Letters
Figure 2. Influence of Azithromycin on Proliferation of Immortalized Human Meibomian Gland Epithelial Cells Baseline
Control
B
Azithromycin
250 000
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and is associated with significant pain, role limitations, low vitality, and poor general health.5 Given our finding that azithromycin stimulates the function and differentiation of IHMGECs in vitro, it is possible that this antibiotic may prove beneficial as a treatment for MGD and its associated DED in vivo.
3. Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2011;52(4):2050-2064. 4. Liu S, Kam WR, Ding J, Hatton MP, Sullivan DA. Effect of growth factors on the proliferation and gene expression of human meibomian gland epithelial cells. Invest Ophthalmol Vis Sci. 2013;54(4):2541-2550. 5. Sullivan DA, Hammitt KM, Schaumberg DA, et al. Report of the TFOS/ARVO Symposium on global treatments for dry eye disease: an unmet need. Ocul Surf. 2012;10(2):108-116.
Yang Liu, MD Wendy R. Kam, MS Juan Ding, PhD David A. Sullivan, PhD
OBSERVATION
Author Affiliations: Schepens Eye Research Institute, Massachusetts Eye and Ear, and Harvard Medical School, Boston. Corresponding Author: Yang Liu, MD, Schepens Eye Research Institute, 20 Staniford St, Boston, MA 02114 ([email protected]). Published Online: December 19, 2013. doi:10.1001/jamaophthalmol.2013.6030. Author Contributions: Dr Liu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Liu, Sullivan. Acquisition of data: Liu. Analysis and interpretation of data: All authors. Drafting of the manuscript: Liu, Sullivan. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Liu, Sullivan. Obtained funding: Liu, Sullivan. Administrative, technical, or material support: Kam, Ding. Study supervision: Liu, Sullivan. Conflict of Interest Disclosures: Schepens Eye Research Institute is planning to submit a provisional patent based, in part, on the data presented in the article. No other disclosures were reported. Funding/Support: This work was supported by grant EY05612 from the National Institutes of Health, the Margaret S. Sinon Scholar in Ocular Surface Research Fund, and the Guoxing Yao Research Fund. Role of the Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci. 2011;52(4):1938-1978. 2. Lemp MA, Nichols KK. Blepharitis in the United States 2009: a survey-based perspective on prevalence and treatment. Ocul Surf. 2009;7(2)(suppl):S1-S14. 228
1
Cells were cultured in the absence (A) or presence (B) of serum for up to 7 days. Cell numbers at day 0 represent the baseline, and data are reported as mean ± standard error. Similar results were found in 2 additional studies. a Significantly less than control (P < .005).
Optic Neuropathy Due to Biotinidase Deficiency in a 19-Year-Old Man Biotinidase deficiency is an autosomal recessive condition in which the normal recycling of biotin is deficient. If untreated, infants with biotinidase deficiency will develop neurologic derangements including optic atrophy.1 We describe a case of optic neuropathy due to biotinidase deficiency in a 19-year-old man. Report of a Case | The patient was identified as having biotinidase deficiency on newborn screening and was provided with appropriate supplementation. However, at approximately age 10 years, supplements were discontinued. At age 19 years, he developed simultaneous bilateral vision loss over several weeks. There were no other neurologic symptoms. Family history was unremarkable. Social history was notable for occasional binge drinking since starting college 2 months prior to onset of symptoms. The patient had visual acuity of 20/70 OD and 20/25 OS, he identified 11 of 14 Ishihara color plates with each eye, the flicker fusion frequency was undetectable in the right eye and 9.5 Hz OS (reference range, >30 Hz), and visual fields showed bilateral cecocentral scotomas with respect of the vertical meridian (Figure 1). The pupils were briskly reactive to light with no relative afferent pupillary defect. There was mild optic disc pallor bilaterally and optical coherence tomography showed atrophy of the papillomacular bundle (Figure 2). Neurologic examination findings were otherwise normal. Findings on magnetic resonance imaging of the brain and orbits with contrast were normal. Biotin levels were un-
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Copyright 2014 American Medical Association. All rights reserved.
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Letters
Figure 1. Goldmann Perimetry A
120
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detectable and biotinidase activity was markedly reduced (0.2 U/L; reference range, 3.5-13.8 U/L). Genetic testing demonstrated a homozygous double mutation (D444H:F403V) predictive of profound biotinidase deficiency. He began treatment with biotin, 20 mg/d. The patient improved within 1 month. After 4 months, he had return of visual acuity to 20/20 OU and the flicker fusion frequency improved to 26.5 Hz OD and 28.8 Hz OS. Minor residual visual field defects remained (Figure 1) and color vision remained similar to his initial presentation. He continued to be stable after an additional year of follow-up. Discussion | Biotin deficiency is known to cause optic neuropathy, typically in infancy but there have been reports of delayedonset optic neuropathy in children and adolescents.2,3 This case is unique because the patient was identified and treated as an infant and thus avoided the typical natural history of biotinidase deficiency. However, supplementation was stopped later in childhood. It is remarkable that he was asymptomatic for nearly a decade after stopping supplementation. It is possible that initiation of alcohol consumption triggered the onset of his symptoms. This case has many features common among other metabolic optic neuropathies such as genetic, toxic, or nutritional optic neuropathies. Similarities include atrophy of the papillomacular bundle and the pattern of vision loss.4 Reported pat-
270
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Goldmann perimetry demonstrates cecocentral scotoma in the left and right eyes (A) with incomplete resolution after treatment (B). OK indicates okay.
terns of vision loss include bilateral central or cecocentral defects or bitemporal loss.5 The similarity in presentation implies a similar underlying pathophysiology. Metabolic optic neuropathies are thought to be due to mitochondrial dysfunction.4 Biotin is important in the normal function of mitochondria, and biotin deficiency has been shown to cause oxidant damage and depletion of mitochondrial complex IV.6 Therefore, it is possible that biotin deficiency also leads to optic neuropathy by way of mitochondrial dysfunction. The most common nutritional deficiencies causing optic neuropathy involve vitamin B12, vitamin B1, and folic acid. In the right clinical setting, biotin deficiency should also be included as a possible cause of optic neuropathy. In this case, there was some evidence of permanent damage to the optic nerve, but prompt initiation of biotin supplementation resulted in good, although imperfect, recovery of visual function. This recovery was most likely due to saving nerve fibers that were injured but not yet lost. Thus, biotin-deficient optic neuropathy is an important consideration because of the potential to reverse vision loss. Scott R. Haines, MD Reid A. Longmuir, MD Author Affiliations: Department of Neurology, Virginia Commonwealth University, Richmond (Haines); Department of Ophthalmology, Virginia
jamaophthalmology.com
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Copyright 2014 American Medical Association. All rights reserved.
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229
Letters
Figure 2. Fundus Photographs and Optical Coherence Tomography A
B
300
Thickness, μm
Thickness, μm
300 240 180 120 60 0 –180 –135 N
–90 I
–45
0 T
45
90 S
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240
Above normal limits (P < .01)
180
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60 0 –180 –135 N
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Position, Degrees
Thickness, μm
N 71 I 81
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Below normal limits (P < .01)
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120 60 0 –180 –135 N
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Position, Degrees
Fundus photographs demonstrate temporal disc pallor (A) and optical coherence tomography shows corresponding atrophy of the temporal peripapillary retinal nerve fiber layer (B). I indicates inferior; N, nasal; S, superior; and T, temporal.
Commonwealth University, Richmond (Haines); Department of Ophthalmology, University of Iowa, Iowa City (Haines, Longmuir). Corresponding Author: Scott R. Haines, MD, Departments of Neurology and Ophthalmology, Virginia Commonwealth University, 417 N 11th St, Fifth Floor, PO Box 980599, Richmond, VA 23298 ([email protected]). Author Contributions: Dr Haines had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Haines. Acquisition of data: Haines, Longmuir. Analysis and interpretation of data: Haines, Longmuir. Drafting of the manuscript: Haines. Critical revision of the manuscript for important intellectual content: Longmuir. Administrative, technical, and material support: Longmuir. Study supervision: Longmuir. Conflict of Interest Disclosures: None reported. 1. Wolf B. The neurology of biotinidase deficiency. Mol Genet Metab. 2011;104(1-2):27-34. 2. Wolf B, Pomponio RJ, Norrgard KJ, et al. Delayed-onset profound biotinidase deficiency. J Pediatr. 1998;132(2):362-365. 3. Hayati AA, Wan-Hitam WH, Cheong MT, Yunus R, Shatriah I. Optic neuritis in a child with biotinidase deficiency: case report and literature review. Clin Ophthalmol. 2012;6:389-395. 4. Sadun AA. Metabolic optic neuropathies. Semin Ophthalmol. 2002;17(1):29-32. 5. Kho RC, Al-Obailan M, Arnold AC. Bitemporal visual field defects in ethambutol-induced optic neuropathy. J Neuroophthalmol. 2011;31(2):121-126. 230
6. Atamna H, Newberry J, Erlitzki R, Schultz CS, Ames BN. Biotin deficiency inhibits heme synthesis and impairs mitochondria in human lung fibroblasts. J Nutr. 2007;137(1):25-30.
COMMENT & RESPONSE
Regarding Macular Xanthophylls and ω-3 Long-Chain Polyunsaturated Fatty Acids in Age-Related Macular Degeneration To the Editor We read with interest the recently published article by Arnold et al titled “Macular Xanthophylls and ω-3 LongChain Polyunsaturated Fatty Acids in Age-Related Macular Degeneration: A Randomized Trial.”1 The authors report the results of a 12-month intervention with macular xanthophylls and ω-3 long-chain polyunsaturated fatty acids in patients with nonexudative age-related macular degeneration (AMD), where the main outcome measures included plasma xanthophyll concentrations and optical density of macular pigment (MP). Unfortunately, however, the methods used to assess these outcome measures were flawed, thereby rendering the conclusion of the article unsafe. With respect to analysis of plasma concentrations of the macular carotenoids, astaxanthin is not an appropriate
JAMA Ophthalmology February 2014 Volume 132, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Georgia User on 06/01/2015
jamaophthalmology.com
Figure 2. Influence of Azithromycin on Proliferation of Immortalized Human Meibomian Gland Epithelial Cells Baseline
Control
B
Azithromycin
250 000
250 000
200 000
200 000
150 000
150 000
100 000
a
Cells/Well
Cells/Well
A
a
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100 000 50 000 a
0
0 0
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5
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0
Day
3
5
7
Day
and is associated with significant pain, role limitations, low vitality, and poor general health.5 Given our finding that azithromycin stimulates the function and differentiation of IHMGECs in vitro, it is possible that this antibiotic may prove beneficial as a treatment for MGD and its associated DED in vivo.
3. Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2011;52(4):2050-2064. 4. Liu S, Kam WR, Ding J, Hatton MP, Sullivan DA. Effect of growth factors on the proliferation and gene expression of human meibomian gland epithelial cells. Invest Ophthalmol Vis Sci. 2013;54(4):2541-2550. 5. Sullivan DA, Hammitt KM, Schaumberg DA, et al. Report of the TFOS/ARVO Symposium on global treatments for dry eye disease: an unmet need. Ocul Surf. 2012;10(2):108-116.
Yang Liu, MD Wendy R. Kam, MS Juan Ding, PhD David A. Sullivan, PhD
OBSERVATION
Author Affiliations: Schepens Eye Research Institute, Massachusetts Eye and Ear, and Harvard Medical School, Boston. Corresponding Author: Yang Liu, MD, Schepens Eye Research Institute, 20 Staniford St, Boston, MA 02114 ([email protected]). Published Online: December 19, 2013. doi:10.1001/jamaophthalmol.2013.6030. Author Contributions: Dr Liu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Liu, Sullivan. Acquisition of data: Liu. Analysis and interpretation of data: All authors. Drafting of the manuscript: Liu, Sullivan. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Liu, Sullivan. Obtained funding: Liu, Sullivan. Administrative, technical, or material support: Kam, Ding. Study supervision: Liu, Sullivan. Conflict of Interest Disclosures: Schepens Eye Research Institute is planning to submit a provisional patent based, in part, on the data presented in the article. No other disclosures were reported. Funding/Support: This work was supported by grant EY05612 from the National Institutes of Health, the Margaret S. Sinon Scholar in Ocular Surface Research Fund, and the Guoxing Yao Research Fund. Role of the Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci. 2011;52(4):1938-1978. 2. Lemp MA, Nichols KK. Blepharitis in the United States 2009: a survey-based perspective on prevalence and treatment. Ocul Surf. 2009;7(2)(suppl):S1-S14. 228
1
Cells were cultured in the absence (A) or presence (B) of serum for up to 7 days. Cell numbers at day 0 represent the baseline, and data are reported as mean ± standard error. Similar results were found in 2 additional studies. a Significantly less than control (P < .005).
Optic Neuropathy Due to Biotinidase Deficiency in a 19-Year-Old Man Biotinidase deficiency is an autosomal recessive condition in which the normal recycling of biotin is deficient. If untreated, infants with biotinidase deficiency will develop neurologic derangements including optic atrophy.1 We describe a case of optic neuropathy due to biotinidase deficiency in a 19-year-old man. Report of a Case | The patient was identified as having biotinidase deficiency on newborn screening and was provided with appropriate supplementation. However, at approximately age 10 years, supplements were discontinued. At age 19 years, he developed simultaneous bilateral vision loss over several weeks. There were no other neurologic symptoms. Family history was unremarkable. Social history was notable for occasional binge drinking since starting college 2 months prior to onset of symptoms. The patient had visual acuity of 20/70 OD and 20/25 OS, he identified 11 of 14 Ishihara color plates with each eye, the flicker fusion frequency was undetectable in the right eye and 9.5 Hz OS (reference range, >30 Hz), and visual fields showed bilateral cecocentral scotomas with respect of the vertical meridian (Figure 1). The pupils were briskly reactive to light with no relative afferent pupillary defect. There was mild optic disc pallor bilaterally and optical coherence tomography showed atrophy of the papillomacular bundle (Figure 2). Neurologic examination findings were otherwise normal. Findings on magnetic resonance imaging of the brain and orbits with contrast were normal. Biotin levels were un-
JAMA Ophthalmology February 2014 Volume 132, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Georgia User on 06/01/2015
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Letters
Figure 1. Goldmann Perimetry A
120
90
105
135 150
75
60
120
105
70
60
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detectable and biotinidase activity was markedly reduced (0.2 U/L; reference range, 3.5-13.8 U/L). Genetic testing demonstrated a homozygous double mutation (D444H:F403V) predictive of profound biotinidase deficiency. He began treatment with biotin, 20 mg/d. The patient improved within 1 month. After 4 months, he had return of visual acuity to 20/20 OU and the flicker fusion frequency improved to 26.5 Hz OD and 28.8 Hz OS. Minor residual visual field defects remained (Figure 1) and color vision remained similar to his initial presentation. He continued to be stable after an additional year of follow-up. Discussion | Biotin deficiency is known to cause optic neuropathy, typically in infancy but there have been reports of delayedonset optic neuropathy in children and adolescents.2,3 This case is unique because the patient was identified and treated as an infant and thus avoided the typical natural history of biotinidase deficiency. However, supplementation was stopped later in childhood. It is remarkable that he was asymptomatic for nearly a decade after stopping supplementation. It is possible that initiation of alcohol consumption triggered the onset of his symptoms. This case has many features common among other metabolic optic neuropathies such as genetic, toxic, or nutritional optic neuropathies. Similarities include atrophy of the papillomacular bundle and the pattern of vision loss.4 Reported pat-
270
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240
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OK
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Goldmann perimetry demonstrates cecocentral scotoma in the left and right eyes (A) with incomplete resolution after treatment (B). OK indicates okay.
terns of vision loss include bilateral central or cecocentral defects or bitemporal loss.5 The similarity in presentation implies a similar underlying pathophysiology. Metabolic optic neuropathies are thought to be due to mitochondrial dysfunction.4 Biotin is important in the normal function of mitochondria, and biotin deficiency has been shown to cause oxidant damage and depletion of mitochondrial complex IV.6 Therefore, it is possible that biotin deficiency also leads to optic neuropathy by way of mitochondrial dysfunction. The most common nutritional deficiencies causing optic neuropathy involve vitamin B12, vitamin B1, and folic acid. In the right clinical setting, biotin deficiency should also be included as a possible cause of optic neuropathy. In this case, there was some evidence of permanent damage to the optic nerve, but prompt initiation of biotin supplementation resulted in good, although imperfect, recovery of visual function. This recovery was most likely due to saving nerve fibers that were injured but not yet lost. Thus, biotin-deficient optic neuropathy is an important consideration because of the potential to reverse vision loss. Scott R. Haines, MD Reid A. Longmuir, MD Author Affiliations: Department of Neurology, Virginia Commonwealth University, Richmond (Haines); Department of Ophthalmology, Virginia
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Copyright 2014 American Medical Association. All rights reserved.
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229
Letters
Figure 2. Fundus Photographs and Optical Coherence Tomography A
B
300
Thickness, μm
Thickness, μm
300 240 180 120 60 0 –180 –135 N
–90 I
–45
0 T
45
90 S
135
240
Above normal limits (P < .01)
180
Borderline above (P < .05)
120
Within normal limits (P < .05)
60 0 –180 –135 N
180 N
Borderline below (P < .05) –90 I
Position, Degrees
Thickness, μm
N 71 I 81
0 T
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90 S
135
180 N
Below normal limits (P < .01)
Position, Degrees
300
S 117 T 29
–45
S 130
240
OD OS
180 N 73
120 60 0 –180 –135 N
–90 I
–45
0 T
45
90 S
135
180 N
T 33 I 82
Position, Degrees
Fundus photographs demonstrate temporal disc pallor (A) and optical coherence tomography shows corresponding atrophy of the temporal peripapillary retinal nerve fiber layer (B). I indicates inferior; N, nasal; S, superior; and T, temporal.
Commonwealth University, Richmond (Haines); Department of Ophthalmology, University of Iowa, Iowa City (Haines, Longmuir). Corresponding Author: Scott R. Haines, MD, Departments of Neurology and Ophthalmology, Virginia Commonwealth University, 417 N 11th St, Fifth Floor, PO Box 980599, Richmond, VA 23298 ([email protected]). Author Contributions: Dr Haines had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Haines. Acquisition of data: Haines, Longmuir. Analysis and interpretation of data: Haines, Longmuir. Drafting of the manuscript: Haines. Critical revision of the manuscript for important intellectual content: Longmuir. Administrative, technical, and material support: Longmuir. Study supervision: Longmuir. Conflict of Interest Disclosures: None reported. 1. Wolf B. The neurology of biotinidase deficiency. Mol Genet Metab. 2011;104(1-2):27-34. 2. Wolf B, Pomponio RJ, Norrgard KJ, et al. Delayed-onset profound biotinidase deficiency. J Pediatr. 1998;132(2):362-365. 3. Hayati AA, Wan-Hitam WH, Cheong MT, Yunus R, Shatriah I. Optic neuritis in a child with biotinidase deficiency: case report and literature review. Clin Ophthalmol. 2012;6:389-395. 4. Sadun AA. Metabolic optic neuropathies. Semin Ophthalmol. 2002;17(1):29-32. 5. Kho RC, Al-Obailan M, Arnold AC. Bitemporal visual field defects in ethambutol-induced optic neuropathy. J Neuroophthalmol. 2011;31(2):121-126. 230
6. Atamna H, Newberry J, Erlitzki R, Schultz CS, Ames BN. Biotin deficiency inhibits heme synthesis and impairs mitochondria in human lung fibroblasts. J Nutr. 2007;137(1):25-30.
COMMENT & RESPONSE
Regarding Macular Xanthophylls and ω-3 Long-Chain Polyunsaturated Fatty Acids in Age-Related Macular Degeneration To the Editor We read with interest the recently published article by Arnold et al titled “Macular Xanthophylls and ω-3 LongChain Polyunsaturated Fatty Acids in Age-Related Macular Degeneration: A Randomized Trial.”1 The authors report the results of a 12-month intervention with macular xanthophylls and ω-3 long-chain polyunsaturated fatty acids in patients with nonexudative age-related macular degeneration (AMD), where the main outcome measures included plasma xanthophyll concentrations and optical density of macular pigment (MP). Unfortunately, however, the methods used to assess these outcome measures were flawed, thereby rendering the conclusion of the article unsafe. With respect to analysis of plasma concentrations of the macular carotenoids, astaxanthin is not an appropriate
JAMA Ophthalmology February 2014 Volume 132, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Georgia User on 06/01/2015
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