck dissection (uRND), in order to compare IOP in the eyes ipsilateral to the uRND with their fellow eyes. The primary objective of this study was to evaluate the change in mean IOP between the baseline (when the cervical lymphatic drainage system was intact) and follow-up (when the system was defective).</p></sec><sec sec-type="materials|methods" id="sec006"><title>Methods</title><p>The study was approved by the Institutional Review Board of Seoul National University Hospital and followed the tenets of the Declaration of Helsinki. Due to the retrospective analysis of data which had already been obtained in routine clinical taking care of patients, the ethics committee decided that an informed consent signed by the individual patients was not necessary. Patient records/information was anonymized and de-identified prior to analysis.</p><sec id="sec007"><title>Study subjects</title><p>We enrolled (1) patients with bilateral POAG who had received pharmaceutical treatment for ocular hypotension (bilateral latanoprost 0.005% monotherapy) and (2) patients with bilateral GS who had never been treated with IOP-lowering medication. Using the customized data-sorting system for medical records (Clinical Data Warehouse; Bestcare software of SNUH, Seoul, South Korea), we consecutively selected those patients who had undergone uRND at the Head and Neck Cancer Clinic between January 2006 and February 2015.</p><p>All of the patients had undergone a complete ophthalmic examination including best-corrected visual acuity (logMAR) assessment, refraction, slit-lamp biomicroscopy, gonioscopy, dilated stereoscopic examination of the optic disc, red-free retinal nerve fiber layer (RNFL) photography, optic nerve head imaging by Cirrus DH-OCT (Carl Zeiss Meditec), and a central 30–2 threshold test of the Humphrey Visual Field (VF; HFA II; Humphrey Instruments Inc., Dublin, CA, USA).</p><p>An eye with GS was defined as that with one of the following findings: (1) a VF abnormality consistent with glaucoma, (2) an optic nerve or RNFL suggestive of glaucoma (enlarged or asymmetric cup/disc ratio, notching or narrowing of the neuroretinal rim, disc hemorrhage, or suspicious alteration in the RNFL), (3) an IOP higher than 21 mmHg. If two or more of these findings were present, the eye was diagnosed with POAG. Glaucomatous VF defects were defined as (1) a cluster of three points with probabilities less than 5% in at least one hemifield on the pattern deviation map, including at least one point with a probability less than 1%, (2) a cluster of two points with a probability less than 1% in at least one hemifield on the pattern deviation map, (3) glaucomatous Hemifield Test results outside the normal limits, or (4) a pattern standard deviation beyond 95% of the normal limits, as confirmed by at least two reliable examinations (false-positives/negatives: < 15%, fixation losses: < 15%).</p><p>Individuals were excluded on the basis of the following criteria: (1) secondary cause of glaucomatous optic neuropathy, (2) history of intraocular surgery (except cataract surgery) or ocular laser treatment (except Nd:YAG posterior capsulotomy), and (3) any neurological or systemic diseases that can affect retinal and VF results.</p></sec><sec id="sec008"><title>Latanoprost monotherapy</title><p>All of the POAG patients had started latanoprost 0.005% monotherapy bilaterally more than 3 months before undergoing uRND, and had continued it for more than 6 months after the uRND. For patients who had been administered other glaucoma drugs, latanoprost monotherapy was started after a withdrawal period of at least 1 month. Patients who had presented with adverse events after the start of latanoprost monotherapy, or who had started any treatments other than latanoprost (such as anti-glaucoma eye drops, laser therapy, or glaucoma surgery), were eliminated from the study as dropouts. Also eliminated as dropouts were GSs who had ever been treated with IOP-lowering medication.</p></sec><sec id="sec009"><title>uRND</title><p>Unilateral radical neck dissection (uRND) involves the unilateral removal of cervical lymph nodes from levels I through V, together with the spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle. The aim of this procedure is to remove lymph nodes into which cancer cells might have migrated. Thus, the procedure is carried out in cases of clinically or radiologically diagnosed lymph-node metastasis or as part of curative surgery in cases where the risk of occult nodal metastasis is deemed sufficiently high. In the present study, all of the patients treated using the uRND had also undergone surgery for a primary tumor (carcinoma of the mouth, oropharynx, hypopharynx, larynx, or thyroid). In some cases, one or more of the non-lymphatic structures (spinal accessory nerve, internal jugular vein and sternocleidomastoid muscle) were preserved, which procedures are defined as modified uRNDs.</p></sec><sec id="sec010"><title>Pre- and post-operative follow-up IOP</title><p>For the POAG patients who had been treated using latanoprost monotherapy, the pre-operative mean IOP was defined as the mean of the IOP values obtained 1 month after the start of medical therapy and at each visit prior to the uRND; for the GSs, it was defined as the mean of the IOP values obtained at the initial visit and at each visit prior to the uRND. For all of the patients, IOP was measured 1, 3, and 6 months after surgery. All of these measurements were performed in the morning (from 9:00 am to 11:30 am) using Goldman applanation tonometry with the patient in a sitting position at the slit lamp. All of the study data were reviewed and analyzed by an author (Y.K.K) masked to all other information including the diagnosis of glaucoma and the side of the neck dissection.</p></sec><sec id="sec011"><title>Statistical analysis</title><p>The nominal variables was analyzed using the Fisher exact test. ANOVA and the students t-test were employed for overall and pairwise comparisons of the continuous variables. Comparisons of overall mean IOP changes between fellow eyes were conducted using 1-way ANOVA for repeated measures. Because there were significant inter-group differences in baseline IOP, ANCOVA was utilized to test for mean IOP differences among the groups from the baseline. Statistical analysis was performed using the SPSS statistical package (SPSS 18.0; Chicago, IL, USA). A <italic>P</italic> value less than 0.05 was considered statistically significant.</p></sec></sec><sec sec-type="results" id="sec012"><title>Results</title><sec id="sec013"><title>Study subjects</title><p>We initially distinguished 28 eyes of 14 patients with POAG and 20 eyes of 10 treatment-naive GSs, all of whom had undergone uRND. On the basis of a medical record review, we then recruited, for the present study, 22 POAG eyes of 11 patients, and 14 eyes of 7 GSs, which fulfilled the eligibility criteria. The POAG patients’ mean age was 54.72 ± 6.08 (38–71) years; seven were men (63.6%) and four were women (36.4%). The GSs’ mean age was 57.29 ± 5.50 (35–68) years; five were men (71.4%) and two were women (28.6%). The eyes in each group were differentiated according to their laterality to the uRND; that is, eyes were either ipsilateral or contralateral to the uRND.</p><p>In the POAG group, there was no significant difference in laterality (P = 0.394); furthermore, the ipsilateral and contralateral eyes did not differ in terms of visual acuity (P = 0.853), VF mean deviation (P = 0.683), refractive error (P = 0.897), central corneal thickness (P = 0.950), circumpapillary RNFL thickness (P = 0.430), baseline pre-treated IOP (P = 0.700) or baseline treated IOP (P = 0.501). Latanoprost monotherapy reduced the mean IOP by 3.7 ± 1.9 mmHg (from 18.2 ± 2.4 mmHg to 14.5 ± 1.7 mmHg); this effect did not differ significantly between fellow eyes (P = 0.812).</p><p>In the GS group, there was no significant difference in the laterality (P = 1.000), and the ipsilateral and contralateral eyes did not differ in terms of visual acuity (P = 0.797), VF mean deviation (P = 0.829), refractive error (P = 0.766), central corneal thickness (P = 0.820), circumpapillary RNFL thickness (P = 0.424) or baseline IOP (P = 0.828). The demographic and clinical characteristics of the POAG group are presented in <xref ref-type="table" rid="pone.0169683.t001">Table 1</xref>, while those of the GS group are provided in <xref ref-type="table" rid="pone.0169683.t002">Table 2</xref>.</p><table-wrap id="pone.0169683.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0169683.t001</object-id><label>Table 1</label><caption><title>Baseline characteristics of POAG eyes ipsilateral to the uRND and in POAG eyes contralateral to the uRND.</title></caption><alternatives><graphic id="pone.0169683.t001g" xlink:href="pone.0169683.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Characteristics</th><th align="center" colspan="2" rowspan="1">Ipsilateral to the uRND (n = 11)</th><th align="center" rowspan="1" colspan="1">Contralateral to the uRND (n = 11)</th><th align="center" rowspan="1" colspan="1"><italic>P</italic></th></tr></thead><tbody><tr><td align="left" colspan="2" rowspan="1">Age</td><td align="center" colspan="2" rowspan="1">54.72 ± 6.08</td><td align="center" rowspan="1" colspan="1">-</td></tr><tr><td align="left" colspan="2" rowspan="1">Gender (Male / Female)</td><td align="center" colspan="2" rowspan="1">7 / 4</td><td align="center" rowspan="1" colspan="1">-</td></tr><tr><td align="left" colspan="2" rowspan="1">Laterality (OD / OS)</td><td align="center" rowspan="1" colspan="1">7 / 4</td><td align="center" rowspan="1" colspan="1">4 / 7</td><td align="center" rowspan="1" colspan="1">0.394</td></tr><tr><td align="left" colspan="2" rowspan="1">Visual acuity (logMAR)</td><td align="center" rowspan="1" colspan="1">0.19 ± 0.42</td><td align="center" rowspan="1" colspan="1">0.23 ± 0.57</td><td align="center" rowspan="1" colspan="1">0.853</td></tr><tr><td align="left" colspan="2" rowspan="1">Visual field mean deviation (dB)</td><td align="center" rowspan="1" colspan="1">-8.61 ± 3.23</td><td align="center" rowspan="1" colspan="1">-9.17 ± 3.10</td><td align="center" rowspan="1" colspan="1">0.683</td></tr><tr><td align="left" colspan="2" rowspan="1">Refractive error (spherical equivalent; diopters)</td><td align="center" rowspan="1" colspan="1">-0.34 ± 2.59</td><td align="center" rowspan="1" colspan="1">-0.52 ± 3.76</td><td align="center" rowspan="1" colspan="1">0.897</td></tr><tr><td align="left" colspan="2" rowspan="1">Central corneal thickness (μm)</td><td align="center" rowspan="1" colspan="1">525.1 ± 30.4</td><td align="center" rowspan="1" colspan="1">524.2 ± 29.9</td><td align="center" rowspan="1" colspan="1">0.950</td></tr><tr><td align="left" colspan="2" rowspan="1">Circumpapillary RNFL thickness (μm)</td><td align="center" rowspan="1" colspan="1">68.3 ± 11.5</td><td align="center" rowspan="1" colspan="1">64.2 ± 12.0</td><td align="center" rowspan="1" colspan="1">0.430</td></tr><tr><td align="left" colspan="2" rowspan="1">Pretreat IOP</td><td align="center" rowspan="1" colspan="1">18.3 ± 2.5</td><td align="center" rowspan="1" colspan="1">17.9 ± 2.3</td><td align="center" rowspan="1" colspan="1">0.700</td></tr><tr><td align="left" colspan="2" rowspan="1">Treat IOP</td><td align="center" rowspan="1" colspan="1">14.7 ± 1.4</td><td align="center" rowspan="1" colspan="1">14.2 ± 1.8</td><td align="center" rowspan="1" colspan="1">0.501</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>POAG, primary open-angle glaucoma; uRND, unilateral radical neck dissection; logMAR, logarithm of the Minimum Angle of Resolution; dB, decibel; RNFL, retinal nerve fiber layer; IOP, intraocular pressure</p></fn></table-wrap-foot></table-wrap><table-wrap id="pone.0169683.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0169683.t002</object-id><label>Table 2</label><caption><title>Baseline characteristics of GS eyes ipsilateral to the uRND and in GS eyes contralateral to the uRND.</title></caption><alternatives><graphic id="pone.0169683.t002g" xlink:href="pone.0169683.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Characteristics</th><th align="center" rowspan="1" colspan="1">Ipsilateral to the uRND (n = 7)</th><th align="center" rowspan="1" colspan="1">Contralateral to the uRND (n = 7)</th><th align="center" rowspan="1" colspan="1"><italic>P</italic></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Age</td><td align="center" colspan="2" rowspan="1">57.29 ± 5.50</td><td align="center" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Gender (Male / Female)</td><td align="center" colspan="2" rowspan="1">5 / 2</td><td align="center" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Laterality (OD / OS)</td><td align="center" rowspan="1" colspan="1">3 / 4</td><td align="center" rowspan="1" colspan="1">4 / 3</td><td align="center" rowspan="1" colspan="1">1.000</td></tr><tr><td align="left" rowspan="1" colspan="1">Visual acuity (logMAR)</td><td align="center" rowspan="1" colspan="1">0.15 ± 0.33</td><td align="center" rowspan="1" colspan="1">0.20 ± 0.38</td><td align="center" rowspan="1" colspan="1">0.797</td></tr><tr><td align="left" rowspan="1" colspan="1">Visual field mean deviation (dB)</td><td align="center" rowspan="1" colspan="1">-0.32 ± 1.12</td><td align="center" rowspan="1" colspan="1">-0.19 ± 1.08</td><td align="center" rowspan="1" colspan="1">0.829</td></tr><tr><td align="left" rowspan="1" colspan="1">Refractive error (spherical equivalent; diopters)</td><td align="center" rowspan="1" colspan="1">-0.78 ± 2.13</td><td align="center" rowspan="1" colspan="1">-0.36 ± 2.97</td><td align="center" rowspan="1" colspan="1">0.766</td></tr><tr><td align="left" rowspan="1" colspan="1">Central corneal thickness (μm)</td><td align="center" rowspan="1" colspan="1">535.3 ± 28.7</td><td align="center" rowspan="1" colspan="1">531.1 ± 38.3</td><td align="center" rowspan="1" colspan="1">0.820</td></tr><tr><td align="left" rowspan="1" colspan="1">Circumpapillary RNFL thickness (μm)</td><td align="center" rowspan="1" colspan="1">89.5 ± 7.8</td><td align="center" rowspan="1" colspan="1">86.4 ± 6.1</td><td align="center" rowspan="1" colspan="1">0.424</td></tr><tr><td align="left" rowspan="1" colspan="1">IOP (mmHg)</td><td align="center" rowspan="1" colspan="1">17.4 ± 2.3</td><td align="center" rowspan="1" colspan="1">17.0 ± 2.8</td><td align="center" rowspan="1" colspan="1">0.828</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p>GS, glaucoma suspect; uRND, unilateral radical neck dissection; logMAR, logarithm of the Minimum Angle of Resolution; dB, decibel; RNFL, retinal nerve fiber layer; IOP, intraocular pressure</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec014"><title>Post-operative IOP changes in POAG eyes</title><p>Among the treated POAG patients, the mean IOP significantly increased immediately after surgery (from 14.5 ± 1.7 mmHg to 16.2 ± 1.8 mmHg; P = 0.034). Interestingly, the POAG eyes ipsilateral to the uRND showed a greater IOP increase than did their fellow eyes (2.4 ± 0.8 mmHg <italic>vs</italic>. 0.2 ± 0.7 mmHg; P < 0.001; <xref ref-type="table" rid="pone.0169683.t003">Table 3</xref>). Specifically, in the POAG eyes ipsilateral to the uRND, the mean IOP values 1, 3, and 6 months after surgery were 115.0% (P = 0.015), 113.6% (P = 0.007), and 120.4% (P = 0.004) of the pre-operative value, respectively (avg.: 116.3% [P = 0.007]). Among the POAG eyes contralateral to the uRND, those values were 105.6% (P = 0.317), 96.5% (P = 0.566), and 101.4% (P = 0.833) of the pre-operative value, respectively (avg.: 101.4% [P = 0.826]). The mean IOP was more likely to be increased in the POAG eyes ipsilateral to the uRND than in their fellow eyes; specifically, IOP had increased by 15% or more in 81.8% (9/11) of the ipsilateral eyes and 9.1% (1/11) of the contralateral eyes (P < 0.001; <xref ref-type="fig" rid="pone.0169683.g001">Fig 1</xref>). <xref ref-type="table" rid="pone.0169683.t004">Table 4</xref> shows the relevant data on each of the POAG patients (gender, age, systemic comorbidities, IOP, site of primary tumor, side of uRND, and type of adjuvant therapies).</p><fig id="pone.0169683.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0169683.g001</object-id><label>Fig 1</label><caption><title>Comparisons of eyes ipsilateral to unilateral radical neck dissection (uRND) with fellow eyes in terms of changes in intraocular pressure (IOP) between pre-operative baseline (prior to uRND) and post-operative follow-up visits (1, 3, and 6 months after uRND).</title><p>POAG = primary open-angle glaucoma, GS = glaucoma suspect. <sup>*</sup><italic>P</italic> = 0.015, <sup>**</sup><italic>P</italic> = 0.007, <sup>***</sup><italic>P</italic> = 0.004 (when comparing post-operative IOP to pre-operative baseline).</p></caption><graphic xlink:href="pone.0169683.g001"></graphic></fig><table-wrap id="pone.0169683.t003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0169683.t003</object-id><label>Table 3</label><caption><title>IOP changes in latanoprost-treated-POAG eyes after the uRND.</title></caption><alternatives><graphic id="pone.0169683.t003g" xlink:href="pone.0169683.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th align="center" colspan="7" rowspan="1">POAG eyes (<italic>n = 22</italic>)</th></tr><tr><th align="left" rowspan="1" colspan="1"></th><th align="center" colspan="3" rowspan="1">Ipsilateral to the uRND (<italic>n = 11</italic>)</th><th align="center" colspan="3" rowspan="1">Contralateral to the uRND (<italic>n = 11</italic>)</th><th align="center" rowspan="3" colspan="1"><italic>P</italic></th></tr><tr><th align="center" rowspan="2" colspan="1">Characteristics</th><th align="center" rowspan="2" colspan="1">IOP (<italic>mmHg</italic>)</th><th align="center" colspan="2" rowspan="1">Change from pre-operative baseline</th><th align="center" rowspan="2" colspan="1">IOP (<italic>mmHg</italic>)</th><th align="center" colspan="2" rowspan="1">Change from pre-operative baseline</th></tr><tr><th align="center" rowspan="1" colspan="1"><italic>%</italic></th><th align="center" rowspan="1" colspan="1"><italic>P</italic></th><th align="center" rowspan="1" colspan="1"><italic>%</italic></th><th align="center" rowspan="1" colspan="1"><italic>P</italic></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Pre-operative baseline</td><td align="center" rowspan="1" colspan="1">14.7 ± 1.4</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">14.2 ± 1.8</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">0.541</td></tr><tr><td align="left" rowspan="1" colspan="1">Post-operative period</td><td align="center" rowspan="1" colspan="1">17.1 ± 2.2</td><td align="center" rowspan="1" colspan="1">116.3</td><td align="center" rowspan="1" colspan="1">0.007</td><td align="center" rowspan="1" colspan="1">14.4 ± 2.0</td><td align="center" rowspan="1" colspan="1">101.4</td><td align="center" rowspan="1" colspan="1">0.826</td><td align="center" rowspan="1" colspan="1">0.007</td></tr><tr><td align="left" rowspan="1" colspan="1"> • <italic>1 month</italic></td><td align="center" rowspan="1" colspan="1">16.9 ± 2.3</td><td align="center" rowspan="1" colspan="1">115.0</td><td align="center" rowspan="1" colspan="1">0.015</td><td align="center" rowspan="1" colspan="1">15.0 ± 1.9</td><td align="center" rowspan="1" colspan="1">105.6</td><td align="center" rowspan="1" colspan="1">0.317</td><td align="center" rowspan="1" colspan="1">0.047</td></tr><tr><td align="left" rowspan="1" colspan="1"> • <italic>3 months</italic></td><td align="center" rowspan="1" colspan="1">16.7 ± 1.6</td><td align="center" rowspan="1" colspan="1">113.6</td><td align="center" rowspan="1" colspan="1">0.007</td><td align="center" rowspan="1" colspan="1">13.7 ± 1.8</td><td align="center" rowspan="1" colspan="1">96.5</td><td align="center" rowspan="1" colspan="1">0.566</td><td align="center" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"> • <italic>6 months</italic></td><td align="center" rowspan="1" colspan="1">17.7 ± 2.7</td><td align="center" rowspan="1" colspan="1">120.4</td><td align="center" rowspan="1" colspan="1">0.004</td><td align="center" rowspan="1" colspan="1">14.4 ± 2.2</td><td align="center" rowspan="1" colspan="1">101.4</td><td align="center" rowspan="1" colspan="1">0.833</td><td align="center" rowspan="1" colspan="1">0.005</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t003fn001"><p>IOP, intraocular pressure; POAG, primary open-angle glaucoma; uRND, unilateral radical neck dissection</p></fn></table-wrap-foot></table-wrap><table-wrap id="pone.0169683.t004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0169683.t004</object-id><label>Table 4</label><caption><title>Patient summary.</title></caption><alternatives><graphic id="pone.0169683.t004g" xlink:href="pone.0169683.t004"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="2" colspan="1">Patient<xref ref-type="table-fn" rid="t004fn001"><sup>*</sup></xref></th><th align="center" rowspan="2" colspan="1">Gender / age,<xref ref-type="table-fn" rid="t004fn001"><sup>*</sup></xref> (y)</th><th align="center" colspan="2" rowspan="1">Comorbidities</th><th align="center" colspan="4" rowspan="1">Glaucoma</th><th align="center" colspan="2" rowspan="1">Primary tumor</th><th align="center" colspan="2" rowspan="1">uRND</th><th align="center" colspan="2" rowspan="1">Adjuvant therapy</th><th align="center" colspan="2" rowspan="1">Post-uRND IOP<xref ref-type="table-fn" rid="t004fn003"><sup>***</sup></xref></th></tr><tr><th align="center" rowspan="1" colspan="1">DM</th><th align="center" rowspan="1" colspan="1">HTN</th><th align="center" colspan="2" rowspan="1">Diagnosis</th><th align="center" colspan="2" rowspan="1">Mean F/U IOP<xref ref-type="table-fn" rid="t004fn002"><sup>**</sup></xref></th><th align="center" rowspan="1" colspan="1">Location</th><th align="center" rowspan="1" colspan="1">Diagnosis</th><th align="center" rowspan="1" colspan="1">Laterality</th><th align="center" rowspan="1" colspan="1">Extent</th><th align="center" rowspan="1" colspan="1">Chemotherapy</th><th align="center" rowspan="1" colspan="1">Radiation therapy</th><th align="center" rowspan="2" colspan="1">OD</th><th align="center" rowspan="2" colspan="1">OS</th></tr><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1">OD</th><th align="center" rowspan="1" colspan="1">OS</th><th align="center" rowspan="1" colspan="1">OD</th><th align="center" rowspan="1" colspan="1">OS</th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th></tr></thead><tbody><tr><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">M / 56</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">16.6</td><td align="center" rowspan="1" colspan="1">16.9</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OD</td><td align="center" rowspan="1" colspan="1">RND</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">20.4</td><td align="center" rowspan="1" colspan="1">17.0</td></tr><tr><td align="center" rowspan="1" colspan="1">2</td><td align="center" rowspan="1" colspan="1">M / 58</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">14.1</td><td align="center" rowspan="1" colspan="1">12.6</td><td align="center" rowspan="1" colspan="1">Oropharynx</td><td align="center" rowspan="1" colspan="1">Squamous cell carcinoma</td><td align="center" rowspan="1" colspan="1">OD</td><td align="center" rowspan="1" colspan="1">RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">16.1</td><td align="center" rowspan="1" colspan="1">12.6</td></tr><tr><td align="center" rowspan="1" colspan="1">3</td><td align="center" rowspan="1" colspan="1">M / 66</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">14.3</td><td align="center" rowspan="1" colspan="1">12.7</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OD</td><td align="center" rowspan="1" colspan="1">RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">15.4</td><td align="center" rowspan="1" colspan="1">13.7</td></tr><tr><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">M / 44</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">15.7</td><td align="center" rowspan="1" colspan="1">15.3</td><td align="center" rowspan="1" colspan="1">Tongue</td><td align="center" rowspan="1" colspan="1">Squamous cell carcinoma</td><td align="center" rowspan="1" colspan="1">OD</td><td align="center" rowspan="1" colspan="1">RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">18.9</td><td align="center" rowspan="1" colspan="1">16.3</td></tr><tr><td align="center" rowspan="1" colspan="1">5</td><td align="center" rowspan="1" colspan="1">F / 47</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">17.5</td><td align="center" rowspan="1" colspan="1">17.5</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OD</td><td align="center" rowspan="1" colspan="1">Modified RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">19.9</td><td align="center" rowspan="1" colspan="1">17.8</td></tr><tr><td align="center" rowspan="1" colspan="1">6</td><td align="center" rowspan="1" colspan="1">F / 50</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">13.6</td><td align="center" rowspan="1" colspan="1">14.6</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OD</td><td align="center" rowspan="1" colspan="1">RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">15.2</td><td align="center" rowspan="1" colspan="1">15.0</td></tr><tr><td align="center" rowspan="1" colspan="1">7</td><td align="center" rowspan="1" colspan="1">M / 59</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">13.2</td><td align="center" rowspan="1" colspan="1">12.2</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OD</td><td align="center" rowspan="1" colspan="1">Modified RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">15.0</td><td align="center" rowspan="1" colspan="1">12.0</td></tr><tr><td align="center" rowspan="1" colspan="1">8</td><td align="center" rowspan="1" colspan="1">F / 56</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">14.4</td><td align="center" rowspan="1" colspan="1">14.9</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Squamous cell carcinoma</td><td align="center" rowspan="1" colspan="1">OS</td><td align="center" rowspan="1" colspan="1">Modified RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">13.8</td><td align="center" rowspan="1" colspan="1">17.3</td></tr><tr><td align="center" rowspan="1" colspan="1">9</td><td align="center" rowspan="1" colspan="1">F / 55</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">14.5</td><td align="center" rowspan="1" colspan="1">14.5</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OS</td><td align="center" rowspan="1" colspan="1">RND</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">14.1</td><td align="center" rowspan="1" colspan="1">16.9</td></tr><tr><td align="center" rowspan="1" colspan="1">10</td><td align="center" rowspan="1" colspan="1">M / 58</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">12.1</td><td align="center" rowspan="1" colspan="1">12.9</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OS</td><td align="center" rowspan="1" colspan="1">Modified RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">12.1</td><td align="center" rowspan="1" colspan="1">13.8</td></tr><tr><td align="center" rowspan="1" colspan="1">11</td><td align="center" rowspan="1" colspan="1">M / 53</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">POAG</td><td align="center" rowspan="1" colspan="1">14.0</td><td align="center" rowspan="1" colspan="1">14.8</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OS</td><td align="center" rowspan="1" colspan="1">Modified RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">13.6</td><td align="center" rowspan="1" colspan="1">19.2</td></tr><tr><td align="center" rowspan="1" colspan="1">12</td><td align="center" rowspan="1" colspan="1">M / 59</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">16.3</td><td align="center" rowspan="1" colspan="1">15.9</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OD</td><td align="center" rowspan="1" colspan="1">Modified RND</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">15.9</td><td align="center" rowspan="1" colspan="1">15.7</td></tr><tr><td align="center" rowspan="1" colspan="1">13</td><td align="center" rowspan="1" colspan="1">M / 63</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">14.9</td><td align="center" rowspan="1" colspan="1">14.1</td><td align="center" rowspan="1" colspan="1">Oropharynx</td><td align="center" rowspan="1" colspan="1">Squamous cell carcinoma</td><td align="center" rowspan="1" colspan="1">OD</td><td align="center" rowspan="1" colspan="1">RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">14.6</td><td align="center" rowspan="1" colspan="1">14.1</td></tr><tr><td align="center" rowspan="1" colspan="1">14</td><td align="center" rowspan="1" colspan="1">F / 65</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">19.6</td><td align="center" rowspan="1" colspan="1">19.2</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Squamous cell carcinoma</td><td align="center" rowspan="1" colspan="1">OD</td><td align="center" rowspan="1" colspan="1">Modified RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">20.2</td><td align="center" rowspan="1" colspan="1">19.0</td></tr><tr><td align="center" rowspan="1" colspan="1">15</td><td align="center" rowspan="1" colspan="1">F / 49</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">18.4</td><td align="center" rowspan="1" colspan="1">18.2</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OS</td><td align="center" rowspan="1" colspan="1">RND</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">18.7</td><td align="center" rowspan="1" colspan="1">18.6</td></tr><tr><td align="center" rowspan="1" colspan="1">16</td><td align="center" rowspan="1" colspan="1">M / 55</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">18.7</td><td align="center" rowspan="1" colspan="1">18.8</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OS</td><td align="center" rowspan="1" colspan="1">Modified RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">18.5</td><td align="center" rowspan="1" colspan="1">19.2</td></tr><tr><td align="center" rowspan="1" colspan="1">17</td><td align="center" rowspan="1" colspan="1">M / 54</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">13.0</td><td align="center" rowspan="1" colspan="1">14.1</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Squamous cell carcinoma</td><td align="center" rowspan="1" colspan="1">OS</td><td align="center" rowspan="1" colspan="1">Modified RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">13.1</td><td align="center" rowspan="1" colspan="1">15.0</td></tr><tr><td align="center" rowspan="1" colspan="1">18</td><td align="center" rowspan="1" colspan="1">M / 56</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">GS</td><td align="center" rowspan="1" colspan="1">19.4</td><td align="center" rowspan="1" colspan="1">19.7</td><td align="center" rowspan="1" colspan="1">Thyroid</td><td align="center" rowspan="1" colspan="1">Papillary carcinoma</td><td align="center" rowspan="1" colspan="1">OS</td><td align="center" rowspan="1" colspan="1">Modified RND</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">19.3</td><td align="center" rowspan="1" colspan="1">20.3</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t004fn001"><p>* Age at operation.</p></fn><fn id="t004fn002"><p>** Mean treat-IOP for glaucoma patients and mean untreat-IOP for glaucoma suspects.</p></fn><fn id="t004fn003"><p>*** Mean IOP during the post-op 6 months.</p></fn><fn id="t004fn004"><p>DM, diabetes mellitus; HTN, hypertension; OD, oculus dexter; OS, oculus sinister; uRND, unilateral radical neck dissection; LN, lymph node; POAG, primary open-angle glaucoma; GS, glaucoma suspect.</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec015"><title>Post-operative IOP changes in GS eyes</title><p>Among the GSs, the mean IOP did not change significantly between the pre-operative baseline and the post-operative period (17.2 ± 3.4 mmHg <italic>vs</italic>. 17.3± 3.2 mmHg; P = 0.957). The mean IOP value in the GS eyes ipsilateral to the uRND increased slightly after surgery (from 17.4 ± 3.1 mmHg to 17.7 ± 3.0 mmHg; P = 0.857). However, in the contralateral eyes, the IOP decreased slightly after surgery (from 17.0 ± 3.6 mmHg to 16.9 ± 3.4 mmHg; P = 0.649; <xref ref-type="table" rid="pone.0169683.t005">Table 5</xref> and <xref ref-type="fig" rid="pone.0169683.g001">Fig 1</xref>). Specifically, in the GS eyes ipsilateral to the uRND, the mean IOP values 1, 3, and 6 months after surgery were 100.6% (P = 0.956), 103.4% (P = 0.398), and 102.3% (P = 0.782), respectively. In the GS eyes contralateral to the uRND meanwhile, those IOP values were 101.2% (P = 0.850), 100.0% (P = 0.962), and 98.8% (P = 0.849), respectively. <xref ref-type="table" rid="pone.0169683.t004">Table 4</xref> shows the relevant data on each of the GSs (gender, age, systemic comorbidities, IOP, site of primary tumor, side of uRND, and type of adjuvant therapies).</p><table-wrap id="pone.0169683.t005" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0169683.t005</object-id><label>Table 5</label><caption><title>IOP changes in non-treated-GS eyes after uRND.</title></caption><alternatives><graphic id="pone.0169683.t005g" xlink:href="pone.0169683.t005"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th align="center" colspan="7" rowspan="1">GS eyes (<italic>n = 14</italic>)</th></tr><tr><th align="left" rowspan="1" colspan="1"></th><th align="center" colspan="3" rowspan="1">Ipsilateral to uRND (<italic>n = 7</italic>)</th><th align="center" colspan="3" rowspan="1">Contralateral to uRND (<italic>n = 7</italic>)</th><th align="center" rowspan="3" colspan="1"><italic>P</italic></th></tr><tr><th align="center" rowspan="2" colspan="1">Characteristics</th><th align="center" rowspan="2" colspan="1">IOP (<italic>mmHg</italic>)</th><th align="center" colspan="2" rowspan="1">Change from pre-operative baseline</th><th align="center" rowspan="2" colspan="1">IOP (<italic>mmHg</italic>)</th><th align="center" colspan="2" rowspan="1">Change from pre-operative baseline</th></tr><tr><th align="center" rowspan="1" colspan="1"><italic>%</italic></th><th align="center" rowspan="1" colspan="1"><italic>P</italic></th><th align="center" rowspan="1" colspan="1"><italic>%</italic></th><th align="center" rowspan="1" colspan="1"><italic>P</italic></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Pre-operative baseline</td><td align="center" rowspan="1" colspan="1">17.4 ± 2.3</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">17.0 ± 2.8</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">-</td><td align="center" rowspan="1" colspan="1">0.828</td></tr><tr><td align="left" rowspan="1" colspan="1">Post-operative period</td><td align="center" rowspan="1" colspan="1">17.7 ± 2.5</td><td align="center" rowspan="1" colspan="1">101.7</td><td align="center" rowspan="1" colspan="1">0.857</td><td align="center" rowspan="1" colspan="1">16.9 ± 2.6</td><td align="center" rowspan="1" colspan="1">99.4</td><td align="center" rowspan="1" colspan="1">0.958</td><td align="center" rowspan="1" colspan="1">0.649</td></tr><tr><td align="left" rowspan="1" colspan="1"> • <italic>1 month</italic></td><td align="center" rowspan="1" colspan="1">17.5 ± 2.7</td><td align="center" rowspan="1" colspan="1">100.6</td><td align="center" rowspan="1" colspan="1">0.956</td><td align="center" rowspan="1" colspan="1">17.2 ± 3.1</td><td align="center" rowspan="1" colspan="1">101.2</td><td align="center" rowspan="1" colspan="1">0.948</td><td align="center" rowspan="1" colspan="1">0.850</td></tr><tr><td align="left" rowspan="1" colspan="1"> • <italic>3 months</italic></td><td align="center" rowspan="1" colspan="1">18.0 ± 2.5</td><td align="center" rowspan="1" colspan="1">103.4</td><td align="center" rowspan="1" colspan="1">0.398</td><td align="center" rowspan="1" colspan="1">17.0 ± 2.5</td><td align="center" rowspan="1" colspan="1">100.0</td><td align="center" rowspan="1" colspan="1">0.962</td><td align="center" rowspan="1" colspan="1">0.469</td></tr><tr><td align="left" rowspan="1" colspan="1"> • <italic>6 months</italic></td><td align="center" rowspan="1" colspan="1">17.8 ± 2.3</td><td align="center" rowspan="1" colspan="1">102.3</td><td align="center" rowspan="1" colspan="1">0.782</td><td align="center" rowspan="1" colspan="1">16.7 ± 2.9</td><td align="center" rowspan="1" colspan="1">98.8</td><td align="center" rowspan="1" colspan="1">0.849</td><td align="center" rowspan="1" colspan="1">0.524</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t005fn001"><p>IOP, intraocular pressure; GS, glaucoma suspect; uRND, unilateral radical neck dissection</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec016"><title>Case study</title><p>A 63-year-old man was diagnosed with bilateral POAG (Humphrey VF mean deviation: -5.67 dB in right eye and -6.09 dB in left eye) in April 2012. His untreated IOP was 18 mmHg in the right eye and 17 mmHg in the left eye. He was prescribed 0.005% latanoprost in both eyes, and the mean treated IOP was 14.2 mmHg in the right eye and 14.4 mmHg in the left eye. In September 2013, he was diagnosed with papillary thyroid cancer on the right lobe. So, he underwent a total thyroidectomy combined with right-sided uRND. One month after surgery, the IOP in the right eye had increased from 14.2 mmHg to 16 mmHg; however, there was no significant change in the left eye (from 14.4 mmHg to 14.5 mmHg). Three (3) months after surgery, the IOP was 17.5 mmHg in the right eye and 14.5 mmHg in the left eye; 6 months after surgery, the values were 17 mmHg in the right eye and 14 mmHg in the left eye. Thus, for both eyes, the patient’s medication was changed from 0.005% latanoprost to 0.5% timolol. One month later, the IOP in the right eye had decreased from 17.5 mmHg to 15 mmHg; after 6 and 12 months, the IOP in that eye was 14 mmHg and 14.5 mmHg, respectively.</p></sec></sec><sec sec-type="conclusions" id="sec017"><title>Discussion</title><p>In the present study, the POAG patients were prescribed 0.005% latanoprost bilaterally and had continuously used it before and after uRND. In the eyes ipsilateral to the uRND, IOP was significantly elevated after surgery. Conversely, there were no significant IOP changes in the fellow eyes. To our knowledge, this is the first study to demonstrate the effect of defective cervical lymphatic drainage on IOP in treated glaucoma patients.</p><p>Lymphatic vessels are well-known to drain extracellular fluid[<xref rid="pone.0169683.ref020" ref-type="bibr">20</xref>–<xref rid="pone.0169683.ref023" ref-type="bibr">23</xref>]; however, until recently, they were believed to be absent from the eye.[<xref rid="pone.0169683.ref024" ref-type="bibr">24</xref>, <xref rid="pone.0169683.ref025" ref-type="bibr">25</xref>] This belief raised several perplexing questions. For instance, how does the normal aqueous humor remain virtually protein free despite the high metabolic activity of the surrounding ocular tissues? And, how is interstitial fluid removed from ocular tissues?[<xref rid="pone.0169683.ref004" ref-type="bibr">4</xref>] Previous pioneering studies have posited the chronic cervical lymphostasis effect on the regions primarily drained by prelymphatics (including the retina, papilla, iris, choroid and Circle of Willis).[<xref rid="pone.0169683.ref026" ref-type="bibr">26</xref>, <xref rid="pone.0169683.ref027" ref-type="bibr">27</xref>] Advances in lymphatic research with lymphatic-specific markers have enabled investigators to identify ciliary-body lymphatic circulation[<xref rid="pone.0169683.ref005" ref-type="bibr">5</xref>] that might allow aqueous humor to flow out of the anterior chamber.[<xref rid="pone.0169683.ref004" ref-type="bibr">4</xref>, <xref rid="pone.0169683.ref006" ref-type="bibr">6</xref>] On this basis, the lymphatic network of the ciliary body was hypothesized, as the “uveolymphatic pathway,”[<xref rid="pone.0169683.ref005" ref-type="bibr">5</xref>, <xref rid="pone.0169683.ref028" ref-type="bibr">28</xref>] to be the third route of aqueous humor drainage.</p><p>Lymphatic vessels respond to PG F2a analogues,[<xref rid="pone.0169683.ref029" ref-type="bibr">29</xref>–<xref rid="pone.0169683.ref031" ref-type="bibr">31</xref>] which are potent inducers of contractility in mesenteric lymphatic vessels.[<xref rid="pone.0169683.ref014" ref-type="bibr">14</xref>, <xref rid="pone.0169683.ref015" ref-type="bibr">15</xref>] In one study, the lymphatic drainage rate from the anterior chamber into the submandibular lymph node was found to be greater in latanoprost-treated mice than in controls.[<xref rid="pone.0169683.ref016" ref-type="bibr">16</xref>] Therefore, lymphatic drainage can be thought to be an active process driven by peristalsis[<xref rid="pone.0169683.ref032" ref-type="bibr">32</xref>, <xref rid="pone.0169683.ref033" ref-type="bibr">33</xref>]; it follows, moreover, that this process can be stimulated pharmacologically.[<xref rid="pone.0169683.ref015" ref-type="bibr">15</xref>, <xref rid="pone.0169683.ref033" ref-type="bibr">33</xref>] Thus prompted, we investigated whether the IOP alters in cases of defective cervical lymphatic drainage. Specifically, because the lymphatic vessels can be stimulated by PG F2a analogues, we studied whether the IOP in latanoprost-treated patients is changed in cases of lymphatic channel deterioration or blockage.</p><p>Our most significant finding was that, in patients with POAG, IOP increased more after surgery in eyes ipsilateral to the uRND. Additionally, those eyes were more likely than their fellow eyes to have increased IOP after surgery. This constitutes circumstantial evidence that the IOP-lowering effect of latanoprost was influenced by defective cervical lymphatic drainage, such as that caused by uRND, and that latanoprost had worked, at least in part, by enhancing aqueous humor outflow via the uveolymphatic pathway.</p><p>To investigate the pure effect of defective cervical lymphatic drainage on IOP, we recruited treatment-naïve bilateral GSs who had undergone uRND. Interestingly, immediately after surgery, the mean IOP had not changed significantly in the GSs. Furthermore, there were no significant differences in post-operative-IOP change between GS eyes ipsilateral to the uRND and their fellow eyes. These findings could be explained in two ways. First, aqueous humor might be drained through the uveolymphatic pathway much less than through the trabecular meshwork or uveoscleral outflow pathways. Second, treatment-naïve patients might not be affected as much by defective lymphatic drainage, because the uveolymphatic pathway is an active process that might need glaucoma medication for its stimulation.</p><p>In the present study, 7 (63.6%) of 11 POAG patients underwent uRND on their right eyes and the remaining 3, on their left eyes. As the microanatomy of the right cervical lymphatic system is different from that of the left cervical lymphatic system,[<xref rid="pone.0169683.ref034" ref-type="bibr">34</xref>] we re-evaluated whether the IOP-lowering effect of latanoprost was different between the right and left eyes of our study subjects. In the results, there was no significant difference (right eye: 0.3±0.5mmHg, left eye: -0.1±0.7mmHg; P = 0.242).</p><p>This study has three clinical significances. First, the evidence of a lymphatic outflow system in human eyes has expanded our understanding of how fluid and particulate materials—such as proteins—move out of the eye, as well as how IOP might be regulated. Second, physicians in future might have to evaluate lymphatic drainage function as a component of IOP management. For example, in patients suffering from decreased lymphatic drainage into the cervical area, such as occurs in lymphatic diseases (i.e., lymphadenopathy, lymphedema, or lymphangitis), the IOP-lowering effects of latanoprost would be altered by these co-morbidities. Finally, the present findings collectively point to lymphatics as a novel target for glaucoma treatment. Clinicians can expand pharmacological IOP-lowering treatment to take into account this third outflow pathway by stimulate them pharmacologically.</p><sec id="sec018"><title>Study limitations</title><p>The findings of this study must be interpreted in the light of several points.</p><list list-type="order"><list-item><p>The sample size was small, and the study was performed retrospectively.</p></list-item><list-item><p>Most of our glaucoma patients had a baseline IOP of 21 mmHg or lower, as well as early-to-moderate glaucoma; therefore, our results might not be relevant to other populations, such as patients with a baseline IOP higher than 21 mmHg or those with advanced glaucoma.</p></list-item><list-item><p>Changes to the optic nerve head [<xref rid="pone.0169683.ref035" ref-type="bibr">35</xref>] or visual functions [<xref rid="pone.0169683.ref036" ref-type="bibr">36</xref>] upon blockage of the cervical lymphatic channel have been reported. However, in this study, there were no significant interval changes in the optic disc parameters or other glaucoma parameters (i.e., VF mean deviation or OCT RNFL thickness) after the uRND. This might have been due to the fact that we investigated relatively short-term changes only (for all of the patients, IOP was measured 1, 3, and 6 months after surgery). Although there were significant differences in post-operative IOP changes between fellow eyes, the pattern of IOP change might also differ more than 6 months after surgery.</p></list-item><list-item><p>The thyroid disorder potentially increases the risk of glaucoma [<xref rid="pone.0169683.ref037" ref-type="bibr">37</xref>] and can have an effect on the diurnal variation of IOP.[<xref rid="pone.0169683.ref038" ref-type="bibr">38</xref>] Also, the thyroid function and IOP could have responded to corticosteroid that was applied after surgery.[<xref rid="pone.0169683.ref039" ref-type="bibr">39</xref>] In fact, 9 (81.8%) of 11 POAG patients and 6 (85.7%) of 7 GS patients had the thyroid tumor in this study. Therefore, the pattern of IOP change could have been affected not only by uRND but also by post-operative thyroid function and the use of corticosteroid.</p></list-item><list-item><p>Our patients had undergone uRND that involved the removal of the spinal accessory nerve, sternocleidomastoid muscle, and internal jugular vein and the resection of primary tumor. The study subjects had also undergone adjuvant therapies such as chemotherapy or radiotherapy. These additional procedures could have affected the IOP during the post-operative period.</p></list-item></list><p>In conclusion, in latanoprost-treated POAG patients, IOP increased significantly after surgery in the eyes ipsilateral to the uRND; however, it remained similar in their fellow eyes as well as in the treatment-naïve GS eyes. These findings signify that in human eyes, latanoprost might work, at least in part, by enhancing aqueous humor outflow via the hypothesized uveolymphatic pathway. Studying the lymphatics in normal and glaucomatous eyes, as well as under pharmacological manipulation, could lead to the discovery of helpful new approaches to IOP management.</p></sec></sec></body><back><ref-list><title>References</title><ref id="pone.0169683.ref001"><label>1</label><mixed-citation publication-type="journal"><name><surname>Heijl</surname><given-names>A</given-names></name>, <name><surname>Leske</surname><given-names>MC</given-names></name>, <name><surname>Bengtsson</surname><given-names>B</given-names></name>, <name><surname>Hyman</surname><given-names>L</given-names></name>, <name><surname>Bengtsson</surname><given-names>B</given-names></name>, <name><surname>Hussein</surname><given-names>M</given-names></name>, <etal>et al</etal><article-title>Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial</article-title>. <source>Arch Ophthalmol</source>. <year>2002</year>;<volume>120</volume>(<issue>10</issue>):<fpage>1268</fpage>–<lpage>79</lpage>. <pub-id pub-id-type="pmid">12365904</pub-id></mixed-citation></ref><ref id="pone.0169683.ref002"><label>2</label><mixed-citation publication-type="journal"><name><surname>Leske</surname><given-names>MC</given-names></name>, <name><surname>Heijl</surname><given-names>A</given-names></name>, <name><surname>Hussein</surname><given-names>M</given-names></name>, <name><surname>Bengtsson</surname><given-names>B</given-names></name>, <name><surname>Hyman</surname><given-names>L</given-names></name>, <name><surname>Komaroff</surname><given-names>E</given-names></name>, <etal>et al</etal><article-title>Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial</article-title>. <source>Arch Ophthalmol</source>. <year>2003</year>;<volume>121</volume>(<issue>1</issue>):<fpage>48</fpage>–<lpage>56</lpage>. <pub-id pub-id-type="pmid">12523884</pub-id></mixed-citation></ref><ref id="pone.0169683.ref003"><label>3</label><mixed-citation publication-type="journal"><name><surname>Goel</surname><given-names>M</given-names></name>, <name><surname>Picciani</surname><given-names>RG</given-names></name>, <name><surname>Lee</surname><given-names>RK</given-names></name>, <name><surname>Bhattacharya</surname><given-names>SK</given-names></name>. <article-title>Aqueous humor dynamics: a review</article-title>. <source>Open Ophthalmol J</source>. <year>2010</year>;<volume>4</volume>:<fpage>52</fpage>–<lpage>9</lpage>. PubMed Central PMCID: PMCPMC3032230. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.2174/1874364101004010052">10.2174/1874364101004010052</ext-link></comment><pub-id pub-id-type="pmid">21293732</pub-id></mixed-citation></ref><ref id="pone.0169683.ref004"><label>4</label><mixed-citation publication-type="journal"><name><surname>Yucel</surname><given-names>YH</given-names></name>. <article-title>Discovery of lymphatics in the human eye and implications</article-title>. <source>Can J Ophthalmol</source>. <year>2010</year>;<volume>45</volume>(<issue>2</issue>):<fpage>115</fpage>–<lpage>7</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.3129/i10-005">10.3129/i10-005</ext-link></comment><pub-id pub-id-type="pmid">20379292</pub-id></mixed-citation></ref><ref id="pone.0169683.ref005"><label>5</label><mixed-citation publication-type="journal"><name><surname>Yucel</surname><given-names>YH</given-names></name>, <name><surname>Johnston</surname><given-names>MG</given-names></name>, <name><surname>Ly</surname><given-names>T</given-names></name>, <name><surname>Patel</surname><given-names>M</given-names></name>, <name><surname>Drake</surname><given-names>B</given-names></name>, <name><surname>Gumus</surname><given-names>E</given-names></name>, <etal>et al</etal><article-title>Identification of lymphatics in the ciliary body of the human eye: a novel "uveolymphatic" outflow pathway</article-title>. <source>Exp Eye Res</source>. <year>2009</year>;<volume>89</volume>(<issue>5</issue>):<fpage>810</fpage>–<lpage>9</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.exer.2009.08.010">10.1016/j.exer.2009.08.010</ext-link></comment><pub-id pub-id-type="pmid">19729007</pub-id></mixed-citation></ref><ref id="pone.0169683.ref006"><label>6</label><mixed-citation publication-type="journal"><name><surname>Tam</surname><given-names>AL</given-names></name>, <name><surname>Gupta</surname><given-names>N</given-names></name>, <name><surname>Zhang</surname><given-names>Z</given-names></name>, <name><surname>Yucel</surname><given-names>YH</given-names></name>. <article-title>Quantum dots trace lymphatic drainage from the mouse eye</article-title>. <source>Nanotechnology</source>. <year>2011</year>;<volume>22</volume>(<issue>42</issue>):<fpage>425101</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1088/0957-4484/22/42/425101">10.1088/0957-4484/22/42/425101</ext-link></comment><pub-id pub-id-type="pmid">21934199</pub-id></mixed-citation></ref><ref id="pone.0169683.ref007"><label>7</label><mixed-citation publication-type="journal"><name><surname>Hollo</surname><given-names>G</given-names></name>. <article-title>Bilateral intraocular pressure elevation and decrease of facility of aqueous humour outflow as a consequence of regional lymphoedema of head and neck</article-title>. <source>Acta Ophthalmol (Copenh)</source>. <year>1993</year>;<volume>71</volume>(<issue>3</issue>):<fpage>415</fpage>–<lpage>8</lpage>.<pub-id pub-id-type="pmid">8362647</pub-id></mixed-citation></ref><ref id="pone.0169683.ref008"><label>8</label><mixed-citation publication-type="journal"><name><surname>Poyer</surname><given-names>JF</given-names></name>, <name><surname>Millar</surname><given-names>C</given-names></name>, <name><surname>Kaufman</surname><given-names>PL</given-names></name>. <article-title>Prostaglandin F2 alpha effects on isolated rhesus monkey ciliary muscle</article-title>. <source>Invest Ophthalmol Vis Sci</source>. <year>1995</year>;<volume>36</volume>(<issue>12</issue>):<fpage>2461</fpage>–<lpage>5</lpage>. <pub-id pub-id-type="pmid">7591635</pub-id></mixed-citation></ref><ref id="pone.0169683.ref009"><label>9</label><mixed-citation publication-type="journal"><name><surname>Thieme</surname><given-names>H</given-names></name>, <name><surname>Schimmat</surname><given-names>C</given-names></name>, <name><surname>Munzer</surname><given-names>G</given-names></name>, <name><surname>Boxberger</surname><given-names>M</given-names></name>, <name><surname>Fromm</surname><given-names>M</given-names></name>, <name><surname>Pfeiffer</surname><given-names>N</given-names></name>, <etal>et al</etal><article-title>Endothelin antagonism: effects of FP receptor agonists prostaglandin F2alpha and fluprostenol on trabecular meshwork contractility</article-title>. <source>Invest Ophthalmol Vis Sci</source>. <year>2006</year>;<volume>47</volume>(<issue>3</issue>):<fpage>938</fpage>–<lpage>45</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1167/iovs.05-0527">10.1167/iovs.05-0527</ext-link></comment><pub-id pub-id-type="pmid">16505027</pub-id></mixed-citation></ref><ref id="pone.0169683.ref010"><label>10</label><mixed-citation publication-type="journal"><name><surname>Lutjen-Drecoll</surname><given-names>E</given-names></name>, <name><surname>Tamm</surname><given-names>E</given-names></name>. <article-title>Morphological study of the anterior segment of cynomolgus monkey eyes following treatment with prostaglandin F2 alpha</article-title>. <source>Exp Eye Res</source>. <year>1988</year>;<volume>47</volume>(<issue>5</issue>):<fpage>761</fpage>–<lpage>9</lpage>. <pub-id pub-id-type="pmid">3197775</pub-id></mixed-citation></ref><ref id="pone.0169683.ref011"><label>11</label><mixed-citation publication-type="journal"><name><surname>Richter</surname><given-names>M</given-names></name>, <name><surname>Krauss</surname><given-names>AH</given-names></name>, <name><surname>Woodward</surname><given-names>DF</given-names></name>, <name><surname>Lutjen-Drecoll</surname><given-names>E</given-names></name>. <article-title>Morphological changes in the anterior eye segment after long-term treatment with different receptor selective prostaglandin agonists and a prostamide</article-title>. <source>Invest Ophthalmol Vis Sci</source>. <year>2003</year>;<volume>44</volume>(<issue>10</issue>):<fpage>4419</fpage>–<lpage>26</lpage>. <pub-id pub-id-type="pmid">14507888</pub-id></mixed-citation></ref><ref id="pone.0169683.ref012"><label>12</label><mixed-citation publication-type="journal"><name><surname>Crawford</surname><given-names>K</given-names></name>, <name><surname>Kaufman</surname><given-names>PL</given-names></name>. <article-title>Pilocarpine antagonizes prostaglandin F2 alpha-induced ocular hypotension in monkeys. Evidence for enhancement of Uveoscleral outflow by prostaglandin F2 alpha</article-title>. <source>Arch Ophthalmol</source>. <year>1987</year>;<volume>105</volume>(<issue>8</issue>):<fpage>1112</fpage>–<lpage>6</lpage>. <pub-id pub-id-type="pmid">3477218</pub-id></mixed-citation></ref><ref id="pone.0169683.ref013"><label>13</label><mixed-citation publication-type="journal"><name><surname>Nilsson</surname><given-names>SF</given-names></name>, <name><surname>Sperber</surname><given-names>GO</given-names></name>, <name><surname>Bill</surname><given-names>A</given-names></name>. <article-title>The effect of prostaglandin F2 alpha-1-isopropylester (PGF2 alpha-IE) on uveoscleral outflow</article-title>. <source>Prog Clin Biol Res</source>. <year>1989</year>;<volume>312</volume>:<fpage>429</fpage>–<lpage>36</lpage>. <pub-id pub-id-type="pmid">2678148</pub-id></mixed-citation></ref><ref id="pone.0169683.ref014"><label>14</label><mixed-citation publication-type="journal"><name><surname>Johnston</surname><given-names>MG</given-names></name>, <name><surname>Gordon</surname><given-names>JL</given-names></name>. <article-title>Regulation of lymphatic contractility by arachidonate metabolites</article-title>. <source>Nature</source>. <year>1981</year>;<volume>293</volume>(<issue>5830</issue>):<fpage>294</fpage>–<lpage>7</lpage>. <pub-id pub-id-type="pmid">7196995</pub-id></mixed-citation></ref><ref id="pone.0169683.ref015"><label>15</label><mixed-citation publication-type="journal"><name><surname>Ohhashi</surname><given-names>T</given-names></name>, <name><surname>Mizuno</surname><given-names>R</given-names></name>, <name><surname>Ikomi</surname><given-names>F</given-names></name>, <name><surname>Kawai</surname><given-names>Y</given-names></name>. <article-title>Current topics of physiology and pharmacology in the lymphatic system</article-title>. <source>Pharmacol Ther</source>. <year>2005</year>;<volume>105</volume>(<issue>2</issue>):<fpage>165</fpage>–<lpage>88</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.pharmthera.2004.10.009">10.1016/j.pharmthera.2004.10.009</ext-link></comment><pub-id pub-id-type="pmid">15670625</pub-id></mixed-citation></ref><ref id="pone.0169683.ref016"><label>16</label><mixed-citation publication-type="journal"><name><surname>Tam</surname><given-names>AL</given-names></name>, <name><surname>Gupta</surname><given-names>N</given-names></name>, <name><surname>Zhang</surname><given-names>Z</given-names></name>, <name><surname>Yucel</surname><given-names>YH</given-names></name>. <article-title>Latanoprost Stimulates Ocular Lymphatic Drainage: An In Vivo Nanotracer Study</article-title>. <source>Transl Vis Sci Technol</source>. <year>2013</year>;<volume>2</volume>(<issue>5</issue>):<fpage>3</fpage> PubMed Central PMCID: PMCPMC3763898. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1167/tvst.2.5.3">10.1167/tvst.2.5.3</ext-link></comment><pub-id pub-id-type="pmid">24049723</pub-id></mixed-citation></ref><ref id="pone.0169683.ref017"><label>17</label><mixed-citation publication-type="journal"><name><surname>Camras</surname><given-names>CB</given-names></name>. <article-title>Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month masked, multicenter trial in the United States. The United States Latanoprost Study Group</article-title>. <source>Ophthalmology</source>. <year>1996</year>;<volume>103</volume>(<issue>1</issue>):<fpage>138</fpage>–<lpage>47</lpage>. <pub-id pub-id-type="pmid">8628544</pub-id></mixed-citation></ref><ref id="pone.0169683.ref018"><label>18</label><mixed-citation publication-type="journal"><name><surname>Alm</surname><given-names>A</given-names></name>, <name><surname>Stjernschantz</surname><given-names>J</given-names></name>. <article-title>Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Scandinavian Latanoprost Study Group</article-title>. <source>Ophthalmology</source>. <year>1995</year>;<volume>102</volume>(<issue>12</issue>):<fpage>1743</fpage>–<lpage>52</lpage>. <pub-id pub-id-type="pmid">9098273</pub-id></mixed-citation></ref><ref id="pone.0169683.ref019"><label>19</label><mixed-citation publication-type="journal"><name><surname>Scherer</surname><given-names>WJ</given-names></name>. <article-title>A retrospective review of non-responders to latanoprost</article-title>. <source>J Ocul Pharmacol Ther</source>. <year>2002</year>;<volume>18</volume>(<issue>3</issue>):<fpage>287</fpage>–<lpage>91</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1089/108076802760116205">10.1089/108076802760116205</ext-link></comment><pub-id pub-id-type="pmid">12099549</pub-id></mixed-citation></ref><ref id="pone.0169683.ref020"><label>20</label><mixed-citation publication-type="journal"><name><surname>Swartz</surname><given-names>MA</given-names></name>, <name><surname>Skobe</surname><given-names>M</given-names></name>. <article-title>Lymphatic function, lymphangiogenesis, and cancer metastasis</article-title>. <source>Microsc Res Tech</source>. <year>2001</year>;<volume>55</volume>(<issue>2</issue>):<fpage>92</fpage>–<lpage>9</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/jemt.1160">10.1002/jemt.1160</ext-link></comment><pub-id pub-id-type="pmid">11596154</pub-id></mixed-citation></ref><ref id="pone.0169683.ref021"><label>21</label><mixed-citation publication-type="journal"><name><surname>Swartz</surname><given-names>MA</given-names></name>, <name><surname>Hubbell</surname><given-names>JA</given-names></name>, <name><surname>Reddy</surname><given-names>ST</given-names></name>. <article-title>Lymphatic drainage function and its immunological implications: from dendritic cell homing to vaccine design</article-title>. <source>Semin Immunol</source>. <year>2008</year>;<volume>20</volume>(<issue>2</issue>):<fpage>147</fpage>–<lpage>56</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.smim.2007.11.007">10.1016/j.smim.2007.11.007</ext-link></comment><pub-id pub-id-type="pmid">18201895</pub-id></mixed-citation></ref><ref id="pone.0169683.ref022"><label>22</label><mixed-citation publication-type="journal"><name><surname>Swartz</surname><given-names>MA</given-names></name>. <article-title>The physiology of the lymphatic system</article-title>. <source>Adv Drug Deliv Rev</source>. <year>2001</year>;<volume>50</volume>(<issue>1–2</issue>):<fpage>3</fpage>–<lpage>20</lpage>. <pub-id pub-id-type="pmid">11489331</pub-id></mixed-citation></ref><ref id="pone.0169683.ref023"><label>23</label><mixed-citation publication-type="journal"><name><surname>Wiig</surname><given-names>H</given-names></name>, <name><surname>Swartz</surname><given-names>MA</given-names></name>. <article-title>Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer</article-title>. <source>Physiol Rev</source>. <year>2012</year>;<volume>92</volume>(<issue>3</issue>):<fpage>1005</fpage>–<lpage>60</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1152/physrev.00037.2011">10.1152/physrev.00037.2011</ext-link></comment><pub-id pub-id-type="pmid">22811424</pub-id></mixed-citation></ref><ref id="pone.0169683.ref024"><label>24</label><mixed-citation publication-type="journal"><name><surname>Bradbury</surname><given-names>MW</given-names></name>, <name><surname>Cole</surname><given-names>DF</given-names></name>. <article-title>The role of the lymphatic system in drainage of cerebrospinal fluid and aqueous humour</article-title>. <source>J Physiol</source>. <year>1980</year>;<volume>299</volume>:<fpage>353</fpage>–<lpage>65</lpage>. PubMed Central PMCID: PMCPMC1279229. <pub-id pub-id-type="pmid">6155466</pub-id></mixed-citation></ref><ref id="pone.0169683.ref025"><label>25</label><mixed-citation publication-type="journal"><name><surname>Krohn</surname><given-names>J</given-names></name>, <name><surname>Rodahl</surname><given-names>E</given-names></name>. <article-title>Expression of 5'-nucleotidase and alkaline phosphatase in human aqueous drainage channels</article-title>. <source>Acta Ophthalmol Scand</source>. <year>2002</year>;<volume>80</volume>(<issue>6</issue>):<fpage>642</fpage>–<lpage>51</lpage>. <pub-id pub-id-type="pmid">12485287</pub-id></mixed-citation></ref><ref id="pone.0169683.ref026"><label>26</label><mixed-citation publication-type="journal"><name><surname>Foldi</surname><given-names>M</given-names></name>, <name><surname>Csanda</surname><given-names>E</given-names></name>, <name><surname>Simon</surname><given-names>M</given-names></name>, <name><surname>Obal</surname><given-names>F</given-names></name>, <name><surname>Schneider</surname><given-names>I</given-names></name>, <name><surname>Dobranovics</surname><given-names>I</given-names></name>, <etal>et al</etal><article-title>Lymphogenic haemangiopathy. "Prelymphatic" pathways in the wall of cerebral and cervical blood vessels</article-title>. <source>Angiologica</source>. <year>1968</year>;<volume>5</volume>(<issue>4</issue>):<fpage>250</fpage>–<lpage>62</lpage>. <pub-id pub-id-type="pmid">5699286</pub-id></mixed-citation></ref><ref id="pone.0169683.ref027"><label>27</label><mixed-citation publication-type="journal"><name><surname>Casley-Smith</surname><given-names>JR</given-names></name>, <name><surname>Clodius</surname><given-names>L</given-names></name>, <name><surname>Foldi-Borcsok</surname><given-names>E</given-names></name>, <name><surname>Gruntzig</surname><given-names>J</given-names></name>, <name><surname>Foldi</surname><given-names>M</given-names></name>. <article-title>The effects of chronic cervical lymphostasis on regions drained by lymphatics and by prelymphatics</article-title>. <source>J Pathol</source>. <year>1978</year>;<volume>124</volume>(<issue>1</issue>):<fpage>13</fpage>–<lpage>7</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/path.1711240104">10.1002/path.1711240104</ext-link></comment><pub-id pub-id-type="pmid">722368</pub-id></mixed-citation></ref><ref id="pone.0169683.ref028"><label>28</label><mixed-citation publication-type="journal"><name><surname>Yucel</surname><given-names>Y</given-names></name>, <name><surname>Gupta</surname><given-names>N</given-names></name>. <article-title>Lymphatic drainage from the eye: A new target for therapy</article-title>. <source>Prog Brain Res</source>. <year>2015</year>;<volume>220</volume>:<fpage>185</fpage>–<lpage>98</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/bs.pbr.2015.07.028">10.1016/bs.pbr.2015.07.028</ext-link></comment><pub-id pub-id-type="pmid">26497791</pub-id></mixed-citation></ref><ref id="pone.0169683.ref029"><label>29</label><mixed-citation publication-type="journal"><name><surname>Unthank</surname><given-names>JL</given-names></name>, <name><surname>Hogan</surname><given-names>RD</given-names></name>. <article-title>The effect of vasoactive agents on the contractions of the initial lymphatics of the bat's wing</article-title>. <source>Blood Vessels</source>. <year>1987</year>;<volume>24</volume>(<issue>1–2</issue>):<fpage>31</fpage>–<lpage>44</lpage>. <pub-id pub-id-type="pmid">2882795</pub-id></mixed-citation></ref><ref id="pone.0169683.ref030"><label>30</label><mixed-citation publication-type="journal"><name><surname>Amann-Vesti</surname><given-names>BR</given-names></name>, <name><surname>Gitzelmann</surname><given-names>G</given-names></name>, <name><surname>Koppensteiner</surname><given-names>R</given-names></name>, <name><surname>Franzeck</surname><given-names>UK</given-names></name>. <article-title>Isoprostane 8-epi-prostaglandin F2 alpha decreases lymph capillary pressure in patients with primary lymphedema</article-title>. <source>J Vasc Res</source>. <year>2003</year>;<volume>40</volume>(<issue>1</issue>):<fpage>77</fpage>–<lpage>82</lpage>. <pub-id pub-id-type="pmid">12644728</pub-id></mixed-citation></ref><ref id="pone.0169683.ref031"><label>31</label><mixed-citation publication-type="journal"><name><surname>Franzeck</surname><given-names>UK</given-names></name>, <name><surname>Spiegel</surname><given-names>I</given-names></name>, <name><surname>Fischer</surname><given-names>M</given-names></name>, <name><surname>Bortzler</surname><given-names>C</given-names></name>, <name><surname>Stahel</surname><given-names>HU</given-names></name>, <name><surname>Bollinger</surname><given-names>A</given-names></name>. <article-title>Combined physical therapy for lymphedema evaluated by fluorescence microlymphography and lymph capillary pressure measurements</article-title>. <source>J Vasc Res</source>. <year>1997</year>;<volume>34</volume>(<issue>4</issue>):<fpage>306</fpage>–<lpage>11</lpage>. <pub-id pub-id-type="pmid">9256091</pub-id></mixed-citation></ref><ref id="pone.0169683.ref032"><label>32</label><mixed-citation publication-type="journal"><name><surname>Shayan</surname><given-names>R</given-names></name>, <name><surname>Achen</surname><given-names>MG</given-names></name>, <name><surname>Stacker</surname><given-names>SA</given-names></name>. <article-title>Lymphatic vessels in cancer metastasis: bridging the gaps</article-title>. <source>Carcinogenesis</source>. <year>2006</year>;<volume>27</volume>(<issue>9</issue>):<fpage>1729</fpage>–<lpage>38</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1093/carcin/bgl031">10.1093/carcin/bgl031</ext-link></comment><pub-id pub-id-type="pmid">16597644</pub-id></mixed-citation></ref><ref id="pone.0169683.ref033"><label>33</label><mixed-citation publication-type="journal"><name><surname>Ohhashi</surname><given-names>T</given-names></name>, <name><surname>Olschowka</surname><given-names>JA</given-names></name>, <name><surname>Jacobowitz</surname><given-names>DM</given-names></name>. <article-title>Vasoactive intestinal peptide inhibitory innervation in bovine mesenteric lymphatics. A histochemical and pharmacological study</article-title>. <source>Circ Res</source>. <year>1983</year>;<volume>53</volume>(<issue>4</issue>):<fpage>535</fpage>–<lpage>8</lpage>. <pub-id pub-id-type="pmid">6138169</pub-id></mixed-citation></ref><ref id="pone.0169683.ref034"><label>34</label><mixed-citation publication-type="book"><name><surname>Harisinghani</surname><given-names>MG</given-names></name>, <source>SpringerLink (Online service). Atlas of Lymph Node Anatomy</source>. <publisher-loc>New York, NY</publisher-loc>: <publisher-name>Springer New York</publisher-name>: Imprint: Springer,; <year>2013</year>.</mixed-citation></ref><ref id="pone.0169683.ref035"><label>35</label><mixed-citation publication-type="journal"><name><surname>Foldi</surname><given-names>M</given-names></name>, <name><surname>Csanda</surname><given-names>E</given-names></name>, <name><surname>Zoltan</surname><given-names>OT</given-names></name>, <name><surname>Dobranovics</surname><given-names>I</given-names></name>. <article-title>Oedema of the optic nerve and the retina as a consequence of experimental cervical lymphatic blockage</article-title>. <source>Angiologica</source>. <year>1967</year>;<volume>4</volume>(<issue>6</issue>):<fpage>341</fpage>–<lpage>7</lpage>. <pub-id pub-id-type="pmid">6075771</pub-id></mixed-citation></ref><ref id="pone.0169683.ref036"><label>36</label><mixed-citation publication-type="journal"><name><surname>Hollo</surname><given-names>G</given-names></name>, <name><surname>Pap</surname><given-names>G</given-names></name>, <name><surname>Bagi</surname><given-names>ZT</given-names></name>, <name><surname>Kovacsovics</surname><given-names>B</given-names></name>. <article-title>Does the lymph drainage from the head influence aqueous humour outflow and visual functions?</article-title><source>Acta Ophthalmol (Copenh)</source>. <year>1991</year>;<volume>69</volume>(<issue>4</issue>):<fpage>527</fpage>–<lpage>9</lpage>.<pub-id pub-id-type="pmid">1750323</pub-id></mixed-citation></ref><ref id="pone.0169683.ref037"><label>37</label><mixed-citation publication-type="journal"><name><surname>Cross</surname><given-names>JM</given-names></name>, <name><surname>Girkin</surname><given-names>CA</given-names></name>, <name><surname>Owsley</surname><given-names>C</given-names></name>, <name><surname>McGwin</surname><given-names>G</given-names><suffix>Jr.</suffix></name><article-title>The association between thyroid problems and glaucoma</article-title>. <source>Br J Ophthalmol</source>. <year>2008</year>;<volume>92</volume>(<issue>11</issue>):<fpage>1503</fpage>–<lpage>5</lpage>. PubMed Central PMCID: PMCPMC2708670. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1136/bjo.2008.147165">10.1136/bjo.2008.147165</ext-link></comment><pub-id pub-id-type="pmid">18927223</pub-id></mixed-citation></ref><ref id="pone.0169683.ref038"><label>38</label><mixed-citation publication-type="journal"><name><surname>Parekh</surname><given-names>AS</given-names></name>, <name><surname>Mansouri</surname><given-names>K</given-names></name>, <name><surname>Weinreb</surname><given-names>RN</given-names></name>, <name><surname>Tafreshi</surname><given-names>A</given-names></name>, <name><surname>Korn</surname><given-names>BS</given-names></name>, <name><surname>Kikkawa</surname><given-names>DO</given-names></name>. <article-title>Twenty-four-hour intraocular pressure patterns in patients with thyroid eye disease</article-title>. <source>Clin Exp Ophthalmol</source>. <year>2015</year>;<volume>43</volume>(<issue>2</issue>):<fpage>108</fpage>–<lpage>14</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1111/ceo.12400">10.1111/ceo.12400</ext-link></comment><pub-id pub-id-type="pmid">25132194</pub-id></mixed-citation></ref><ref id="pone.0169683.ref039"><label>39</label><mixed-citation publication-type="journal"><name><surname>Krupin</surname><given-names>T</given-names></name>, <name><surname>Jacobs</surname><given-names>LS</given-names></name>, <name><surname>Podos</surname><given-names>SM</given-names></name>, <name><surname>Becker</surname><given-names>B</given-names></name>. <article-title>Thyroid function and the intraocular pressure response to topical corticosteroids</article-title>. <source>Am J Ophthalmol</source>. <year>1977</year>;<volume>83</volume>(<issue>5</issue>):<fpage>643</fpage>–<lpage>6</lpage>. <pub-id pub-id-type="pmid">868963</pub-id></mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/LymphedemaV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 004413 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 004413 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= LymphedemaV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:5231387
|texte= Intraocular Pressure-Lowering Effect of Latanoprost Is Hampered by Defective Cervical Lymphatic Drainage
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:28081184" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a LymphedemaV1
| This area was generated with Dilib version V0.6.31. |  |