Thursday, June 11, 2009

Drug/device news: Lacrisert study

I'm afraid I'm very late posting this - it was from just before ARVO so the "will presents" have already happened.

It's very interesting however - the first fullblown study on Lacriserts in many years. Feel free to post comments here if you are a Lacriserts user.

Results from a large (n = 520) multi-center patient registry study of Lacrisert® (hydroxypropyl cellulose ophthalmic insert) will be presented during the upcoming ARVO Meeting and later in the month at AOS. Lacrisert is a preservative-free, once-daily, sustained release prescription insert indicated for moderate to severe dry eye, that helps to retain moisture, stabilize the tear film, and lubricate the eye. This is the first major study of Lacrisert to be undertaken in more than two decades.

Highlights of the study include:

- After 4 weeks of treatment with the Lacrisertophthalmic insert, mean ocular surface disease index (OSDI) scores significantly improved by more than 21%, from a mean of 42 to a mean of 33.

- Treatment with Lacrisert resulted in significant improvement in quality of life measures and reduction of dry eye signs and symptoms.

- 70% of a subset of 30 contact lens patients in the registry study experienced improvement of dry eye symptoms, and 53% experienced an improvement in dry eye signs, including significant improvements in dryness and grittiness, an increase in TFBUT and a decrease in mean corneal/conjunctival staining.

- Lacrisert was longer lasting 93% of the time when compared to rewetting solutions.
The results of the study suggest that the insert can meaningfully improve ocular health and quality of life for dry eye sufferers, including contact lens wearers, in a relatively short time.

Bruce H. Koffler, M.D., will present data from the study in a poster at ARVO, “LACRISERT® (hydroxypropyl cellulose ophthalmic insert) Significantly Improves Symptoms of Dry Eye Syndrome and Patient Quality of Life” (Bruce H. Koffler for the LAC-07-01 Study Group, poster 4660/D904, Wednesday, May 6, 1:45-3:30 PM).

Ophthalmic Research Associates (ORA) will also present a poster at ARVO, and Dr. Marguerite McDonald, will present additional data from the study at AOS.

Abstract: Cyclosporine in trachomatous dry eye

Clin Exp Optom. 2009 Mar 27. [Epub ahead of print]Links
The effect of topical cyclosporine A treatment on corneal thickness in patients with trachomatous dry eye.

Guzey M, Satici A, Karaman SK, Ordulu F, Sezer S.
Harran University School of Medicine, Department of Ophthalmology, Sanliurfa, Turkey E-mail:

Purpose: The purpose of the present study was to evaluate the effect of topical cyclosporine A (CsA) treatment on corneal thickness (CT) in patients with trachomatous dry eye.

Methods: Sixty-four patients with trachomatous dry eye with a Schirmer test showing 5 mm or less and a tear film break-up time (TFBUT) of five seconds or less were included. Thirty-two patients were treated with twice daily application of CsA (0.05% ophthalmic emulsion) plus non-preserved artificial tears, while the remaining 32 patients serving as controls received only non-preserved artificial tears. CT was measured using ultrasonic pachymetry at five locations of the central (CCT) and mid-peripheral cornea, at baseline and after one, three and six months of treatment.

Results: At the sixth month of treatment, CT measurements were significantly changed in both groups, compared to baseline. In the CsA treatment group, the mean CCT before and after six months of treatment were 517.4 +/- 36.2 and 546.5 +/- 32.4 microm, respectively (p < 0.001); yielding an average CCT increase of 29.1 +/- 8.0 microm (5.62 per cent) from baseline. In the control group, corresponding figures were 520.2 +/- 34.2 and 526.0 +/- 35.4 microm, respectively (p < 0.01), with an average increase of 5.8 +/- 3.1 microm (1.11 per cent).

Conclusions: In the present study, the CsA treatment group exhibited significantly greater increases in CT compared to controls. Such an increase may indicate an improvement in the integrity of the ocular surface and resolution of the underlying inflammation as a consequence of topical CsA treatment.

Abstract: Wavefront aberrations and dry eyes

Clin Exp Optom. 2009 May;92(3):267-73.
Dynamic wavefront aberrations and visual acuity in normal and dry eyes.

Wang Y, Xu J, Sun X, Chu R, Zhuang H, He JC.
Shanghai Eye and ENT Hospital, Fudan University, Shanghai, China.

PURPOSE: The aim was to study the dynamic properties of wavefront aberrations and visual acuity in normal and dry eyes.

METHODS: Thirty dry-eye patients and 27 normal subjects participated in this study. Multi-file mode of a Hartmann-Shack wavefront sensor was used to measure dynamic wavefront aberrations for a period of 45 seconds. Dynamic measurements of visual acuity (VA) were made for 150 seconds using a multi-functional VA tester. Standard deviation of the measurements (RMS or VA) over the testing period was used to estimate instability of the dynamic wavefront aberration and VA.

RESULTS: For most subjects, both wavefront aberration and VA changed over time and the instability varied substantially among individuals. Blink-dependent fluctuation in wavefront aberration or VA was observed for some dry-eye subjects. On average, the dry-eye group had greater instability than the normal group in either the higher order wavefront aberrations (t = 2.09, p = 0.03, for OD; t = 3.76, p = 0.001, for OS) or the VA (t = 2.09,p = 0.02, for OD; t = 204, p = 0.03, for OS). Instability of VA in the dry-eye group was significantly correlated with blink rate (r = 0.28, p = 0.02).

CONCLUSION: Dynamic changes in wavefront aberrations and VA are highly individual dependent, while the dry eye tends to be less stable than the normal eye. The results suggest that tear-film fluctuation might play a role in determining dynamic wavefront aberration and VA; however, contributions from other factors should not be overlooked. For dry eye, dynamic change in VA

Abstract: Prevalence of dry eye disease among US men

Prevalence of Dry Eye Disease Among US Men
Estimates From the Physicians' Health Studies

Debra A. Schaumberg, ScD, OD, MPH; Reza Dana, MD, MPH; Julie E. Buring, ScD; David A. Sullivan, PhD
Arch Ophthalmol. 2009;127(6):763-768.

Objective To estimate the prevalence and risk factors for dry eye disease (DED) among US men.

Methods Cross-sectional prevalence survey among male participants 50 years and older in the Physicians' Health Studies I (N = 18 596) and II (N = 6848). We defined DED as the presence of clinically diagnosed dry eye or severe symptoms (both dryness and irritation constantly or often). We calculated the age-standardized prevalence of DED adjusted to the age distribution of US men in 2004 and projected estimates forward to 2030. We compared DED prevalence with a similar cohort of women and examined associations with possible risk factors.

Results The prevalence of DED increased with age, from 3.90% among men aged 50 to 54 years to 7.67% among men 80 years and older (P for trend <.001). High blood pressure (odds ratio, 1.28; 95% confidence interval, 1.12-1.45) and benign prostatic hyperplasia (odds ratio, 1.26; 95% confidence interval, 1.09-1.44) were associated with a higher risk of DED. Use of antidepressants, antihypertensives, and medications to treat benign prostatic hyperplasia were also associated with increased risk of DED. The age-standardized prevalence of DED was 4.34%, or 1.68 million men 50 years and older, and is expected to affect more than 2.79 million US men by 2030.

Conclusions Dry eye disease is prevalent and increases with age, hypertension, benign prostatic hyperplasia, and antidepressant use.

Drug news: ISTA / Xibrom phase II results

ISTA Pharmaceuticals Announces Positive Results for Phase 2 Study of Low-Dose Bromfenac in Dry Eye Disease
PR Newswire, June 8

IRVINE, Calif., June 8 /PRNewswire-FirstCall/ -- ISTA Pharmaceuticals, Inc. (Nasdaq: ISTA), today announced positive results from a proof-of-concept Phase 2 clinical study in subjects with dry eye disease (keratoconjuctivitis sicca) using a new, proprietary, low-dose formulation of bromfenac, the active ingredient in Xibrom(R) (bromfenac ophthalmic solution) 0.09%. The study achieved statistical significance in the primary endpoint of the objective sign of conjunctival staining (Lissamine Green test) as compared to baseline. The study also achieved statistical significance on the objective sign of corneal staining (Fluorescein test) as compared to baseline. Patients also achieved statistically significant improvements in subjective symptoms measured by the Ocular Surface Disease Index (OSDI) and improvement in patients' most bothersome ocular symptoms....

ISTA's proof-of-concept, Phase 2 bromfenac study enrolled 38 patients who exhibited signs and symptoms consistent with moderate dry eye disease. All patients received low-dose bromfenac bilaterally twice a day for 42 days. Patient baseline scores were recorded prior to the first treatment with low-dose bromfenac and were compared to baseline at Day 14, Day 42 and Day 52. The study was designed to investigate the effects of low-dose bromfenac compared to baseline on the objective signs of conjunctival staining (Lissamine Green test) and corneal staining (Fluorescein test), as well as subjective symptoms (OSDI and patient's most bothersome ocular symptoms), when administered under normal environmental conditions.

Results of the Lissamine Green test in the Phase 2 study revealed statistical significance for low-dose bromfenac versus the patients' baseline scores starting as early as Day 14 and sustained through Day 52, ten days post treatment. Lissamine Green, a validated staining technique that stains the entire ocular surface, allows analysis of dry eye damage on the conjunctiva to determine the severity of dry eye disease. Adverse events were uncommon, and there were no serious ocular or systemic adverse events.

Abstract: Lid wiper epitheliopathy & dry eye

Nippon Ganka Gakkai Zasshi. 2009 May;113(5):596-600.
[Lid-wiper epitheliopathy in patients with dry eye symptoms]

[Article in Japanese]

Shiraishi A, Yamanishi S, Yamamoto Y, Yamaguchi M, Ohashi Y.
Department of Ophthalmology, Graduate School of Medical Science, Ehime University, Japan.

PURPOSE: Lid-wiper epitheliopathy (LWE) is characterized by one part of the marginal conjunctiva of the upper eyelid being affected and is correlated with dry eye symptoms. This is a study of the clinical features of LWE.

METHODS: Three hundred and sixty-four eyes of 182 patients with dry eye symptoms were studied. In all subjects the presence of LWE was determined by lissamine green staining followed by tests for dry eye.

RESULTS: LWE was detected in 48 of 364 eyes (13.2%). One hundred thirty-four eyes were diagnosed with dry eye and LWE was detected in 25 of 134 eyes (18.7%). This rate was higher than that of non-dry eyes with LWE (23 of 230 eyes, 10.0%). Since LWE was detected at a high rate in contact lens (CL) wearers (22 of 37 eyes, 59.4%), LWE background factors in CL wearers and non-CL wearers were compared. Significantly higher fluorescein staining scores were detected in the LWE positive CL wearers compared to LWE negative CL wearers, whereas no significant differences were detected between the LWE positive and negative groups in any other dry eye examination. LWE-like lissamine green staining was detected on the lower eyelids in 122 eyes (33.0%).

CONCLUSION: LWE was detected in more than 10% of patients with dry eye symptoms. Although LWE was detected in dry eye patients, no clear relationship was recognized between LWE and the presence of dry eye.

Abstract: Use of limbal stem cells

Key area to keep an eye on IMHO.

Int Rev Cell Mol Biol. 2009;275:133-81.
Chapter 5 limbal stem cells application in ocular biomedicine.

Vemuganti GK, Fatima A, Madhira SL, Basti S, Sangwan VS.
Sudhakar and Sreekanth Ravi Stem Cell Biology Laboratory, Ophthalmic Pathology Service, LV Prasad Eye Institute, Hyderabad, India.

Corneal opacification due to limbal stem cell deficiency (LSCD) is an important cause for ocular morbidity, resulting from a number of intrinsic and extrinsic factors. While the extrinsic factors include conditions such as chemical or thermal injuries, intrinsic include dysfunction, or reduction in the number of stem cells either due to pathological changes in autoimmune diseases or secondary to certain clinical conditions such as diabetes, dry eye disorders, or multiple previous eye surgeries. LSCD is characterized by a classic triad of signs-conjunctivalization, neovascularization and decrease in vision. With the increasing knowledge of limbal stem cells, the treatment of this condition has evolved from simple debridement to use of biological materials, direct transplantation of the healthy limbal tissue from the contralateral eye, or allogenic source to the use of cultivated limbal epithelial sheets. This chapter provides an update on the disease pathology, various treatment methodologies, with specific emphasis on the fast developing field of cell therapy and tissue engineering.

Abstract: Bleph treatment

Ophthalmologe. 2009 Jun 6. [Epub ahead of print]
[Treatment of chronic blepharokeratoconjunctivitis with local calcineurin inhibitors.]

[Article in German]

Auw-Hädrich C, Reinhard T.
Universitäts-Augenklinik, Killianstrasse 5, 79106, Freiburg, Deutschland,

Topical calcineurin inhibitors (cyclosporin A 1%, FK506, pimecrolimus) can be useful for treating chronic blepharokeratoconjunctivitis in addition to lid hygiene and lubricants. This treatment leads to an improvement of dry eye symptoms and reduces inflammation.

Underscoring the need for attention to mental health...

...when suffering from severe dry eye. This is tragic.

Woman kills herself after eye care fears

A pensioner with a painful eye condition took her own life after becoming anxious that her new GP would not be able to afford to treat her, an inquest in Wolverhampton heard.

Mavis Blunt, of Hilary Drive, Penn, had suffered from a condition called dry eye syndrome, which can cause the eyes to become inflamed and had caused her considerable pain for five years.

The court heard that she was upset that her regular doctor who had been treating her was retiring. Her daughter Louise Whitton told the hearing yesterday: “She was worried about moving to a new GP. She thought it would cost them too much to give her the treatment she required.”

Mrs Blunt, a 75-year-old former dinner lady, was described as outgoing and sociable before her illness. Since then, she tended to stay at home and was generally more unhappy, said Mrs Whitton.

Drug news: EyeGate Pharma EGP-437 Phase II results

EyeGate Pharma Announces That EGP-437 Improved Signs And Symptoms Of Dry Eye Syndrome In A Phase II Study

altham, MA – June 3, 2009 – Based on the top-level analysis of a Phase II study, EyeGate Pharma announces that EGP-437, a corticosteroid solution administered by a non-invasive ocular drug delivery system, improved signs and symptoms in patients with dry eye syndrome (DES)....

In the top-level analysis, investigators observed that EGP-437 significantly (p < 0.05) improved signs and symptoms of DES during the three-week environmental component, which included three CAE exposures and two doses. EGP-437 also improved signs and symptoms when studied as a treatment and preventative in conjunction with the CAE.

Device news: TearLab gets FDA clearance

TearLab Corporation Announces FDA 510(k) Clearance of the TearLab(tm) Osmolarity System
May 19, 2009
Global Newswire

SAN DIEGO, May 19, 2009 (GLOBE NEWSWIRE) -- OccuLogix, Inc. dba TearLab Corporation (Nasdaq:TEAR) (TSX:TLB) an ophthalmic, in-vitro diagnostics company, today announced FDA 510(k) clearance of its award winning TearLab Osmolarity System. The TearLab Osmolarity System is intended to measure the osmolarity of human tears to aid in the diagnosis of patients with signs or symptoms of Dry Eye Disease (DED), in conjunction with other methods of clinical evaluation. The 510(k) clearance allows the Company to immediately begin market activities in the U.S. to clinical facilities categorized as high or moderate complex under the Clinical Laboratory Improvement Act of 1988 (CLIA '88).

Drug news: Can-Fite CF101

Can-Fite BioPharma announces positive results for phase 2 study of dry eye drug
May 21, 2009
OSN SuperSite

PETACH TIKVA, Israel — Can-Fite BioPharma's phase 2 clinical trial of an investigational oral treatment for dry eye syndrome has met the primary efficacy endpoint of relieving signs and symptoms of related ocular surface inflammation, the company announced in a press release.

The drug, called CF101, targets A3 adenosine receptors on the surface of pathologic cells.

In the masked study, 80 patients with moderate to severe dry eye were randomly assigned to receive either 1 mg of oral CF101 or placebo monotherapy for 12 weeks. According to fluorescein staining measurements, patients who received CF101 experienced a statistically significant improvement in superficial punctate keratitis. In addition, the compound was safe and well-tolerated.

The investigators also found that patients who received oral CF101 demonstrated a decrease in IOP, suggesting that adenosine A3 agonists may show benefit for treating glaucoma, the release said.

Abstract: Cyclosporine

Surv Ophthalmol. 2009 May-Jun;54(3):321-38.
Topical ophthalmic cyclosporine: pharmacology and clinical uses.

Donnenfeld E, Pflugfelder SC.
Ophthalmic Consultants of Long Island and Connecticut, Rockville Centre, New York, USA.

Cyclosporine has been used successfully as a systemic immunomodulator for more than two decades, and numerous studies have investigated its mechanisms of action. In 2003 an ophthalmic formulation, cyclosporine 0.05% ophthalmic emulsion, was approved by the FDA to treat dry eye disease. Topical cyclosporine emulsion has also been investigated for treatment of other ocular surface disorders that may have an immune-based inflammatory component. In these trials, cyclosporine 0.05% ophthalmic emulsion has shown efficacy for management of posterior blepharitis, ocular rosacea, post-LASIK dry eye, contact lens intolerance, atopic keratoconjunctivitis, graft-versus-host disease, and herpetic stromal keratitis. As these disorders are often refractory to other available treatments, ophthalmic cyclosporine is a welcome nontoxic adjunct or replacement to potentially toxic topical or systemic immunosuppressive therapies.

Abstract: Unnamed artificial tear

Eye Contact Lens. 2009 May;35(3):149-55. Links
An investigation of the efficacy of a novel ocular lubricant.

Dumbleton K, Woods C, Fonn D.
Centre for Contact Lens Research, School of Optometry, University of Waterloo, Waterloo, Canada.

OBJECTIVE: To investigate the efficacy of a novel ocular lubricant compared with a commercially marketed ocular lubricant in a group of noncontact lens wearers currently using over-the-counter products for the management of symptoms of moderate to severe dry eye.

METHODS: This was a prospective, double-masked study that randomized 110 subjects in a ratio of 1:1 to receive a novel ocular lubricant (test group) or a marketed ocular lubricant (control group). Subjects were instructed to instill the lubricant eye drops at least three times daily. After enrollment, subjects were evaluated at baseline and at 7 and 30 days. They were also required to complete a series of home-based subjective questionnaires after 15 days. Main outcomes were subjective symptoms and objective clinical assessment at 7 and 30 days.

RESULTS: The test group had higher overall comfort ratings than the control group (P = 0.012). Seventy-one percent of the test group and 57% of the control group said the drops used "somewhat" or "definitely" improved ocular comfort; 62% of the test group had greater end-of-day comfort compared with 45% of the control group (P = 0.015). There were no between-group differences in visual acuity, tear quality or quantity, corneal staining, conjunctival staining, or bulbar and limbal conjunctival hyperemia.

CONCLUSIONS: The novel ocular lubricant offers equivalent or superior comfort compared with a marketed lubricant eye drop. Objective clinical outcomes were not statistically significantly different between the two groups.

Abstract: Dry eye, sjogrens

Cornea. 2009 Jun;28(5):493-7.
Evaluation of patients with dry eye for presence of underlying Sjögren syndrome.

Akpek EK, Klimava A, Thorne JE, Martin D, Lekhanont K, Ostrovsky A.
Ocular Surface Diseases and Dry Eye Clinic, Division of Cornea, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

PURPOSE: To evaluate the rate of Sjögren syndrome (SS) in a cohort of patients with dry eye syndrome.

METHODS: Medical records of patients with a primary diagnosis of dry eye syndrome (International Classification of Diseases [ICD] code 375.15 or 370.33) were reviewed retrospectively. Patients who had 2 or more visits to a single dry eye center during a 2-year period (January 2004 to January 2006) were considered.

RESULTS: Two hundred twenty patients with dry eye syndrome were identified. A total of 57 patients (25.9%) had an underlying rheumatic condition: 25 patients (11.4%) had rheumatoid arthritis and 24 (10.9%) had primary Sjögren syndrome (PSS). Majority of the patients with rheumatoid arthritis (96%) carried the diagnosis at the time of presentation. Of all patients with PSS, only 33.3% (8/24) carried the diagnosis at the time of presentation. Fifty percent (12/24) were diagnosed as a result of the initial evaluation. Among those, only 66.6% (8/12) tested SSA (anti-Ro antibodies) or SSB (anti-La antibodies) positive. One third of patients (4/12) tested only antinuclear antibody positive at a titer of <1/320 and required minor salivary gland biopsy for definitive diagnosis. Additional 16.7% (4/24), who were initially serologically negative, eventually underwent minor salivary gland biopsy and became diagnosed with SS.

CONCLUSIONS: PSS seems to be underdiagnosed in patients with dry eye syndrome and should be the focus of diagnostic evaluations. A minor salivary gland biopsy might be required for a definitive diagnosis in a significant proportion of the patients with SS.

Abstract: Omega 3s and dry eye

Graefes Arch Clin Exp Ophthalmol. 2009 May 5. [Epub ahead of print]
Efficacy of a 2-month dietary supplementation with polyunsaturated fatty acids in dry eye induced by scopolamine in a rat model.

Viau S, Maire MA, Pasquis B, Grégoire S, Acar N, Bron AM, Bretillon L, Creuzot-Garcher CP, Joffre C.
INRA, UMR1129 FLAVIC, Eye and Nutrition Research Group, Dijon, 21000, France.

BACKGROUND: This study was conducted to evaluate the efficacy of dietary n-6 and n-3 polyunsaturated fatty acids (PUFAs) in dry eye in a rat model.

METHODS: Female Lewis rats were fed with diets containing (1) gamma-linolenic acid (GLA), (2) eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), or (3) GLA + EPA + DHA, for 2 months before the induction of dry eye using a continuous delivery of scopolamine and during scopolamine treatment. Two, 10 and 28 days after dry-eye induction, clinical signs of corneal dryness were evaluated in vivo using fluorescein staining. MHC II expression and mucin rMuc5AC production in the conjunctival epithelium were evaluated by immunostaining. Lipids and prostaglandins (PGs) E(1) and E(2) were analysed from the exorbital lacrimal gland (LG).

RESULTS: Dietary PUFAs minimised the occurrence of corneal keratitis 28 days after induction of dry eye. The decrease in mucin production observed on the conjunctival epithelium was partially prevented by EPA + DHA supplementation after 2 days of scopolamine treatment, as well as by GLA and GLA + EPA + DHA diets after 10 days of treatment. The overexpression of MHC II in the conjunctival epithelium caused by dry eye induction was significantly reduced only with the GLA + EPA + DHA diet after 28 days of treatment. Dietary PUFAs were incorporated into phospholipids of the exorbital LG. Induction of dry eye was associated with a significant increase in PGE(1) and PGE(2) levels in the exorbital LG, which was inhibited by dietary EPA + DHA at 10 days (for PGE(2)) and 28 days (for PGE(1)).

CONCLUSIONS: Dietary GLA, EPA and DHA significantly interfered with lipid homeostasis in the exorbital LG and partially prevented the course of dry eye. In particular, our results demonstrate the efficacy of the combination of n-6 and n-3 PUFAs.

New drug news: Resolvyx RX-10045

Resolvyx Presents Data Demonstrating Potential for Resolvin Therapeutics to Treat Corneal and Retinal Eye Diseases at ARVO 2009 Meeting

In an oral presentation, Resolvyx and its collaborators reported new data on the company’s lead development candidate, RX-10045. RX-10045 is currently in development to treat dry eye, a disease that affects more than 30 million people in the US. This study showed that RX-10045 promotes tissue repair in human corneal epithelial cells in vitro in a dose dependent manner. This finding may expand the potential benefits of the compound beyond its previously reported anti-inflammatory effects. RX-10045 is currently being evaluated in a randomized, controlled clinical trial in patients with chronic dry eye. The trial is fully enrolled and the last patient is anticipated to complete dosing in May 2009.

Abstract: In vivo confocal microscopy in TEN and SJS

Cornea. 2009 May;28(4):401-7.
In vivo confocal microscopic evaluation of corneal changes in chronic Stevens-Johnson syndrome and toxic epidermal necrolysis.

Vera LS, Gueudry J, Delcampe A, Roujeau JC, Brasseur G, Muraine M.
Department of Ophthalmology, Charles Nicolle Hospital, University of Rouen, Rouen, France.

PURPOSE: To describe corneal changes visible on in vivo confocal microscopy, in patients with debilitating ocular sequelae because of toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS).

PATIENTS AND METHODS: Forty-one eyes of 25 consecutive patients suffering from chronic TEN or SJS were studied using in vivo confocal microscopy.

RESULTS: Severe dry eye syndrome with no associated limbal stem cell deficiency (25 eyes, 16 patients, 61%) was the most frequent clinical pattern. Limbal stem cell deficiency was noted in 16 eyes (12 patients, 39%). Three patients had asymmetric disease. Confocal microscopy showed a consistent change in the superficial epithelial cells in both clinical presentations. Patients with dry eye syndrome had frequent pathological nerve damages, and the presence of dendritic cells was prevalent (65%). Inflammatory cells were observed in a large number in 4 of the 12 patients presenting neovascularization of the cornea.

CONCLUSIONS: The corneas of patients with chronic ocular sequelae linked to SJS and TEN present a number of abnormalities. In vivo confocal microscopy is a potentially useful tool for therapeutic indications and for follow-up of the debilitating chronic ocular problems associated with these diseases.

Abstract: Coal dust exposure and dry eye

Ocul Immunol Inflamm. 2009 Mar-Apr;17(2):76-82.
Coal dust contiguity-induced changes in the concentration of TNF-alpha and NF-kappa B p65 on the ocular surface.

Sun Z, Hong J, Liu Z, Jin X, Gu C.
Department of Ophthalmology, First Affiliated Hospital of China Medical University, Shenyang, China.

To observe the influence of coal dust on ocular surface of coal miners and rabbits with coal dust contiguity on expression TNF-alpha and NF-kappa Bp65 and dry eye occurrence. Tear production, BUT and lysozyme decreased for coal miners and rabbits with coal dust contiguity. Expression TNF-alpha and NF-kappa Bp65 in ocular surface were determined. Results showed tear production, BUT and lysozyme decreased for coal miners and rabbits with coal dust contiguity. Coal dust exposure was linked to development of xerophthalmia, and induced a higher expression of NF-kappa B p65 and TNF-alpha perhaps as a mechanism to resist coal dust ocular surface injury.

Abstract: Fgf10 mutation, atrophy of the Harderian gland

Invest Ophthalmol Vis Sci. 2009 Apr 30. [Epub ahead of print]Links
A new Fgf10 mutation in the mouse leads to atrophy of the Harderian gland and slit-eye phenotype in heterozygotes: A novel model for dry-eye disease?

Puk O, Esposito I, Söker T, Löster J, Budde B, Nürnberg P, Michel-Soewarto D, Fuchs H, Wolf E, Hrabé de Angelis M, Graw J.
Helmholtz Center Munich, Neuherberg, Germany.

Purpose: Aim of the present study is the molecular and phenotypical characterization of a new slit-eye phenotype in the mouse.

Methods: Genome-wide linkage analysis was performed and a candidate gene has been sequenced. Eyes of the mutants were described morphologically, histologically, and by in-situ hybridization. To allow morphological and functional studies of the retina, mutants have been out-crossed to C57BL/6.

Results: Within an ongoing ENU mutagenesis screen with C3HeB/FeJ mice, we identified a new mutant (referred to as Aey17) showing a slit-eye phenotype in heterozygotes; homozygous mutants are not viable because of major developmental defects. We mapped this mutation to the distal end of mouse chromosome 13 suggesting Fgf10 (encoding the fibroblast growth factor 10) as a candidate gene. We identified an A-->G transition in the penultimate base of the first intron of Fgf10 leading to aberrant splicing with an additional 49 bp in exon 2 and to a frame shift with a premature stop codon after 54 new amino acids. The histological analysis of the major ocular tissues (cornea, lens, retina) did not reveal major alterations as compared to the wild type, but the size of the Harderian gland was remarkably reduced in heterozygotes. Although Fgf10 is expressed in the developing retina, neither eletroretinography nor the virtual drum indicated any abnormalities in heterozygous mutants; the overall eye size was identical in wild types and heterozygotes.

Conclusions: The mutation in the Fgf10 gene leads a dominant slit-eye phenotype caused by an atrophy of the Harderian gland.

Abstract: Mucin in non Sjogrens dry eye

Invest Ophthalmol Vis Sci. 2009 Apr 30. [Epub ahead of print]
Mucin-type O-glycans in Tears of Normal Subjects and Patients with Non-Sjogrens Dry Eye.

Guzman-Aranguez A, Mantelli F, Argueso P.
Schepens Eye Research Institute, Boston, Massachusetts, United States; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.

Purpose. O-linked carbohydrates (O-glycans) contribute to the hydrophilic character of mucins in mucosal tissues. This study aimed to identify the repertoire of O-glycans in the tear film, and the glycosyltransferases associated with their biosynthesis, in normal subjects and patients with non-Sjögren's dry eye.

Methods. Human tear fluid was collected from the inferior conjunctival fornix. O-glycans were released by hydrazinolysis, labeled with 2-aminobenzamide, and analyzed by fluorometric, high-performance liquid chromatography (HPLC) coupled with exoglycosidase digestions. O-glycan structures identified in tears were related to potential biosynthetic pathways in human conjunctival epithelium using a glycogene microarray database. Lectin-binding analyses were performed using agglutinins from Arachis hypogaea, Maackia amurensis, and Sambucus nigra.

Results. The O-glycan profile of human tears consisted primarily of core 1 (Galbeta1-3GalNAcalpha1-Ser/Thr)-based structures. Mono-sialyl O-glycans represented approximately 66% of the glycan pool, being alpha2-6-sialyl core 1 the predominant O-glycan structure in human tears (48%). Four families of glycosyltranferases potentially related to the biosynthesis of these structures were identified in human conjunctiva. These included thirteen polypeptide-GalNAc-transferases (GALNT), the core 1 beta-3-galactosyltransferase (T-synthase), three alpha2-6-sialyltransferases (ST6GalNAc), and two alpha2-3-sialyltransferases (ST3Gal). No significant differences in total amount of O-glycans were detected between tears of normal subjects and dry eye patients, by HPLC and lectin blot. Likewise, no differences in glycosyltransferase expression were found by glycogene microarray.

Conclusions. This study identifies the most common mucin-type O-glycans in human tears and their expected biosynthetic pathways in ocular surface epithelia. Patients with non-Sjögren's dry eye show no alterations in composition and amount of O-glycans in the tear fluid.

Abstract: Nerve Growth Factor (NGF)

Invest Ophthalmol Vis Sci. 2009 Apr 30. [Epub ahead of print]
Nerve Growth Factor promotes in vitro human conjunctival epithelial cells differentiation and mucin gene expression.

Lambiase A, Micera A, Pellegrini G, Merlo D, Rama P, De Luca M, Bonini S, Bonini S.
Ophthalmology, University of Rome Campus Bio-Medico, Rome, Italy.

Purpose. Mucins released into the tear film are crucial to maintaining a healthy ocular surface. Alterations in goblet cell numbers and mucin secretion are peculiar of chronic ocular surface inflammatory diseases. Nerve growth factor (NGF) plays a crucial role in healing and inflammation of the ocular surface. The aim of this study was to evaluate in vitro the effect of NGF on conjunctival goblet cell differentiation and mucin production and secretion.

Methods. Human conjunctival epithelial cells were exposed to increasing NGF concentrations (1-250ng/mL) and analysed to quantify cell growth (MTT/Ki67/BrdU), goblet cell differentiation (PAS/MUC5AC confocal staining), and mucin mRNA expression (Real-Time PCR). Secreted and cellular MUC5AC were also analyzed by sandwich-ELISA and FACS, respectively. To confirm the biological effects of NGF, the same evaluations were performed on primary cultures, and changes in markers of stemness (p63) and commitment (14-3-3sigma) were also investigated.

Results. In cell cultures NGF induced a dose-dependent increase of goblet cell numbers, MUC5AC production, storage and release. Additionally, in primary cultures NGF induced an increase of abortive colonies and 14-3-3sigma protein, and a decrease of p63 mRNA and protein, suggesting a differentiating effect of NGF on human conjunctival epithelium.

Conclusions. Our findings show that NGF might play a role in the complex mechanism leading to conjunctival epithelium differentiation and mucin secretion. In addition to the known roles of NGF in promoting ocular surface healing and sensitivity, its effects on conjunctival goblet cells support a rationale to investigate the therapeutic effectiveness of NGF in dry eye disease.

Abstract: Scraping cytology score system

Curr Eye Res. 2009 May;34(5):340-6.
A novel scraping cytology score system (SCSS) grades inflammation in dry eye patients.

Versura P, Profazio V, Fresina M, Campos EC.
Ophthalmology Unit, Alma Mater Studiorum University of Bologna, Bologna, Italy.

PURPOSE: We propose a conjunctival Scraping Cytology Scoring System (SCSS) as a reliable method to diagnose and score ocular surface inflammation in dry eye.

METHODS: Twenty normal subjects and 46 patients with dry eye of various severities were included in the study. Clinical signs were scored 1-4; an Ocular Surface Disease Index (OSDI) questionnaire was used to grade subjective symptoms. Concentrations of serum albumin and interleukin-6 (IL-6) in tears were evaluated. Scraped conjunctival cytology samples were processed and examined with light microscopy. The number of inflammatory cells was staged and sub-scores were assigned. SCSS resulted from their sum and ranged from 0-12. Statistical evaluation was performed by applying the unpaired Student's t-test and the Spearman's correlation test (significance p < 0.05). SCSS was also analyzed for sensitivity, specificity, ROC curves, likelihood ratio LR+, positive (PPV) predictive value.

RESULTS: SCSS was positively correlated to clinical sign score, OSDI score, exudated serum albumin, and IL-6 in either control (Spearman's correlation test always p < 0.05) and in dry eye patients (respectively, p < 0.0001, p < 0.01, p < 0.05, and p < 0.0001). SCSS >or= 4 was selected as the cut-off value for moderate dry eye (LR+ 10,9; PPV 22,5), SCSS >or= 9 was selected as the cut-off value for severe dry eye (LR+ 15,6; PPV 26,2).

CONCLUSIONS: SCSS can be applied in any trained laboratory. It is correlated with clinical signs and symptoms, and it shows a diagnostic performance to grade inflammation in dry eye, comparable to more expensive cytokine assay.

Abstract: Dry eye in 2008

Curr Opin Ophthalmol. 2009 Apr 24. [Epub ahead of print]
Dry eye in 2008.

Abelson MB, Ousler GW 3rd, Maffei C.
aOra, Andover, USA bSchepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA.

PURPOSE OF REVIEW: Although researchers continue to investigate the multifarious etiologic, anatomical, physiological, and pathological factors of dry eye, successful treatment remains a challenge. RECENT FINDINGS: Dry eye prevalence is substantial across populations and the term 'dry eye' is used to describe numerous causes and varied pathophysiologies. Advanced study of the physiological aspects of the ocular anatomy (e.g. cornea and conjunctiva, tear film, eyelids) allows improved understanding of the mechanisms involved in dry eye and the impact of different causes on these entities. Sophisticated diagnostics are being developed to efficiently identify dry eye. Management options include a variety of novel agents in the pipeline. SUMMARY: The development of improved etiological understanding and diagnostics for dry eye, as well as emerging therapeutics, will likely allow targeted therapy in the future.

Abstract: Accutane and dry eye

Eur J Ophthalmol. 2009 Mar-Apr;19(2):196-200.
Comparison of dose-related ocular side effects during systemic isotretinoin administration.

Cumurcu T, Sezer E, Kilic R, Bulut Y.
Department of Ophthalmology, Gaziosmanpasa University School of Medicine, Tokat - Turkey.

PURPOSE: To compare the effects of high- (Group 1) and low-dose (Group 2) isotretinoin treatments for acne vulgaris on lacrimal functions and other ocular complications.

METHODS: Twenty-six patients receiving high-dose (>0.5 mg/kg per day) systemic isotretinoin treatment and 25 patients treated with low-dose systemic isotretinoin (<0.5 mg/kg per day) underwent complete ophthalmologic assessment of both eyes before treatment, at days 45 and 90 of treatment, and 1 month after the completion of treatment, together with a microbiologic evaluation of conjunctival flora, tear film break-up time (BUT), and anesthetized Schirmer test of the right eye of each patient.

RESULTS: When the results of the anesthetized Schirmer test for Groups 1 and 2 were compared (pretreatment, days 45 and 90 of treatment, and 1 month after treatment), there was no statistically significant difference between the groups (p > 0.05). Although BUT did not differ significantly between the two groups before treatment (p >0.05), there was a statistically significant decrease in BUT in Group 1 when compared with Group 2 at days 45 and 90 of treatment (p <0.05). One month after the completion of treatment, there was no difference in BUT between the two groups (p >0.05). No difference in Staphylococcus aureus colonization was detected between the two groups at days 45 and 90 of treatment (p >0.05).

CONCLUSIONS: During systemic isotretinoin treatment, eye dryness was related to the dose used, at least during the period of treatment. Conversely, the rate of conjunctival S aureus colonization was unrelated to the dose of isotretinoin.

Abstract: Antioxidants and dry eye

Very interesting... I don't think I've seen anything like this before.

Eur J Ophthalmol. 2009 May-Jun;19(3):337-42.
Antioxidants intake and dry eye syndrome: a crossover, placebo-controlled, randomized trial.

Drouault-Holowacz S, Bieuvelet S, Burckel A, Rigal D, Dubray C, Lichon JL, Bringer P, Pilon F, Chiambaretta F.
PiLeJe, Paris - France.

PURPOSE: To assess whether an orally administered antioxidant dietary supplement could improve the objective clinical signs and alleviate the subjective symptoms of dry eye syndrome.

METHODS: Twenty-four subjects diagnosed with dry eye syndrome were randomized in a crossover, double-blind, controlled, randomized study to receive a placebo or an antioxidants combination (Oxybiane) for 12 weeks. In all subjects, break-up time (BUT) test, Schirmer test, ocular symptoms (sore eyes, burning, itching, sensation of foreign object in the eye, photophobia, sticky eyes, and redness), visual comfort, and general well-being were evaluated weekly.

RESULTS: After 12 weeks of supplementation with Oxybiane, both the BUT scores (27.3%+/-8.4% with Oxybiane versus 3.61%+/-4.3% with the placebo, p=0.017) and the Schirmer scores (26.9%+/-14.2% with Oxybiane versus -4.7%+/-3.4% with the placebo, p=0.037) were significantly increased. A significantly improvement was also observed considering subjective clinical symptoms such as burning (p=0.031), itching (p=0.027), sensation of foreign body in eye (p=0.030), and redness (p=0.043).

CONCLUSIONS. Supplementation with oral antioxidants can improve both tear stability and quantity but also subjective clinical signs.

Abstract: How long it takes for a healthy MG to refill its tank

Cornea. 2009 Apr;28(3):293-7.
Recovery time of an optimally secreting meibomian gland.

Blackie CA, Korb DR.
Korb Associates, Boston, MA, USA.

PURPOSE: To investigate the times for an optimally secreting meibomian gland (OSMG) to be drained of available liquid secretion, to recover with expressible liquid secretion, and then to be redrained.

METHODS: Twelve subjects with no dry eye symptoms and mean age 21.3 +/- 1.9 years were recruited. Lipid layer thickness and tear breakup time were measured. The number of meibomian glands yielding liquid secretion for both right and left lower eyelids was counted using a meibomian gland diagnostic expression device. A single OSMG in the central third of the right and left lower eyelids was marked. A second diagnostic expression device was used to drain the liquid secretion from each marked gland. The times to drain the gland of available liquid secretion, for the drained gland to recover, and then be redrained were measured.

RESULTS: The mean lipid layer thickness and tear breakup time were 98 +/- 44 nm and 12.4 +/- 1.9 seconds. The mean time to drain the marked meibomian gland was 12.1 +/- 3.5 seconds, range: 8-20 seconds; for partial recovery of the drained meibomian gland was 2.17 +/- 0.49 hours, range: 1.5-2.5 hours; and to redrain the meibomian gland after recovery was 5.54 +/- 1.9 seconds, range: 5-10 seconds.

CONCLUSIONS: This report shows that (1) a single OSMG can be drained of its liquid secretion in 8-20 seconds upon application of a constant force of 1 g/mm, and (2) a partial recovery occurs after approximately 2 hours, evidenced by detectable liquid secretion which then expressed for only half of the original time.

Abstract: Blepharitis survey

Ocul Surf. 2009 Apr;7(2 Suppl):S1-S14.
Blepharitis in the United States 2009: a survey-based perspective on prevalence and treatment.

Lemp MA, Nichols KK.
Department of Ophthalmology, George Washington University School of Medicine, Washington, DC, USA.

ABSTRACT Like dry eye disease 15 years ago, blepharitis today is a poorly defined condition about which there is considerable misunderstanding. For a variety of reasons, there is little good data on either the prevalence of blepharitis or how eyecare practitioners currently treat it. The work reported herein consists of two recent studies: a telephone survey of a representative sample of the adult US population (n = 5,000) whose purpose was to discover the frequency of common ocular surface symptoms associated with blepharitis; and a study that queried a selected group of ophthalmologists (n = 120) and a similarly selected group of optometrists (n = 84) about the frequency of blepharitis in their practices, the existence comorbid conditions, and their management strategies. This data suggests that blepharitis symptoms are very common in the US population, with younger individuals reporting more, and more frequent, symptoms than older people, contrary to clinical dogma. Ophthalmologists and optometrists report that blepharitis is commonly seen in clinical practice in 37% and 47% of their patients, respectively, and it is widely agreed that meibomian gland dysfunction (MGD) is the most common cause of evaporative dry eye disease. In addition, management paradigms are shifting away from more traditional management with antibiotic ointment and warm compress therapy to prescription therapy for anterior and posterior blepharitis.

Abstract: Development of hybrid dry eye over time

Ocul Surf. 2009 Apr;7(2):78-92.
Predicted phenotypes of dry eye: proposed consequences of its natural history.

Bron AJ, Yokoi N, Gafney E, Tiffany JM.
Nuffield Laboratory of Ophthalmology, University of Oxford, UK.

This paper reviews current knowledge of the pathophysiology of dry eye and predicts that the clinical picture in late disease differs in both severity and quality from that in early disease. It is hypothesized that hybrid forms evolve, in which aqueous-deficient dry eye (ADDE) takes on features of evaporative dry eye (EDE) and vice versa. As a consequence, early and late forms may require different diagnostic criteria and respond to different therapeutic regimes. Tear hyperosmolarity plays a key role in the damage mechanism of dry eye, and ADDE is recognized to be a low-volume, hyperosmolar state. As ADDE advances, a progressive decrease in lacrimal secretion occurs, exacerbated by loss of the corneal reflex. This causes a decrease in tear volume, thinning of the aqueous tear film, and retarded spreading of the tear film lipid layer. The latter is hypothesized to cause an increase in evaporative water loss and an added evaporative component to the dry eye. Thus, in advanced disease, the hybrid state would be an organic ADDE, accompanied by a functional EDE in the absence of meibomian gland dysfunction. This functional EDE would respond to agents that expand the tear volume, restore corneal sensitivity, or provide an artificial tear film lipid layer.

Abstract: Impression cytology advances

Ocul Surf. 2009 Apr;7(2):93-110.
Impression cytology: recent advances and applications in dry eye disease.

Lopin E, Deveney T, Asbell PA.
Department of Ophthalmology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Impression cytology (IC) allows cells to be harvested from the ocular surface noninvasively. Superficial layers of the epithelium are removed by application of cellulose acetate filters or Biopore membranes, and the cells can be subsequently analyzed by various methods, depending on the objective of the investigation or pathology involved. IC techniques are easily learned, can be performed in an outpatient setting, and cause virtually no discomfort to the patient. IC facilitates the diagnosis of ocular surface disorders, including, among others, keratoconjunctivitis sicca, ocular surface squamous neoplasia, and ocular surface infections. During the past decade, IC has been used increasingly to assist in diagnosis of ocular surface disease, improve our understanding of the pathophysiology of ocular surface disease, and provide biomarkers to be used as outcome measures in clinical trials. Dry eye disease is one area in which IC has contributed to significant advances.

Abstract: Tacrolimus safety

Klin Monatsbl Augenheilkd. 2009 Apr;226(4):234-6. Epub 2009 Apr 21.
[Safety of treatment with tacrolimus ointment for anterior segment inflammatory diseases]

[Article in German]

Wyrsch S, Thiel MA, Becht CN.
Augenklinik, Luzerner Kantonsspital, Luzern, Schweiz.

BACKGROUND: The off-label use of topical tacrolimus (Protopic) for inflammatory external eye diseases is gaining popularity. However, there are no reports on the safety profile of this new treatment option.

PATIENTS AND METHODS: We treated six patients with different inflammatory eye diseases with topical tacrolimus (Protopic 0.03 %) as off-label use in addition to the conventional anti-inflammatory treatment. Patients were interviewed for side effects and serum drug concentrations were measured under steady state conditions one hour after topical application of tacrolimus ointment.

RESULTS: Two patients reported a slight burning sensation immediately after application, in one patient we found a slight worsening of the dry eye problems. No patient abandoned the treatment due to side effects. Serum drug concentrations remained below the analytical threshold in all cases (< 1.5 ng/ml).

CONCLUSIONS: Tacrolimus for the topical treatment of anterior segment inflammatory eye diseases is well tolerated without detectable systemic drug resorption.

Abstract: Neural regulation of lacrimal gland secretion

Prog Retin Eye Res. 2009 May;28(3):155-77. Epub 2009 Apr 17.
Neural regulation of lacrimal gland secretory processes: relevance in dry eye diseases.

Dartt DA.
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.

The lacrimal gland is the major contributor to the aqueous layer of the tear film which consists of water, electrolytes and proteins. The amount and composition of this layer is critical for the health, maintenance, and protection of the cells of the cornea and conjunctiva (the ocular surface). Small changes in the concentration of tear electrolytes have been correlated with dry eye syndrome. While the mechanisms of secretion of water, electrolytes and proteins from the lacrimal gland differ, all three are under tight neural control. This allows for a rapid response to meet the needs of the cells of the ocular surface in response to environmental conditions. The neural response consists of the activation of the afferent sensory nerves in the cornea and conjunctiva to stimulate efferent parasympathetic and sympathetic nerves that innervate the lacrimal gland. Neurotransmitters are released from the stimulated parasympathetic and sympathetic nerves that cause secretion of water, electrolytes, and proteins from the lacrimal gland and onto the ocular surface. This review focuses on the neural regulation of lacrimal gland secretion under normal and dry eye conditions.

Abstract: Demodex bleph - diagnosis, treatment with pilocarpine gel

Turkiye Parazitol Derg. 2009;33(1):32-6.
Diagnosis and treatment of demodectic blepharitis.

Inceboz T, Yaman A, Over L, Ozturk AT, Akisu C.
Dokuz Eylul University, School of Medicine, Department of Parasitology Inciralti, Izmir, Turkey.

The aim of this study was to investigate the prevalence of Demodex spp. in the eyelash follicles obtained from patients seen in our ophthalmology clinic, to define the symptoms of this infestation, and to examine the effectivity of the therapy. This study was conducted in Department of Ophthalmology and Parasitology, Dokuz Eylül University, School of Medicine. Our study included 82 cases that were seen in the Ophthalmology Department and Parasitology Department for various reasons. We have also observed that the presence of Demodex spp. provokes itching and redness in the eyes and that using baby shampoo for cleansing the face reduces the risk of infestation. After the treatment of 32 cases with 4% pilocarpin HCl gel, we achieved a total cure in 12 eyes (37.5%), partial improvement in 13 eyes (40.6%), (making a total of 25 eyes, 78.1%). The treatment was unsuccessful in 7 eyes (21.9%). In patients with Demodex spp. cleansing with baby shampoo and treating by pilocarpin gel may be used in treatment.

Abstract: Cholesteryl esters & meibum

J Lipid Res. 2009 Mar;50(3):501-13. Epub 2008 Oct 4. Cholesteryl esters as a depot for very long chain fatty acids in human meibum.

Butovich IA.
Department of Ophthalmology and Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Human meibomian gland secretions (also known as meibum) were analyzed for the presence of cholesteryl esters (Chl-E) using HPLC in combination with atmospheric pressure chemical ionization mass spectrometry. A special procedure based on detection of the in-source generated ion m/z 369 was developed to monitor all Chl-E simultaneously. The structures of the detected compounds were studied using in-source and postsource fragmentation of the precursor (M+H)(+) ions. In concordance with previous studies, Chl-E were found in all of the tested samples and comprised approximately 31% of the entire lipid pool (w/w, dry weight). There were at least 20 different saturated and unsaturated Chl-E species observed, whose fatty acid residues ranged from C18 to C34. Monounsaturated fatty acids were the most visible components of the Chl-E pool. The eleven most prominent compounds were: C20:0-, C22:1-, C22:0-, C24:1-, C24:0, C25:0-, C26:1-, C26:0-, C28:1-, C28:0-, and C30:1-Chl-E. Other Chl-containing compounds were detected but not identified at the time. Therefore, Chl-E are a depot for very long chain saturated and monounsaturated fatty acids in human meibum.

Abstract: Systane

J Ocul Pharmacol Ther. 2009 Jun;25(3):271-8.
Protecting the ocular surface and improving the quality of life of dry eye patients: a study of the efficacy of an HP-guar containing ocular lubricant in a population of dry eye patients.

Rolando M, Autori S, Badino F, Barabino S.
Center for Clinical and Experimental Research of Ocular Surface Diseases, Department of Neurosciences, Ophthalmology, and Genetics, University of Genova, Genova, Italy.

PURPOSE: The aim of this study was to evaluate the efficacy of a non-Newtonian tear substitute containing 0.4% polyethylene glycol 400 (PEG 400) and 0.3% propylene glycol in an 0.18% hydroxypropyl-guar (HPG) containing vehicle (Systane Lubricant Eye Drops; Alcon) in reducing the signs and symptoms of dry eye, as well as its effect on ocular protection.

METHODS: Twenty patients with moderate to severe dry eye were enrolled in a 28-day prospective, randomized, controlled study. Subjects self-administered the HPG containing ocular lubricant four times daily (QID) over the study duration. After 28 days, the effect of the HPG containing ocular lubricant was evaluated by means of the Global Staining Score (a measure of the corneal and conjunctival staining), inter-blink tear film stability, Ocular Protection Index (OPI), and subjective symptoms.

RESULTS: The HPG containing ocular lubricant produced statistically significant improvements compared with baseline in dry eye symptoms (P < 0.0001 at Days 7, 14, and 28); in ocular surface staining, as measured by a reduction in the Global Staining Score (P < 0.0001 at Days 7, 14, and 28); and in the OPI (P = 0.0025 at Day 14 and P = 0.0067 at Day 28).

CONCLUSIONS: The improvements in ocular surface staining and dry eye symptoms with the HPG containing ocular lubricant -- evident as early as the first follow-up visit (Day 7) and continued throughout the 28 days of the study with a concurrent, increase in OPI to a level greater than unity -- indicate that this preparation is a fast-acting, long-lasting, and effective treatment for dry eye. In concurrence with the results from previously published clinical studies, the HPG containing ocular lubricant has shown efficacy in alleviating the signs and symptoms of dry eye as well as affording improved ocular surface protection.

Abstract: Case study of plug complication

J Laryngol Otol. 2009 Jan;123(1):129-30. Epub 2008 Jun 9.
Common canalicular obstruction secondary to the use of Herrick lacrimal plugs, requiring endoscopic dacryocystorhinostomy.

Dolan L, MacEwen CJ, White P.
Department of Ophthalmology, Ninewells Hospital and Medical School, Dundee, Scotland, UK.

We report the case of a 40-year-old woman who developed left common canalicular obstruction following insertion of a lacrimal plug. The patient underwent endoscopic dacryocystorhinostomy, revealing the presence of the lacrimal plug occluding the common canaliculus. The patient experienced symptomatic improvement of her epiphora post-operatively.

Abstract: Treating botox-induced dry eye with C-NAC

Arch Ophthalmol. 2009 Apr;127(4):525-32.
Effect of chitosan-N-acetylcysteine conjugate in a mouse model of botulinum toxin B-induced dry eye.

Hongyok T, Chae JJ, Shin YJ, Na D, Li L, Chuck RS.
Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland 21287, USA.

OBJECTIVE: To evaluate the effect of a thiolated polymer lubricant, chitosan-N-acetylcysteine conjugate (C-NAC), in a mouse model of dry eye.

METHODS: Eye drops containing 0.5% C-NAC, 0.3% C-NAC, a vehicle (control group), artificial tears, or fluorometholone were applied in a masked fashion in a mouse model of induced dry eye from 3 days to 4 weeks after botulinum toxin B injection. Corneal fluorescein staining was periodically recorded. Real-time reverse transcriptase-polymerase chain reaction and immunofluorescence staining were performed at the end of the study to evaluate inflammatory cytokine expressions.

RESULTS: Mice treated with C-NAC, 0.5%, and fluorometholone showed a downward trend that was not statistically significant in corneal staining compared with the other groups. Chitosan-NAC formulations, fluorometholone, and artificial tears significantly decreased IL-1beta (interleukin 1beta), IL-10, IL-12alpha, and tumor necrosis factor alpha expression in ocular surface tissues.

CONCLUSIONS: The botulinum toxin B-induced dry eye mouse model is potentially useful in evaluating new dry eye treatment. Evaluation of important molecular biomarkers suggests that C-NAC may impart some protective ocular surface properties. However, clinical data did not indicate statistically significant improvement of tear production and corneal staining in any of the groups tested.

CLINICAL RELEVANCE: Topically applied C-NAC might protect the ocular surface in dry eye syndrome, as evidenced by decreased inflammatory cytokine expression.

Abstract: Immune profile of squamous metaplasia in autoimmune dry eye

Mol Vis. 2009;15:563-76. Epub 2009 Mar 23. Immune profile of squamous metaplasia development in autoimmune regulator-deficient dry eye.

Chen YT, Li S, Nikulina K, Porco T, Gallup M, McNamara N.
University of California, San Francisco, Francis I. Proctor Foundation, San Francisco, CA 94143, USA.

PURPOSE: Squamous metaplasia of the ocular surface epithelium in severe Sjögren syndrome (SS) dry eye has been implicated to be associated with chronic engagement of immune-mediated inflammation. While the detailed immunopathological mechanism underlying keratinization of the ocular muco-epithelium in this setting remains unclear, mice deficient in the autoimmune regulator gene (Aire) demonstrate SS-like pathological changes in the exocrine organs and ocular surface including squamous metaplasia. Using this murine model, we sought to determine the specific immune events that predict squamous metaplasia of the cornea in Aire deficiency.

METHODS: Lissamine green staining, goblet cell density, and corneal small proline-rich protein 1B (SPRR1B) were compared in Aire-sufficient and -deficient mice at 4, 8, and 16 weeks of age. Corneal, limbal and conjunctival infiltration of CD4(+) and CD8(+) T cells as well as CD11c(+) and MHC class II (I-A(d+)) dendritic cells (DCs) were examined at the same time points. Ordinary least squares regression was used to model SPRR1B's relationship with lissamine green staining, goblet cell density, and immune cell infiltration.

RESULTS: Lissamine green staining was present in Aire-deficient mice by four weeks of age and increased over time. Compared to Aire-sufficient controls, conjunctival goblet cell density (GCD) decreased and corneal SPRR1B increased in Aire-deficient mice with significant differences noted at both 8 and 16 weeks. Immune-mediated CD4(+) T cell infiltration of the conjunctiva and limbus peaked at eight weeks and then decreased. In contrast, corneal T cell infiltration continued to increase over time, reaching a maximum cell number at 16 weeks. CD11c(+) myeloid-derived DCs were found in the conjunctiva and limbus at all time points. As the mice aged, there was a notable increase in corneal CD11c(+) cell counts. Interestingly, the dynamic of activated MHC class II(+) DCs was nearly identical to that of CD4(+) T cells, peaking first in the limbus at eight weeks with maximum infiltration of the cornea by 16 weeks. Regression analysis showed that squamous metaplasia biomarker, SPRR1B, is strongly related to the lissamine green staining of the ocular surface. Corneal infiltration of activated DCs was most prognostic of corneal SPRR1B expression while the presence of precursor DCs, activated DCs, and CD4(+) T cells in the limbus were also significant predictors of SPRR1B.

CONCLUSIONS: Aire-deficient mice represent a useful model to study Sjögren-like autoimmune-mediated ocular surface disease. Results of the current study suggest that squamous cell precursor protein, SPRR1B, provides an important readout to evaluate ocular surface damage and specific events related to immune-mediated inflammation. Results also define an appropriate time frame for interventional studies to develop more effective therapies for keratinizing ocular surface disease.

Abstract: Trace elements and blepharitis

Cont Lens Anterior Eye. 2009 Jun;32(3):120-2. Epub 2009 Apr 7.
Trace elements and blepharitis.

Yülek F, Cakmak HB, Simşek S, Serkant U, Kösebalaban S.
SB Atatürk Eğitim ve Araştirma Hastanesi, Ankara, Turkey.

INTRODUCTION: Investigating the relationship between the serum levels of zinc and copper with blepharitis.

METHODS: Twenty seven patients with blepharitis and 24 control group patients were evaluated for Schirmer, fluorescein break up time (FBUT) scores and serum levels of zinc and copper. Symptoms and clinical examination scores of blepharitis patients were also assessed.

RESULTS: The serum level of zinc (65.78+/-15.51 in patients with blepharitis and 65.71+/-10.43 in patients without blepharitis, normal values in the laboratory: 70-127 microg/dl) and copper (67.17+/-22.24 in patients with blepharitis and 69.35+/-14.44 in patients without blepharitis, normal values in the laboratory: 70-150 microg/dl) were not different between the two groups. The symptom and clinical examination scores of blephraritis patients were not correlated with the serum levels of either zinc or copper.

DiSCUSSiON: The zinc and copper levels in serum do not seem to be related to blepharitis. Their tear levels and sensory status of cornea should also be evaluated to better evaluate a possible relation.

Abstract: Trehalose (experimental drug)

Exp Eye Res. 2009 Apr 2. [Epub ahead of print]
Trehalose protects against ocular surface disorders in experimental murine dry eye through suppression of apoptosis.

Chen W, Zhang X, Liu M, Zhang J, Ye Y, Lin Y, Luyckx J, Qu J.
School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical College, 270 Xue Yuan West Road, Wenzhou, Zhejiang 325027, China.

The disaccharide trehalose is a key element involved in anhydrobiosis (the capability of surviving almost complete dehydration) in many organisms. Its presence also confers resistance to desiccation and high osmolarity in bacterial and human cells by protecting proteins and membranes from denaturation. The present study used a novel murine dry eye model induced by controlled low-humidity air velocity to determine whether topically applied trehalose could heal ocular surface epithelial disorders caused by ocular surface desiccation. In addition, the efficacy of 87.6 mM trehalose eyedrops was compared with that of 20% serum, the efficacy of which has been well documented. Mice ocular surface epithelial disorders were induced by exposure of murine eyes to continuous controlled low-humidity air velocity in an intelligently controlled environmental system (ICES) for 21 days, which accelerated the tear evaporation. The mice were then randomized into three groups: the control group received PBS (0.01M) treatment; a second group received 87.6 mM trehalose eyedrops treatment; and the third group received mice serum eyedrops treatment. Each treatment was administered as a 10 mul dose every 6 h for 14 days. The resultant changes in corneal barrier function and histopathologic examination of cornea and conjunctiva were analyzed and the level of apoptosis on the ocular surface was assessed using active caspase-3. After 14 days of treatment, the corneal fluorescein staining area, the ruffling and desquamating cells on the apical corneal epithelium, as well as the apoptotic cells on ocular surface epithelium had significantly reduced in eyes treated with trehalose compared with those treated with serum and PBS. In contrast, after 14 days of treatment, improvements in the thickness of the corneal epithelium, the squamous metaplasia in conjunctival epithelium and the number of goblet cells of the conjunctiva were less marked in eyes treated with trehalose compared with serum. These results demonstrated that trehalose could improve the appearance of ocular surface epithelial disorders due to desiccation through suppression of apoptosis. Trehalose produces some of the same responses as serum upon topical application and can maintain corneal health.

Newsblurb (UK): Ophthalmologists unaware of preservative-free glaucoma drugs

Glaucoma Survey: Half Unaware of Preservative-Free Beta-Blocker, Ophthalmologists Cite Benefits of Preservative-Free Medications on Ocular Comfort and Quality of Life
April 6, 2009 - EarthTimes

In a recent survey of ophthalmologists across the nation, virtually all (97%) believe preservative-free glaucoma medications can enhance the ocular comfort of glaucoma patients....

...nearly half (47%) do not know a preservative-free beta-blocker is available....

...Six out of ten of the ophthalmologists (60%) would prefer to prescribe glaucoma medications with no preservatives at all for their glaucoma patients with ocular surface disease or dry eye syndrome, compared to glaucoma medications preserved with BAK (3%) or non-BAK preservatives (36%).

Abstract: Pinning down those T cells...

Invest Ophthalmol Vis Sci. 2009 Apr 1.
Characterization of Effector T cells in Dry Eye Disease.

El Annan J, Chauhan SK, Ecoiffier T, Zhang Q, Saban DR, Dana R.
Harvard Dept. Ophthalmology, Schepens Eye Research Inst., Boston, Massachusetts, United States.

Purpose: Dry eye disease (DED) is associated with ocular surface inflammation that is thought to be primarily mediated by CD4 T cells. The purpose of this study was to investigate whether this T cell mediated immune response is generated in the lymphoid compartment, and to characterize the functional phenotype of the T cells activated in DED.

Methods: DED was induced in female C57BL/6 mice by exposure to a desiccating environment in the controlled environment chamber (CEC) and to systemic scopolamine. T cells from regional draining lymph nodes (LN) of DED mice and normal mice were analyzed for surface activation markers (CD69 and CD154), chemokine and cytokine receptors, and for their proliferation potential.

Results: Draining LN of DE mice showed increased frequencies of CD69 and CD154 expressing T cells with higher proliferative capacity. In addition, these LN T cells primarily showed a Th-1 phenotype, expressing significantly higher levels of IFN-gamma and IL-12Rbeta2 but not IL-4R. Similarly, the LN of DE mice showed significantly increased frequencies of T cells expressing CXCR3 and CCR5, but not CCR4, suggesting a bias toward a Th-1 phenotype.

Conclusions: Our data demonstrate that a Th-1 type immune response is induced in the regional LN of DE mice. The identification of specific cytokine/chemokine receptors overexpressed by these T cells may signify potential novel targets/strategies for the treatment of DED.

Abstract: Tear instability and hypoosmolarity

Invest Ophthalmol Vis Sci. 2009 Mar 25.

Liu H, Begley CG, Chen M, Bradley A, Bonanno JA, McNamara N, Nelson JD, Simpson T.
School of Optometry, Indiana University, 800 E atwater ave, Bloomington, Indiana, 47405, United States.

Purpose: Tear film instability and tear hyperosmolarity are considered core mechanisms in the development of dry eye. We hypothesize that evaporation and instability produce transient shifts in tear hyperosmolarity that lead to chronic epithelial stress, inflammation, and symptoms of ocular irritation. The purpose of this study was to (1) provide indirect evidence for short term hyperosmolar conditions during tear instability and to (2) test whether the corneal epithelium responds to transient hyperosmolar stress.

Methods. Five subjects kept one eye open as long as possible and overall discomfort and sensations associated with tear break-up were scaled. Later, the same subjects used the same scales to report discomfort sensations after instillation of NaCl and sucrose hyperosmolar drops (300mOsm/Kg to 1000mOsm/Kg). A two-alternative forced choice experiment was used to obtain osmolarity thresholds. Exp#2: Primary cultured bovine corneal epithelial cells were transiently stressed with the same range of hyperosmolar culture media and pro-inflammatory Mitogen Activated Protein Kinase (MAPKs were measured by western blot).

Results. Tear instability lead to an average discomfort rating of 6.13 and sensations of burning and stinging. These sensations also occurred with hyperosmolar solutions (thresholds between 450-460mOsm/Kg) that required 800-900mOsm/Kg to generate the same discomfort levels reported during tear break-up. MAPK was activated at 600mOsm/Kg of transient hyperosmolar stress.

Conclusion. These experiments provide a link between hyperosmolarity and tear instability, suggesting that hyperosmolar levels in the tear film may transiently spike during tear instability, resulting in corneal inflammation and triggering sensory neurons.

Abstract: Fibromyalgia and reduced corneal sensitivity

Decreased corneal sensitivity and tear production in fibromyalgia.
Invest Ophthalmol Vis Sci. 2009 Mar 25
Gallar J, Morales C, Freire V, Acosta MC, Belmonte C, Duran JA.
Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, San Juan de Alicante, Spain.

Purpose: To investigate corneal sensitivity to selective mechanical, chemical, heat and cold stimulation in fibromyalgia (FM) patients.

Methods: Twenty FM patients (18 female, 2 male; 51,9+/-2,3 years old) and 18 control subjects (16 female, 2 male; 51,7+/-2,4 years) participated voluntarily in the study. Subjective symptoms of ocular dryness were explored and Schirmer's 1 test was performed. The response to selective stimulation of the central cornea with the Belmonte gas esthesiometer was measured.

Results: The majority (18 out of 20) of FM patients reported dry eye symptoms, being the ocular dryness score significantly higher than in healthy subjects (2,3+/-0,1 vs. 0,05+/-0,02; p<0,001). Schirmer's test values were significantly reduced in FM patients compared to those of the control group (10,5+/-,2 mm and 30,6+/-1,6 mm, respectively; p<0,001). Mean corneal threshold sensitivity to chemical stimulation (31,16+/-2,04 %CO2 FM; 15,72+/-0,67 %CO2 control) to heating (1,87+/-0,11 degrees C FM; 0,99+/-0,05 degrees C control) and to cooling (-2,53+/-0,11 degrees C FM; -0,76+/-0,05 degrees C control) were increased in FM patients while threshold to mechanical stimulation did not vary significantly (123,0+/-8,0 ml/min FM; 107,8+/-4,4 ml/min control).

Conclusions: The reduced corneal sensitivity of patients with fibromyalgia is attributable to a moderate decrease of corneal polymodal and cold nociceptor sensitivity, that may be the consequence or the cause of the chronic reduction in tear secretion also observed in these patients.

Abstract: Sjogrens, sex steroid hormones and DHEA therapy

Low serum levels of sex steroids are associated with disease characteristics in primary Sjogren's syndrome; supplementation with dehydroepiandrosterone restores the concentrations.
J Clin Endocrinol Metab. 2009 Jun;94(6):2044-51. Epub 2009 Mar 24.

Forsblad-d'Elia H, Carlsten H, Labrie F, Konttinen YT, Ohlsson C.
Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, Göteborg S-413 46, Sweden.

CONTEXT: Serum levels of the sex steroid prohormones dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) decline upon aging and are reduced in primary Sjogren's syndrome.

OBJECTIVE: Our aim was to investigate: 1) effects of 50 mg oral DHEA/day on changes in serum levels of DHEA and 12 of its metabolites; 2) relationships between steroid levels and disease characteristics; and 3) whether these parameters were influenced by DHEA. DESIGN: Twenty-three postmenopausal women with primary Sjogren's syndrome and subnormal levels of DHEA-S were included in a randomized, 9-month, controlled, double blind crossover study. Liquid chromatography/mass spectrometry (MS)/MS and gas chromatography/MS were used to measure the sex steroids. Anti-SS-A/Ro and/or anti-SS-B/La, salivary gland focus score, salivary flow rates, dry mouth and eye symptoms, and routine laboratory tests were assessed.

RESULTS: Baseline erythrocyte sedimentation rate was inversely correlated with testosterone (Testo), dihydrotestosterone, and DHEA-S (rs = -0.42, -0.45, and -0.58, respectively). Dry mouth symptoms correlated with low Testo and androstenedione, whereas dry eyes correlated with low estrogens, most strongly estrone (rs = -0.63). Presence of anti-SS-A and/or anti-SS-B was independently associated with low estradiol (area under the receiver operating characteristic curve, 0.82). All metabolites increased during DHEA but not during placebo. The relative increases were less for estrogens and Testo compared to dihydrotestosterone and glucuronidated androgen metabolites. Dry mouth symptoms decreased during DHEA therapy.

CONCLUSIONS: Disease manifestations in primary Sjogren's syndrome were associated with low sex hormone levels, dry mouth symptoms with low androgens, and dry eyes with low estrogens. Exogenous DHEA was preferentially transformed into androgens rather than into estrogens.

Abstract: Reduced blinking and vision (and contacts and LASIK)

Visual performance after reduced blinking in eyes with soft contact lenses or after LASIK.
J Refract Surg. 2009 Jan;25(1):69-73.
Toda I, Yoshida A, Sakai C, Hori-Komai Y, Tsubota K.
Minamiaoyama Eye Clinic, Tokyo, Japan.

PURPOSE: To evaluate visual performance during concentrated visual work in patients wearing soft contact lenses or after LASIK.

METHODS: Thirty-one eyes of 17 patients who had worn soft contact lenses before LASIK were examined by the following tests immediately and 10 seconds after eye opening: 1) functional visual acuity, which is defined as visual acuity measured after prolonged eye opening without blinking; 2) surface regularity index (SRI) and surface asymmetry index (SAI) in corneal topography; and 3) higher order aberration measured with NIDEK OPD-Scan. Results were compared in the same patients before (with soft contact lenses and no eye surgery) and 1 month after LASIK (without soft contact lenses).

RESULTS: Functional visual acuity was significantly decreased 10 seconds after eye opening compared with immediately after eye opening, both with soft contact lenses and after LASIK, and decreased to a greater extent with soft contact lenses. The SRI and SAI were significantly increased 10 seconds after eye opening compared with immediately after eye opening, both with soft contact lenses and after LASIK, and increased to a greater extent with soft contact lenses. Higher order aberration was increased 10 seconds after eye opening with soft contact lenses, but not after LASIK.

CONCLUSIONS: Our results suggest that prolonged eye opening induces a decreased quality of vision in eyes of soft contact lens wearers and after LASIK. Under conditions in which blinking is restricted due to concentrated visual work, such as visual display terminal work, reading, and driving, visual performance may be more compromised with soft contact lens wear than after LASIK.

Wednesday, June 10, 2009

Abstract: Effect of dessicating stress on epithelium

Interesting study showing thickening of parts of the epithelium in dry-eyed mice.

Corneal epithelial proliferation and thickness in a mouse model of dry eye.

Exp Eye Res. 2009 Mar 17. [Epub ahead of print]
Corneal epithelial proliferation and thickness in a mouse model of dry eye.

Fabiani C, Barabino S, Rashid S, Dana MR.
The Schepens Eye Research Institute, and Cornea Service, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, 02114 Boston, MA, USA.

Although several studies have previously focused on the conjunctival epithelial response to surface dryness, little is known about the effect of a dry environment on corneal epithelium, which is the most clinically significant tissue affected in dry eye. The aim of this study was to quantitatively evaluate the effect of desiccating stress on the number of proliferating corneal epithelial cells and corneal epithelial thickness in mice placed in a controlled-environment chamber (CEC) that induces dry eye. Corneal epithelial cell proliferation and thickness were studied in 8- to 12-week-old female BALB/c mice placed in the CEC (temperature: 22.3+/-0.7 degrees C; relative humidity: 22.5+/-4.5%; airflow: 15L/min) for 7 days and compared to a control group of mice with no dry eye. Actively proliferating cells were identified by immunofluorescence using a FITC-conjugated antibody against the Ki-67 protein, a cell proliferation marker expressed during active phases of the cell cycle. To detect the spatial distribution of proliferative cells, Ki-67(+) cells were counted in three areas of the epithelium: center, periphery, and limbus. Corneal epithelial thickness was evaluated in the central cornea after staining with hematoxylin-eosin. Results from each experimental group were compared using the Mann-Whitney test. The number of Ki-67(+) cells observed in the corneal epithelium of mice exposed to the CEC was significantly higher in each area (center: 32.1+/-1.1; periphery: 94.2+/-5.3; limbus: 4.0+/-1.5) than in the control group (center: 13.2+/-1.0, p=0.02; periphery: 42.9+/-2.3, p=0.02; limbus: 0.0, p=0.01). In mice subjected to desiccating stress, a significant number of Ki-67(+) positive cells were detected in the basal and suprabasal cell layers (central area 46%; periphery 30.8%: limbus 0%), whereas in the control group the cells were exclusively distributed through the basal cell layer. Ki-67(+) cells were not found in the corneal stroma or endothelium in any group. The corneal epithelium was found to be significantly thicker in dry eye mice (54.94+/-6.09mum) as compared to the controls (43.9+/-6.23mum, p<0.0001) by a mean of 25%. These results demonstrate that desiccating stress increases corneal epithelial turnover and thickness, similar to what is observed in other chronic inflammatory states of other epithelialized surfaces. The CEC can facilitate the study of the regulation of epithelial cell function and turnover at the molecular and cellular levels under desiccating stress conditions.