Cytochrome P450-2D6 Genotype Definition May Improve Therapy for Paroxysmal Atrial Fibrillation A Case of Syncope Following "Pill-in-the-Pocket" Quinidine plus Propafenone.

Classes 1A, 1C and III anti-arrhythmics may be ineffective or induce adverse events including potentially fatal arrhythmias when administered in recommended doses. Serum levels of these medications vary widely during conventional dosing due in large part to variations in cytochrome P450-2D6 isoenzyme activity which metabolizes most antiarrhythmics in addition to over 25% of other commonly prescribed medications. 2D6 activity is also profoundly inhibited by some antiarrhythmics and other commonly used medications and varies widely between the individuals of all populations, a pattern which has resulted in separation of subjects into 4 phenotypes and genotypes consisting of poor metabolizers (PM), intermediate metabolizers (IM), efficient metabolizers (EM), and ultra-rapid metabolizers (UM). Patients with a phenotype PM classification almost universally are also genotype PM due to the possession of two inactive 2D6 alleles, with this PM pattern often inducing supratherapeutic and toxic antiarrhythmic blood levels during conventional antiarrhythmic therapy. UM individuals have supranormal levels of 2D6 activity often created by the presence of 3 or more active alleles which often induce subtherapeutic and ineffective drug levels during antiarrhythmic administration in conventional doses. We searched for evidence relating Cytochrome P450-2D6 phenotypes or genotypes to antiarrhythmic metabolism in order to judge whether this analysis might contribute to improved safety and effectiveness of antiarrhythmic medications commonly utilized in the treatment of atrial fibrillation. The available evidence strongly supported these possibilities. We also describe a patient in whom knowledge of his IM/PM CYP2D6 genotype might have prevented the only episode of syncope and myocardial stunning which developed during his 28 years of "Pill-in-a-Pocket" therapy.

Myogel supports the ex-vivo amplification of corneal epithelial cells.

Limbal stem cell deficiency leads to conjunctivalisation of the cornea and subsequent loss of vision. The recent development of transplantation of ex-vivo amplified corneal epithelium, derived from limbal stem cells, has shown promise in treating this challenging condition. The purpose of this research was to compare a variety of cell sheet carriers for their suitability in creating a confluent corneal epithelium from amplified limbal stem cells. Cadaveric donor limbal cells were cultured using an explant technique, free of 3T3 feeder cells, on a variety of cell sheet carriers, including denuded amniotic membrane, Matrigel, Myogel and stromal extract. Comparisons in rate of growth and degree of differentiation were made, using immunocytochemistry (CK3, CK19 and ABCG2). The most rapid growth was observed on Myogel and denuded amniotic membrane, these two cell carriers also provided the most reliable substrata for achieving confluence. The putative limbal stem cell marker, ABCG2, stained positively on cells grown over Myogel and Matrigel but not for those propagated on denuded amniotic membrane. In the clinical setting amniotic membrane has been demonstrated to provide a suitable carrier for limbal stem cells and the resultant epithelium has been shown to be successful in treating limbal stem cell deficiency. Myogel may provide an alternative cell carrier with a further reduction in risk as it is has the potential to be derived from an autologous muscle biopsy in the clinical setting.

Moraxella keratitis: predisposing factors and clinical review of 95 cases.

AIM: To analyse the clinical presentation, identify predisposing risk factors and evaluate the outcome of treatment of Moraxella keratitis. METHODS: A retrospective analysis was carried out of culture-proved cases of Moraxella keratitis from hospital records during a 10-year period (from December 1995 to November 2005) at the Corneal Unit of the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. RESULTS: 95 episodes of Moraxella keratitis were identified in 92 patients. 3 (3.2%) patients had recurrent keratitis. The mean age of the patients was 70 (range 17-93) years. Multiple predisposing factors were identified in 23 (24%) eyes, including corneal graft (n = 15), previous herpes keratitis (n = 15) and eye lid diseases (n = 15). Adjunctive procedures were carried out in 42 eyes. These included botulinum toxin injection (n = 17), tarsorraphy (n = 12), penetrating keratoplasty (n = 8), enucleation (n = 3), tissue adhesive and bandage contact lens (n = 4), and conjunctival flap (n = 5). Polymicrobial infection was present in 17 eyes. Final visual acuity was counting finger or less in 25 (26%) eyes. CONCLUSIONS: Local ocular predisposing factors play a major role in Moraxella keratitis. This infection has a poor visual outcome attributable to both the nature of the infection and the predisposing factors.

Randomised controlled trial of topical ciclosporin A in steroid dependent allergic conjunctivitis.

AIM: To evaluate the efficacy, safety, and therapeutic effect of topical ciclosporin A 0.05% as a steroid sparing agent in steroid dependent allergic conjunctivitis. METHODS: Prospective, randomised, double masked, placebo controlled trial comparing signs, symptoms, and the ability to reduce or stop concurrent steroid in steroid dependent atopic keratoconjunctivitis and vernal keratoconjunctivitis using 0.05% topical ciclosporin A compared to placebo. Steroid drop usage per week (drug score), symptoms, and clinical signs scores were the main outcome measures. RESULTS: The study included an enrolment of 40 patients, 18 with atopic keratoconjunctivitis and 22 with vernal keratoconjunctivitis. There was no statistical significant difference in drug score, symptoms, or clinical signs scores between the placebo and ciclosporin group at the end of the treatment period. No adverse reactions to any of the study formulations were encountered. CONCLUSIONS: Topical ciclosporin A 0.05% was not shown to be of any benefit over placebo as a steroid sparing agent in steroid dependent allergic eye disease.

Controlled study of the use of autologous serum in dry eye patients.

PURPOSE: To determine the efficacy and safety of topical autologous serum as a treatment of dry eye patients. METHODS: A 2-month, prospective, single-masked, placebo-controlled study was conducted in patients with bilateral severe dry eye. One eye was randomized to receive the patient's own serum as a tear substitute, and the fellow eye received unpreserved normal saline solution as a placebo. Subjective symptoms and clinical parameters of dry eye including conjunctival impression cytology were assessed at baseline and 1 week, 1 month, and 2 months after treatment. RESULTS: Twelve dry eye patients were enrolled. Both subjective symptoms (discomfort, foreign-body sensation, dryness, and photophobia), objective signs (fluorescein and rose bengal staining and conjunctival impression cytology) improved significantly in treated eyes compared with baseline. Control eyes also had improvement in symptoms, signs, and rose bengal staining compared with baseline. Neither Schirmer test results nor tear break-up time improved in either group. The means score of all parameters were improved in both groups, and the results of conjunctival impression cytology were better in treated eyes; however, these results are not significantly different. There were no serious adverse effects observed in this study. CONCLUSIONS: There was a trend toward improvement in symptoms and signs of dry eye including cytologic changes after application of autologous serum in severe dry eye patients. However, this trend was not statistically significant. A larger scale study is warranted.

Impression cytology following mitomycin C therapy for ocular surface squamous neoplasia.

BACKGROUND/AIMS: Topical mitomycin C (MMC) therapy has been used for treatment of ocular surface squamous neoplasia (OSSN) since 1994. Relatively few studies have reported the cellular changes in ocular surface following MMC. METHODS: Impression cytology was studied in four patients with ocular surface squamous neoplasia, either primary or recurrence after previous excisional biopsy. The authors studied samples obtained using Millipore filters at intervals between 4 and 17 weeks after commencement of MMC, and compared them with pretreatment cytology. RESULTS: MMC induced changes of cytomegaly, cytoplasmic vacuolation, nucleomegaly with nuclear wrinkling, and binucleation or multinucleation were seen in some cells in all samples. However, nuclear/cytoplasmic (N/C) ratio in these enlarged cells was normal. These changes mimicked those seen following radiation therapy in uterine cervix. Changes of increased nuclear and cell size with increased N/C ratio were seen in some dysplastic cells. The predominant form of cell death was apoptosis with fewer cells showing necrosis. CONCLUSIONS: MMC appears to produce cell death in OSSN by apoptosis and necrosis. Cellular changes related to MMC mimic those caused by radiation-cytomegaly, nucleomegaly, and vacuolation. MMC related changes may persist in ocular surface epithelium for at least 8 months following MMC therapy.

Experimental demonstration of four-photon entanglement and high-fidelity teleportation.

We experimentally demonstrate observation of highly pure four-photon GHZ entanglement produced by parametric down-conversion and a projective measurement. At the same time this also demonstrates teleportation of entanglement with very high purity. Not only does the achieved high visibility enable various novel tests of quantum nonlocality, it also opens the possibility to experimentally investigate various quantum computation and communication schemes with linear optics. Our technique can, in principle, be used to produce entanglement of arbitrarily high order or, equivalently, teleportation and entanglement swapping over multiple stages.

Increased incidence of corneal perforation after topical fluoroquinolone treatment for microbial keratitis.

PURPOSE: To compare the incidence of corneal perforation in eyes treated with topical fluoroquinolone or fortified antibiotics for microbial keratitis. METHODS: A retrospective medical record review of patients hospitalized for bacterial keratitis from January 1991 through November 1999. RESULTS: Two hundred seventy-seven cases of bacterial keratitis were identified. The incidence of corneal perforations was significantly higher in fluoroquinolone-treated eyes (18 out of 142, 12.7%) compared with eyes treated with fortified antibiotics (1 out of 135, 0.7%) (chi-square = 13.6, degrees of freedom (df) = 2, P <.001). Within the fluoroquinolone-treated group, all corneal perforations occurred in those eyes treated with ofloxacin (18 out of 125, 14.4%). Corneal perforations that occurred in the ofloxacin-treated eyes were not associated with any particular microbial isolate. CONCLUSION: Our data suggest an increased risk of corneal perforation after fluoroquinolone treatment for bacterial keratitis compared with treatment with fortified antibiotics. Further studies are warranted to verify this association and establish possible mechanisms by which topical fluoroquinolones may alter corneal collagen or keratocyte function.

Reliability of impression cytology for the diagnosis of ocular surface squamous neoplasia employing the Biopore membrane.

AIM: To evaluate the accuracy of impression cytology employing a Biopore membrane device in the diagnosis of ocular surface squamous neoplasia (OSSN). METHODS: The histology of patients undergoing excision biopsy for the suspected diagnosis of OSSN over a 20 month period was compared with the reported cytology of impression cytology specimens obtained preoperatively using the Biopore membrane device. RESULTS: 25 excision biopsies were performed for suspected OSSN. There was accurate correlation in 20 out of the 25 cases (80%). In three cases (12%), there was poor correlation in that only a few dysplastic cells and hyperkeratosis were noted on cytology, whereas histology showed keratinising dysplasia in two cases and a moderately differentiated keratinising squamous cell carcinoma in the third. There were two cases (8%) of non-correlation--one keratinising dysplasia on histology, but anucleate keratin, squamous metaplasia, and rare atypical cells on cytology, and another case with very mild focal dysplasia on histology but squamous metaplasia on cytology. Review of the cytology showed that dysplastic cells were either rare or absent from the cytology specimens in these two cases; it was felt that these represented sampling problems rather than true false negatives. There were no false positives on cytology. Final diagnosis on histology was squamous cell carcinoma in one; carcinoma in situ in two; keratinising dysplasia in 15, non-keratinising dysplasia in seven. CONCLUSION: Impression cytology employing the Biopore membrane accurately predicts the histological diagnosis of OSSN. The presence of hyperkeratosis, inflammatory cells with only a few dysplastic cells, may indicate high grade keratinising dysplasia or squamous cell carcinoma. The method is both rapid and easy to perform in routine clinical practice. These findings suggest that there may be a role for its use in the initial assessment and follow up of patients with suspected OSSN.

Use of cyclosporin in the treatment of steroid resistant post-keratoplasty atopic sclerokeratitis.

AIMS: To demonstrate that oral cyclosporin is successful in the management of steroid refractory post-keratoplasty atopic sclerokeratitis (PKAS). METHODS: Series of three patients. RESULTS: The patients developed PKAS between 2 and 11 days after surgery. All cases failed to respond to oral prednisolone 60-80 mg daily for 10-30 days but resolved with the addition of systemic cyclosporin 5.0-7.5 mg/kg/day. There have been no relapses following withdrawal of therapy after 3-18 months. CONCLUSIONS: PKAS is an uncommon, but severe, complication of corneal graft surgery and often responds to oral prednisolone treatment. Oral cyclosporin results in rapid resolution of PKAS in steroid unresponsive cases.

An evaluation of the safety and efficacy of botulinum toxin type A (BOTOX) when used to produce a protective ptosis.

PURPOSE: To evaluate the safety and efficacy of botulinum toxin type A (BOTOX, Allergan) when used to produce a protective ptosis in patients where a surgical tarsorrhaphy would otherwise be required. METHODS: A total of 21 patients entered into the study. Doses of 2.5 and 5.0 units of BOTOX were injected into the levator palpebrae superioris muscle through the eyelid. The patients were followed daily where practical until a ptosis developed and then monitored 1-2 weekly until the ptosis was resolved. Injections were repeated, if necessary until the underlying condition had healed. RESULTS: Ptosis took an average +/- SE of 4.0 +/- 0.5 days to develop (range 2-8 days). Duration of ptosis was an average +/- SE of 46.0 +/- 12.1 days (range 1-206 days). The effective dosage was 5 units of BOTOX in 0.1 mL. In 16 patients, the ptosis produced by BOTOX was sufficient to allow the underlying disease to heal and a surgical tarsorrhaphy was avoided. One patient required a surgical tarsorrhaphy and three patients required other surgical intervention to correct the underlying condition. One patient was lost to follow up. Diplopia was seen in five patients but resolved in all cases. CONCLUSIONS: BOTOX was a suitable alternative to a surgical tarsorrhaphy.

Management of alkali burns : an 11-year retrospective review.

OBJECTIVE: To review the spectrum of patients with alkali burns admitted over an 11-year period and to assess the clinical outcomes after the introduction of a standard alkali burn treatment protocol. DESIGN: Retrospective nonrandomized comparative study. PATIENTS AND INTERVENTIONS: A total of 121 patient records with alkali burns (n = 177 eyes) admitted to a tertiary hospital between 1987 and 1998 were reviewed. Eyes treated with a standard alkali burn treatment protocol, which included intensive topical steroids, ascorbate, citrate, and antibiotics, were compared with eyes treated by conservative management with antibiotics, and a short course of steroids. MAIN OUTCOME MEASURES: Time to corneal reepithelialization, final best-corrected visual acuity, and time to visual recovery, length of hospital stay, and complications were analyzed. RESULTS: The standard protocol tended to delay corneal reepithelialization by one day (P: = not significant) in eyes with grade 1 burns (n = 76) and by 2 days (P: = 0.04) in grade 2 burns (n = 52), with no difference in final visual outcome. There were 37 eyes with grade 3 burns. Those treated with the standard protocol showed a trend toward more rapid corneal reepithelialization. Twenty-seven of 29 (93%) eyes with grade 3 injuries achieved a final best-corrected visual acuity of 20/40 or better compared with 3 of 6 (50%) eyes not treated according to the standard protocol (P: = 0.02). Eyes with grade 4 burns (n = 12), whether treated with the standard protocol or not, required 10 to 12 weeks for corneal reepithelialization. There was no statistically significant difference in final visual acuity. CONCLUSIONS: On the basis of our findings, a number of recommendations can be made for the management of alkali injuries. Patients with a grade 1 or 2 injury do not require routine admission and do not benefit from the use of intensive treatment with ascorbate and citrate. A trend toward more rapid healing and a better final visual outcome were apparent in grade 3 burns, but our standard protocol made no difference in grade 4 burns.

Fluoroquinolone and fortified antibiotics for treating bacterial corneal ulcers.

AIM: To compare the clinical efficacy of commercially available fluoroquinolone drops with the use of combined fortified antibiotics (tobramycin 1.3%-cefazolin 5%) in treatment of bacterial corneal ulcer. METHODS: The medical records of 140 patients with a diagnosis of bacterial corneal ulcer who were admitted to the Royal Victorian Eye and Ear Hospital, Melbourne, Australia between January 1993 and December 1997 were reviewed retrospectively. Final outcome and results of 138 ulcer episodes were compared between those treated initially with fluoroquinolone and those who received fortified antibiotics. Two patients had been treated with chloramphenicol. RESULTS: No significant treatment difference was found between fluoroquinolone and fortified therapy in terms of final visual outcome. However, serious complications such as corneal perforation, evisceration, or enucleation of the affected eye were more common with fluoroquinolone therapy (16.7%) compared with the fortified therapy (2.4%, p= 0.02). The duration of intensive therapy was less with fluoroquinolone especially in those over 60 years of age (4 days v 6 days, p=0.01). Hospital stay was also less in the fluoroquinolone group compared with the fortified group for all patients and was significantly less with fluoroquinolone treatment (7 days v 10 days, p=0.02) in patients in the age group over 60 years old. CONCLUSIONS: Monotherapy with fluoroquinolone eye drops for the treatment of bacterial corneal ulcers led to shorter duration of intensive therapy and shorter hospital stay compared with combined fortified therapy (tobramycin-cefazolin). This finding may have resulted from quicker clinical response of healing as a result of less toxicity found in the patients treated with fluoroquinolone. However, as some serious complications were encountered more commonly in the fluoroquinolone group, caution should be exercised in using fluoroquinolones in large, deep ulcers in the elderly.

Experimental test of quantum nonlocality in three-photon Greenberger-Horne-Zeilinger entanglement

Bell's theorem states that certain statistical correlations predicted by quantum physics for measurements on two-particle systems cannot be understood within a realistic picture based on local properties of each individual particle-even if the two particles are separated by large distances. Einstein, Podolsky and Rosen first recognized the fundamental significance of these quantum correlations (termed 'entanglement' by Schrodinger) and the two-particle quantum predictions have found ever-increasing experimental support. A more striking conflict between quantum mechanical and local realistic predictions (for perfect correlations) has been discovered; but experimental verification has been difficult, as it requires entanglement between at least three particles. Here we report experimental confirmation of this conflict, using our recently developed method to observe three-photon entanglement, or 'Greenberger-Horne-Zeilinger' (GHZ) states. The results of three specific experiments, involving measurements of polarization correlations between three photons, lead to predictions for a fourth experiment; quantum physical predictions are mutually contradictory with expectations based on local realism. We find the results of the fourth experiment to be in agreement with the quantum prediction and in striking conflict with local realism.

Visual outcome and progression of retinopathy after cataract surgery in diabetic patients.

PURPOSE: Diabetes mellitus is a major cause of visual impairment in developed countries through retinopathy and is frequently complicated by cataract formation. The present study examines the visual outcome of cataract surgery in diabetic pat ents. METHODS: A retrospective study was performed over a 26 month period in a general hospital eye clinic. Eighty-five consecutive diabetic patients who underwent cataract surgery were categorized according to their type of diabetes, duration and treatment, operative technique, pre-operative visual acuity (VA) and degree of retinopathy. Visual acuity and retinopathy status were recorded at a minimum of 4 months postoperatively. Factors affecting visual outcome and progression of retinopathy were then examined. RESULTS: Of the 107 eyes of the 85 consecutive cases, 55 were without retinopathy (NR), 21 had background retinopathy (BDR), six had background retinopathy with macular oedema (BDR/MO), four had proliferative retinopathy and 12 cases had inadequate fundal view. In the NR and BDR groups, 90 and 81% of patients, respectively, had improved VA compared with 33% of patients with BDR/MO. Retinopathy progressed in 50% of BDR/MO patients compared with progression in 9 and 19% of NR and BDR patients, respectively. CONCLUSION: The present study illustrates the poor visual outcome in patients with severe, untreated retinopathy, particularly maculopathy, following cataract surgery. Larger prospective studies are needed to better define risk groups and pre-operative treatment strategies.