Further to the article of Behbehani R, Sergott RC and Savino PJ
Tobacco-alcohol amblyopia: a maculopathy? [1], we question whether either
patient had tobacco-alcohol amblyopia (TAA).
“TAA” occurs in patients with high alcohol and tobacco
intake, but is perhaps a misnomer with “nutritional optic
neuropathy” being more appropriate. Many such patients are
nutritionally deficient consequent u...
Further to the article of Behbehani R, Sergott RC and Savino PJ
Tobacco-alcohol amblyopia: a maculopathy? [1], we question whether either
patient had tobacco-alcohol amblyopia (TAA).
“TAA” occurs in patients with high alcohol and tobacco
intake, but is perhaps a misnomer with “nutritional optic
neuropathy” being more appropriate. Many such patients are
nutritionally deficient consequent upon a poor diet [2] and even with
continuation of smoking, improvement in vision can occur following dietary
supplementation.[3] Pure “tobacco amblyopia” has been
described [4] and is usually associated with pipe and cigar smoking rather
than cigarettes.[2] One of us (GH) has seen only two cases of presumed
“tobacco optic neuropathy”, and both patients smoked large
amounts of pipe tobacco, inhaling the smoke. However, despite the
explosion of cigarette smoking during the 20th Century, the number of
reported cases significantly decreased, leading to the suggestion that the
disorder may not exist as a single nosological entity.[5] In addition, it
has been suggested that mitochondrial function may be implicated in, for
example, the “epidemic” optic neuropathies in Tanzania, Cuba
or Nigeria,[6] and that some cases of “tobacco-alcohol
amblyopia” were in fact Leber hereditary optic neuropathy (LHON).[7]
The authors present two cases. In both the level of alcohol and
tobacco consumption is considerably less than our experience dictates
would be required to consider a tobacco-alcohol related aetiology. Case 1
smoked only one pack of cigarettes per week, and consumed two to three
beers daily, only slightly more than the UK recommended limit for women;
less than that for men. Case 2 consumed even less alcohol (5-8 drinks per
week), yet the authors state that both patients had a “high alcohol
intake”. Further, the second patient was shown by mutational
analysis to be suffering from LHON, previously shown by the same group to
be a disorder that can be mistaken for tobacco-alcohol amblyopia.[7]
Electrophysiology may be valuable in such cases, but only mfERGs are
presented. Delayed VEPs may occur in maculopathy, but as delayed VEPs
usually occur in toxic optic neuropathy, a normal latency would have been
re-assuring evidence of the lack of optic nerve involvement.[8,9] The
pattern ERG, because of its ability both to separate optic nerve and
macular dysfunction and directly to assess the retinal ganglion cells with
the N95 component [10], may have provided confirmatory evidence of macular
dysfunction, particularly in the patient with LHON; it has been reported
that fixation errors in a poorly sighted patient may give artefactual
central mfERG abnormality.[11]
ACKNOWLEDGEMENT:
The authors do not declare any financial support or relationships that
may pose a conflict of interest.
Funding/support: none.
Financial disclosures: none.
References:
1. Behbehani R, Sergott RC, Savino PJ. Tobacco-alcohol amblyopia: a
maculopathy? Brit J Ophthalmol 2005; 89:1543-4.
2. Heaton JM, McCormick AJA, Freeman AG. Tobacco amblyopia: A clinical
manifestation of vitamin B12 deficiency. Lancet 1958;2:286-290.
3. Victor M. Tobacco-alcohol amblyopia. A critique of current concepts of
this disorder, with the special reference to the role of nutritional
deficiency in its causation. Arch Ophthalmol 1963;70:313-318.
4. Dunphy EB. Alcohol and tobacco amblyopia: a historical survey. Am J
Ophthalmol 1969;68:569-578.
5. Grzybowski A. Rozwój badañ wp³ywu tytoniu na narz±d wzroku w ostatnich
200 latach (The development of research on the effect of tobacco
consumption on the visual organ over the last 200 years). Przegląd Lekarski (Medical Review) 2005; 62:1167-1170.
6. Carelli V, Ross-Cisneros FN, Sadun AA. Optic nerve degeneration and
mitochondrial dysfunction: genetic and acquired optic neuropathies.
Neurochem Int 2002;40:573-584.
7. Cullom ME, Heher KL, Miller NR, Savino PJ, Johns DR. Leber’s
hereditary optic neuropathy masquerading as tobacco-alcohol amblyopia.
Arch Ophthalmol 1993;111: 1482-1485.
We congratulate the authors of their adequately designed study(1) that demonstrates the high concentration of the free acid (the product of hydrolysis) of bimatoprost (BP), an amide, in the aqueous humor of patients receiving a single drop of BP 1, 3, or 6 hours prior to cataract surgery. This important study confirms the results found in previous studies.(2,3) However, despite providing important confirmat...
We congratulate the authors of their adequately designed study(1) that demonstrates the high concentration of the free acid (the product of hydrolysis) of bimatoprost (BP), an amide, in the aqueous humor of patients receiving a single drop of BP 1, 3, or 6 hours prior to cataract surgery. This important study confirms the results found in previous studies.(2,3) However, despite providing important confirmatory data, Cantor et al1 appear to reach conclusions that are not supported by their own data. Whereas the 2 previous studies(2,3) conclude that BP is a prodrug that is hydrolyzed to its free acid to account for its ocular hypotensive effect by activation of known FP prostanoid receptors, the current publication1 surprisingly concludes that BP is not a prodrug and acts directly as an amide to reduce intraocular pressure (IOP).
The clinical studies cited above(1-3) are not the only ones that have demonstrated the hydrolysis of BP in ocular tissues. Previous studies have demonstrated its hydrolysis in vitro in rabbit, bovine, and human ocular tissues(4-7) and after topical application in vivo in rabbit and monkey ocular tissues.(8) The hydrolysis of BP to produce sufficient concentrations of its very potent free acid, a well-described FP receptor agonist, provides clear evidence of its prodrug properties. Studies in FP receptor knockout mice have clearly demonstrated the importance of FP receptors for effective IOP reduction after topical application of FP receptor agonists, including BP.(9-12)
The 3 clinical studies1-3 provide very consistent data. Each demonstrates equal or higher levels of the free acid than the intact amide of BP in aqueous humor. Each demonstrates peak levels occurring within the first few hours after topical application of BP, with lower levels afterwards. Peak concentrations of the free acid were 35 nM,3 22 nM,2 and 7 nM1 in each of the 3 studies. After topical application of latanoprost (LP), Cantor et al1 demonstrated a free acid concentration in aqueous of 41 nM at 3 hours, which is less that half of the 100 nM concentration found in a previous study.13 Therefore, when assessing the 4 clinical studies1-3,(13) which evaluated the hydrolysis of LP and/or BP, the lowest concentrations (2 to 5-fold less than the other studies) of the free acids of either LP or BP were consistently demonstrated by Cantor et al.1 Cantor et al1 suggest that the lower levels might be partially explained by single dose administration of BP or LP in their study, compared with multiple dosing in other studies. However, another clinical study also involved single dose administration and yet found approximately 2-fold higher concentrations of LP acid.(13)
The key and unambiguous observation that we believe is critical is that, no matter what values were obtained in each and every study, all of the concentrations, including the lower concentrations of the free acid of either LP or BP found by Cantor et al,1 are sufficiently high enough to account for their activity at FP prostanoid receptors. At 24 hours after LP, the aqueous humor concentration of the free acid was found to be well less than 1 nM,13 demonstrating that very low aqueous concentrations are found during periods of substantial IOP reduction. Therefore, the lower limits of quantitation of 1.3 nM for BP acid and 2.6 nM for LP acid in the current study1 apparently are not sensitive enough to detect substantial, clinically significant aqueous concentrations of the free acids of these prodrugs.
Although lower than the free acid concentrations, the relatively high concentrations of the amide of BP in the aqueous1-3 compared with nondetectable levels of the LP ester is hardly an adequate criterion to support the hypothesis that BP is not a prodrug. These data instead demonstrate that BP amide is an inefficient prodrug compared with LP ester simply because the ester bond is more labile than the amide bond. BP is topically applied at 6 times the concentration of LP, but, unlike LP, is not completely hydrolyzed. 1-3,13 Despite its 6-fold higher concentration, BP yields peak free acid concentrations in the aqueous 3 to 6 times lower than LP acid, 1-3,13 clearly demonstrating the inefficiency of hydrolysis of the amide compared with ester prodrug. Despite these lower concentrations of the BP free acid, they appear to be sufficient to fully account for the effect of BP. Studies have repeatedly demonstrated that the free acid of BP is 3 to 10 times more potent at the FP receptor than the free acid of LP.(14-23) Therefore, the 3 to 6-fold lower concentrations of BP, compared with LP, acid in aqueous still can account for similar activation of FP receptors when their differences in potency are considered.
Despite the overwhelming evidence for greater potency of the acid of BP compared with LP, (14-23) Cantor et al1 claim that the acids are equally potent and cite a single published study(19) using trabecular meshwork cells from a limited number of donor eyes to support their claim. Cantor et al fail to acknowledge that BP acid exhibits a potency (EC50) of 2.8 to 3.8 nM in numerous cell-types derived from several different species (e.g. human ciliary muscle cells, mouse fibroblast, and rat smooth muscle cells)(18) such that even the amount of BP acid they detected (7 nM) would be sufficient to occupy and stimulate many of the FP receptors in the target tissues. In more comprehensive studies using trabecular meshwork cells derived from numerous donor eyes,(18) BP acid still exhibits a relatively high potency (EC50 = 26 ± 10 nM) at the FP receptor that could help account for the observations of Cantor et al.(1) By citing and concentrating on only a single reference as opposed to the many other published studies, Cantor et al1 appear to bias their interpretation of their data.
We fully agree that drugs might reach target tissues via routes independent of aqueous humor. However, in the case of prostaglandin analogs, including both LP and BP, drug concentrations measured in the aqueous will leave the eye via trabecular or uveoscleral outflow pathways, thereby providing active drug to these tissues. These drugs also might enter these outflow tissues by other routes, and also might be hydrolyzed to their active free acids either along these alternative routes or after they arrive at their target tissue. Therefore, the possibility of alternative routes of delivery of these drugs to target tissues does not negate their action as prodrugs.
While the manufacturer of BP has repeatedly tried to present data to support the hypothesis that BP’s mechanism of action does not rely on FP receptor agonism of the free acid but rather is due to intrinsic receptor occupancy of the amide, their arguments fail to be convincing for several reasons. First, as previously reported, the presence of FP receptors are essential for BP’s hypotensive action as demonstrated by experiments in FP knockout mice.(10,11) More importantly, there has not been, to the best of our knowledge, any putative receptor that has been adequately identified that can explain the actions of BP at a unique non-FP receptor. The elusive, mystery receptor in question has never been cloned or characterized by receptor binding kinetics. In short, BP’s hypotensive action appears to require FP receptor agonism that occurs following the hydrolysis of the prodrug that liberates the free acid that then activates the classic FP receptors in the target tissues. The shared characteristics of BP with other prostaglandin analogs, including the side effects of iris color darkening and eyelash changes, also would argue that BP exerts its biological actions by activating the FP receptor. Even if “prostamide” receptors were demonstrated to exist in the anterior uvea, the IOP effect of BP still can be more reasonably explained by its ability to activate FP prostanoid receptors following its demonstrated hydrolysis to its potent free acid.
In conclusion, we agree with the data presented by Cantor et al1 finding substantial, albeit somewhat lower,(2,3,13) concentrations of the free acid of BP or LP in aqueous after topical application in humans. However, we strongly disagree with their conclusions. Cantor et al,(1) like others,(2,3,13) have confirmed that BP is an inefficient prodrug that is hydrolyzed to its free acid to activate well-described FP prostanoid receptors resulting in IOP reduction. Postulation of the existence of enigmatic “prostamide” or yet to be identified unknown receptors is not necessary or warranted.
Carl B. Camras, M.D., Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska
Najam A. Sharif, Ph.D., Molecular Pharmacology Unit, Alcon Research, Ltd. Fort Worth, TX
Martin B. Wax, M.D., Research and Development, Ophthalmology Discovery Research, Alcon Laboratories, Fort Worth, TX; Department of Ophthalmology and Visual Sciences, University of Texas Southwestern Medical School, Dallas, TX
Johan Stjernschantz, M.D., Ph.D., Department of Neuroscience, Uppsala University Biomedical Center, Uppsala, Sweden
Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY.
Dr. Camras was a consultant to Pfizer Ophthalmics. Drs. Sharif and Wax are employees of Alcon Laboratories. Dr. Stjernschantz was an employee of Pharmacia Ophthalmics.
Correspondence to: Carl B. Camras, M.D., Department of Ophthalmology and Visual Sciences, 985540 Nebraska Medical Center, Omaha, NE 68198-5540
References:
1 Cantor LB, Hoop J, WuDunn D, et al. Levels of bimatoprost acid in the aqueous humour after bimatoprost treatment of patients with cataract. Br J Ophthalmol 2007;91:629-32.
2 Camras CB, Toris CB, Sjoquist B, et al. Detection of the free acid of bimatoprost in aqueous humor samples from human eyes treated with bimatoprost before cataract surgery. Ophthalmology Same 2004;111:2193-8.
3 Dahlin DC, Craven ER, Moster M, et al. Human aqueous humor concentrations of bimatoprost and bimatoprost free acid following topical ocular dosing of Lumigan (bimatoprost (17-phenyl-trinor-PGF2a) 0.03% ophthalmic solution) [abstract]. Invest Ophthalmol Vis Sci 2004;45:ARVO E-Abstract 2096.
4 Maxey KM, Johnson JL, LaBrecque J. The hydrolysis of bimatoprost in corneal tissue generates a potent prostanoid FP receptor agonist. Surv Ophthalmol 2002;47(Suppl 1):S34-S40.
5 Davies SS, Ju WK, Neufeld AH, et al. Hydrolysis of bimatoprost (Lumigan) to its free acid by ocular tissue in vitro. J Ocul Pharmacol Ther 2003;19:45-54.
6 Hellberg MR, Ke TL, Haggard K, et al. The hydrolysis of the prostaglandin analog prodrug bimatoprost to 17-phenyl-trinor PGF2a by human and rabbit ocular tissue . J Ocul Pharmacol Ther 2003;19:97-103.
7 Kriatchko A, Zhan G, Cheruvu N, et al. In vitro transport and hydrolysis of bimatoprost in bovine cornea [abstract]. ARVO 2003;B81.
8 Dahlin DC, Bergamini MVW, Curtis MA, et al. Bimatoprost hydrolysis to 17-phenyl PGF2a by rabbit and monkey ocular tissues, in vivo [abstract]. Invest Ophthalmol Vis Sci 2002;43:ARVO E-Abstract 4109.
9 Ota T, Aihara M, Saeki T, et al. The IOP-lowering effects and mechanism of action of tafluprost in prostanoid receptor-deficient mice. Br J Ophthalmol 2007;91:673-6.
10 Crowston JG, Lindsey JD, Morris CA, et al. Effect of bimatoprost on intraocular pressure in prostaglandin FP receptor knockout mice. Invest Ophthalmol Vis Sci 2005;46:4571-7.
11 Ota T, Aihara M, Narumiya S, et al. The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice. Invest Ophthalmol Vis Sci 2005;46:4159-63.
12 Crowston JG, Lindsey JD, Aihara M, et al. Effect of latanoprost on intraocular pressure in mice lacking the prostaglandin FP receptor. Invest Ophthalmol Vis Sci 2004;45:3555-9.
13 Sjöquist B, Stjernschantz J. Ocular and systemic pharmacokinetics of latanoprost in humans. Surv Ophthalmol 2002;47(Suppl 1):S6-S12.
14 Resul B, Stjernschantz J, Selén G, et al. Structure-activity relationships and receptor profiles of some ocular hypotensive prostanoids. Surv Ophthalmol 1997;41(Suppl 2):S47-S52.
15 Stjernschantz JW. From PGF2a-isopropyl ester to latanoprost: a review of the development of Xalatan: the Proctor Lecture. Invest Ophthalmol Vis Sci 2001;42:1134-45.
16 Sharif NA, Williams GW, Kelly CR. Bimatoprost and its free acid are prostaglandin FP receptor agonists. Eur J Pharmacol 2001;432:211-3.
17 Sharif NA, Kelly CR, Crider JY, et al. Ocular hypotensive FP prostaglandin (PG) analogs: PG receptor subtype binding affinities and selectivities, and agonist potencies at FP and other PG receptors in cultured cells. J Ocul Pharmacol Ther 2003;19:501-15.
18 Sharif NA, Crider JY, Husain S, et al. Human ciliary muscle cell responses to FP-class prostaglandin analogs: phosphoinositide hydrolysis, intracellular Ca2+ mobilization and MAP kinase activation. J Ocul Pharmacol Ther 2003;19:437-55.
19 Sharif NA, Kelly CR, Crider JY. Human trabecular meshwork cell responses induced by bimatoprost, travoprost, unoprostone, and other FP prostaglandin receptor agonist analogues. Invest Ophthalmol Vis Sci 2003;44:715-21.
20 Sharif NA, Kelly CR, Williams GW. Bimatoprost (Lumigan®) is an agonist at the cloned human ocular FP prostaglandin receptor: real-time FLIPR-based intracelluar Ca2+ mobilization studies . Prostaglandins Leukot Essent Fatty Acids 2003;68:27-33.
21 Sharif NA, Kelly CR, Crider JY. Agonist activity of bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester and other prostaglandin analogs at the cloned human ciliary body FP prostaglandin receptor. J Ocul Pharmacol Ther 2002;18:313-24.
22 Kelly CR, Williams GW, Sharif NA. Real-time intracellular Ca2+ mobilization by travoprost acid, bimatoprost, unoprostone, and other analogs via endogenous mouse, rat, and cloned human FP prostaglandin receptors. J Pharmacol Exp Ther 2003;304:238-45.
23 Stjernschantz J, Albert D, Hu D, et al. Mechanism and clinical significance of prostaglandin-induced iris pigmentation. Surv Ophthalmol 2002;47 (suppl 1):S162-S175.
We read with interest the recently published paper by Manzano et al.
titled ‘Inhibition of experimental corneal neovascularisation by
bevacizumab (Avastin)’. The authors used topical eyedrop application of
either saline or bevacizumab in a rat model of corneal neovascularization,
with apparent moderate success. Furthermore, in their discussion, they
mention that there was incomplete inhibition of th...
We read with interest the recently published paper by Manzano et al.
titled ‘Inhibition of experimental corneal neovascularisation by
bevacizumab (Avastin)’. The authors used topical eyedrop application of
either saline or bevacizumab in a rat model of corneal neovascularization,
with apparent moderate success. Furthermore, in their discussion, they
mention that there was incomplete inhibition of the neovascularization and
speculate several other cytokines or growth factors may be responsible.
However, bevacizumab has previously been reported to be incapable of
binding rodent VEGF [2]. The findings in this study suggest that either
there is in fact a low affinity interaction with bevacizumab and rat VEGF,
or the effects observed are due to other non-VEGF mediated interactions of
bevacizumab. If the latter is the case, then the question arises as to
whether this interaction is specific to bevacizumab or can be replicated
with other type specific normal IgG. Recently Gerber et al. reported the
generation of transgenic mice producing humanized VEGF-A [1], which
produce a VEGF protein that, in contrast to wild type mouse protein, does
bind bevacizumab. This mouse would be suitable for evaluating human
specific anti-VEGF therapies in vivo. We anticipate Lucentis will be
evaluated in this new model and await the results eagerly.
References
1. Gerber, H.P., Wu, X., Yu, L., Wiesmann, C., Liang, X.H., Lee,
C.V., Fuh, G., Olsson, C., Damico, L., Xie, D., Meng, Y.G., Gutierrez, J.,
Corpuz, R., Li, B., Hall, L., Rangell, L., Ferrando, R., Lowman, H.,
Peale, F., and Ferrara, N., Mice expressing a humanized form of VEGF-A may
provide insights into the safety and efficacy of anti-VEGF antibodies.
Proc Natl Acad Sci U S A, 2007. 104(9): p. 3478-83.
2. Lin, Y.S., Nguyen, C., Mendoza, J.L., Escandon, E., Fei, D., Meng,
Y.G., and Modi, N.B., Preclinical pharmacokinetics, interspecies scaling,
and tissue distribution of a humanized monoclonal antibody against
vascular endothelial growth factor. J Pharmacol Exp Ther, 1999. 288(1): p.
371-8.
The rising use of Avastin injection for choroidal neovascular membranes
and other conditions has been successful in preliminary reports.
However, I have experienced 5 cases with optic neuropathy following
Avastin
injection after an interval of 2-4 months. Although my number of cases
is
very small, it suggests that a study be conducted to investigate the
effect of intravitreal Avastin on the optic nerve u...
The rising use of Avastin injection for choroidal neovascular membranes
and other conditions has been successful in preliminary reports.
However, I have experienced 5 cases with optic neuropathy following
Avastin
injection after an interval of 2-4 months. Although my number of cases
is
very small, it suggests that a study be conducted to investigate the
effect of intravitreal Avastin on the optic nerve using VEP.
Prof Dr Sherif Ahmed Kamel Amer
MBBCh, MSc ophthalmology, MD ophthalmology, Cairo University, ICO.Ophth.
Fellow of The Ophthalmology Department, Cairo University Hospitals (Kasr
Al Aini).
Supervisor of The Neuro-Ophthalmology Clinic
National Eye Center (Rod El Farag).
Ass Professor of Ophthalmology Beni Suif University, Egypt
I wish to thank Ganesh et al for confirming (p <0.001) the marked
and obvious difference between the age distribution of retinal and
subdural haemorrhages in America and Japan. Finding this difference "not
surprising" neither negates nor explains it. More sophisticated child
abuse teams could not discover cases in Japan months before they occur.
Variations in incidence of osteogenesis imperfecta wou...
I wish to thank Ganesh et al for confirming (p <0.001) the marked
and obvious difference between the age distribution of retinal and
subdural haemorrhages in America and Japan. Finding this difference "not
surprising" neither negates nor explains it. More sophisticated child
abuse teams could not discover cases in Japan months before they occur.
Variations in incidence of osteogenesis imperfecta would not either. While
in America apparently people "lose it" and shake kids 4-6 weeks after they
cry (the "lag time" between the crying and SBS incidence curves), it is
unlikely the Japanese wait several months more. The traditional
explanations of differences in relative head size and strength of neck
muscles and vitreo-retinal adherence also fail to explain it. Thus, my
suggestion of an inquiry into this difference remains unaddressed.
The authors would like to thank Dr. J.J. Wang for her constructive
comments about the statistical analysis of the data obtained in the
Beijing Eye Study.[1] As already pointed out in another recent reply to a
letter by Dr. Wang, the authors became aware of the limitations in their
statistical analysis of the data of the Beijing Eye Study.[2] The authors
are grateful to Dr. Wang for clarifying these wea...
The authors would like to thank Dr. J.J. Wang for her constructive
comments about the statistical analysis of the data obtained in the
Beijing Eye Study.[1] As already pointed out in another recent reply to a
letter by Dr. Wang, the authors became aware of the limitations in their
statistical analysis of the data of the Beijing Eye Study.[2] The authors
are grateful to Dr. Wang for clarifying these weaknesses so that these
weaknesses may be avoided in future statistical analyses of the data of
the Beijing Eye Study. In the article on the associated factors for age-related maculopathy in the adult population in China,[1] the figures in
the brackets of the Table generally give the 95% confidence intervals of
the odds ratios. The use of the abbreviation ”ARD” for “age-related
maculopathy” was a typographical error, instead of using “ARM” as
explained in the first paragraph of the Abstract. The association
estimates presented in the Table are crude (unadjusted).
Although Dr. Wang´s letter is rather critical about the statistical
analysis of the Beijing Eye Study, the authors are grateful to her for
showing up limitations in the statistical analysis, weaknesses that may be
avoided in future statistical analyses of the data of the Beijing Eye
Study.
References
1. Xu L, Li Y, Zheng Y, Jonas JB. Associated factors for age-related
maculopathy in the adult population in China. The Beijing Eye Study. Br J
Ophthalmol 2006; 90:1087-90.
2. Jonas JB, Xu L. Reply to the Letter-to-the-Editor, written by Wang JJ,
concerning the Beijing Eye Study. Am J Ophthalmol 2007; In Press.
I read with interest the report from the Beijing Eye Study by Xu, et al. published in BJO last year (BJO 2006;90:1087-1090), titled:
Associated
factors for age related maculopathy in the adult population in China:
the
Beijing Eye Study.
In the abstract, Results and Table 1 of this report, some
association
estimates are provided as p values and 95% confidence intervals without
point estimate...
I read with interest the report from the Beijing Eye Study by Xu, et al. published in BJO last year (BJO 2006;90:1087-1090), titled:
Associated
factors for age related maculopathy in the adult population in China:
the
Beijing Eye Study.
In the abstract, Results and Table 1 of this report, some
association
estimates are provided as p values and 95% confidence intervals without
point estimates for the likelihood (such as the associations with age,
refractive error, education and rural area), others are provided as p
values, odds ratios (OR) and 95% confidence intervals (such as the
associations with systemic and ocular diseases). For the association
between posterior subcapsular cataract and late ARM, only a p value is
provided. It is very confusing to the reader to determine what these 95%
confidence intervals are for: are they for the p values, or the odds
ratios? Does this depend on what they follow? It is also unclear to the
reader why the authors describe their data in such an inconsistent way.
By reading the Table alone, I could not find information about
whether the association estimates are crude (unadjusted) or had been
adjusted for other co-variables, and if they are adjusted, what the co-variables are.
I am also surprised that during the reviewing process the reviewers
did not find this confusing way of data presentation strange, and also
did
not find the Table insufficiently self explanatory.
The authors abbreviate age-related macular degeneration as ARD but
not AMD. This is unique.
Jie Jin Wang MMed PhD
Centre for Vision Research
Department of Ophthalmology
University of Sydney
We thank Dr. Holló [1] for his comments and the opportunity to
elaborate further on our findings. We had considered the point that both
eyes from an individual may not be fully independent from one another. As
such, in our initial analysis, we calculated the Pearson’s correlation
coefficient (r) between left and right eyes for both of our measures. We
found the central corneal thickness (CCT) between...
We thank Dr. Holló [1] for his comments and the opportunity to
elaborate further on our findings. We had considered the point that both
eyes from an individual may not be fully independent from one another. As
such, in our initial analysis, we calculated the Pearson’s correlation
coefficient (r) between left and right eyes for both of our measures. We
found the central corneal thickness (CCT) between the two eyes of a same
individual to be significantly correlated with each other, r = 0.88 (p
< 0.001). However, there was no significant correlation between right
and left disc diameter (DA) r = 0.1 (p = 0.4), demonstrating reasonable
variability between left and right eye measures. Bearing this in mind,
along with the fact that our analysis examined the correlation between CCT
and DA within each eye and not across eyes, we view each CCT-DA
correlation as a separate measure.
We also took into consideration the potential for bias induced by
including two eyes from some individuals, and only one from others (a
consequence of our exclusion factors). Therefore, as a validation model,
we analyzed our data using only one random eye per subject to check for
any inconsistencies in results based on our analytical approach. The
results were consistent to those we presented in the manuscript using both
eyes [2]. Using one random eye, we found the Caucasian subgroup CCT-DA
correlation r = - 0.24 (p = 0.15), similar to the correlation r = - 0.28
in our two-eye model. We also performed a secondary analysis in the single
eye model by using a slightly relaxed exclusion criterion to allow for HRT
images with a standard deviation of less than 100 to increase the number
of subjects and hence statistical power. Again we found a matching
significant correlation r = - 0.28 (p = 0.02).
To summarize, in addition to left and right eyes demonstrating
significant variability in DA, the correlation values between CCT and DA
were reproducible in our single eye validation model and our secondary
analysis. In view of these confirmatory findings, we feel confident that
our analytic model is fitting and has not induced any significant level of
bias.
Afshin Parsa, M.D., M.P.H.
Masoumeh Sanagou, M.S.C.
Mohammad Pakravan, M.D.
Cameron F. Parsa, M.D.
References
1. Gábor Holló. Central corneal thickness and correlation to disc
size. 5 January 2007.
2. Pakravan M, Parsa A, Sanagou M, Parsa CF. Central corneal
thickness and correlation to disc size: a potential link for
susceptibility to glaucoma. Br J Ophthalmol 2007;91:26-28.
After going through the above mentioned scientific report, I have
some queries and suggestions as mentioned below:
1. Is a surgeon's opinion enough to declare a case as having
Vitreomacular traction as mentioned in this study? Or is a definite
documentation possible with aid like OCT?
2. In 2 cases, single sessions of PDT were done, which does not
match the criterion of repeated...
After going through the above mentioned scientific report, I have
some queries and suggestions as mentioned below:
1. Is a surgeon's opinion enough to declare a case as having
Vitreomacular traction as mentioned in this study? Or is a definite
documentation possible with aid like OCT?
2. In 2 cases, single sessions of PDT were done, which does not
match the criterion of repeated PDT as mentioned.
3. Number of cases were very low to come to such a conclusion.
Dr Gitumoni Sharma,
Flat 5 D, Park Apartment,
Kanaklata Path, Lachitnagar,
Guwahati, Assam,India
ZIP-781007
We read the paper titled “Anti-permeability and anti-proliferative
effects of standard and frozen bevacizumab on choroidal endothelial cells”
by Peters et al [1] in Br J Ophthalmol. Dec. 2006 issue with great interest.
There are a number of issues that we would like to point out with regards
to the methodology. The authors have solely used scratch assay in the
presence of 50ng/ml VEGF +- 0.5mg/ml b...
We read the paper titled “Anti-permeability and anti-proliferative
effects of standard and frozen bevacizumab on choroidal endothelial cells”
by Peters et al [1] in Br J Ophthalmol. Dec. 2006 issue with great interest.
There are a number of issues that we would like to point out with regards
to the methodology. The authors have solely used scratch assay in the
presence of 50ng/ml VEGF +- 0.5mg/ml bevacizumab to assess cell
proliferation. They demonstrate that when bevacizumab was added wound
closure was retarded (data presented in figures 4 and 5) and they infer
that this is because of antiproliferative effect of bevacizumab on
choroidal endothelial cells. We would like to point out that scratch assay
is an accepted method for assessing cell migration,[2-4] but it is not a
method for assessing cell proliferation. There are several limitations in
using this assay for estimating cell proliferation. If proliferating cells
fail to migrate, the wound will not close. On the other hand, the
migrating cells can close the wound without undergoing proliferation.
Therefore, based on this evidence the authors can not draw conclusions
regarding proliferation of cells. The authors have cited Roberts and
Palade [5] for the proliferation assay used in this paper. However, the cited
paper has not used any such method for assessing cell proliferation.
Additionally, in figure 5, the authors have provided microscopic evidence
for the cell proliferation assay they have used. In the micrographs
provided it appears that the cell density in bevacizumab treated sample is
much less than sample treated with VEGF alone that would add additional
bias. With regards to proliferation assay, there are excellent methods
available to do this in cell cultures.[6-8] These methods utilize
Bromodeoxyuridine, tritiated thymidine and carboxyl fluorescent
succinimidyl ester. There appears to be no apparent limitation why these
methods could not be employed, especially in a paper wherein proliferation
is a major focus.
Sincerely,
Rajesh K Sharma, M.D., Ph.D.
Kakarla V. Chalam, M.D., Ph.D.
Department of Ophthalmology
University of Florida Health Science Center
Jacksonville, FL
References
1. Peters S, Julien S, Heiduschka P et al. Anti-permeability and
anti-proliferative effects of standard and frozen bevacizumab on choroidal
endothelial cells. Br.J.Ophthalmol. 2006.
2. Johnson DA, Fields C, Fallon A et al. Polyamine-dependent
migration of retinal pigment epithelial cells. Invest Ophthalmol.Vis.Sci.
2002;43:1228-33.
3. Theisen CS, Wahl JK, III, Johnson KR et al. NHERF Links the N-
Cadherin/Catenin Complex to the PDGF Receptor to Modulate the Actin
Cytoskeleton and Regulate Cell Motility. Mol.Biol.Cell 2007.
4. Soderholm J, Heald R. Scratch n' screen for inhibitors of cell
migration. Chem.Biol. 2005;12:263-5.
5. Roberts WG, Palade GE. Increased microvascular permeability and
endothelial fenestration induced by vascular endothelial growth factor.
J.Cell Sci. 1995;108 ( Pt 6):2369-79.
6. Luzyanina T, Mrusek S, Edwards JT et al. Computational analysis
of CFSE proliferation assay. J.Math.Biol. 2007;54:57-89.
7. Nakamura T, Ang LP, Rigby H et al. The use of autologous serum in
the development of corneal and oral epithelial equivalents in patients
with Stevens-Johnson syndrome. Invest Ophthalmol.Vis.Sci. 2006;47:909-16.
8. Ye L, Haider HK, Jiang S et al. High efficiency transduction of
human VEGF165 into human skeletal myoblasts: in vitro studies.
Exp.Mol.Med. 2003;35:412-20.
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