Eradication of Posterior Capsule Opacification: Documentation of a Marked Decrease in Nd:YAG Laser Posterior Capsulotomy Rates Noted in an Analysis of 5416 Pseudophakic Human Eyes Obtained Postmortem.

OBJECTIVE: (1) To report the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser posterior capsulotomy rate (%) of eight rigid and foldable intraocular lens (IOL) designs in a series of 5416 pseudophakic human eyes obtained postmortem, accessioned in our center between January 1988 and January 2000. (2) To identify factors that are instrumental in reducing the incidence of posterior capsule opacification, (PCO, secondary cataract) and hence the need for Nd:YAG laser posterior capsulotomy. DESIGN: Comparative autopsy tissue analysis. PARTICIPANTS: A total of 5416 globes with posterior chamber intraocular lens (PC-IOLs) obtained postmortem received from Lions Eye Banks between 1988 and 2000. METHODS: Miyake-Apple posterior photographic technique. Special reference was given to the presence or absence of Nd:YAG laser posterior capsulotomy orifice on the posterior capsule of each eye. MAIN OUTCOME MEASURES: The Nd:YAG laser posterior capsulotomy rate (%) as of January 2000 was documented. In addition, the Nd:YAG laser posterior capsulotomy rate for each lens was plotted on a monthly basis for the same period, creating a computerized trend or "timeline" for each IOL style. RESULTS: Relatively high Nd:YAG laser posterior capsulotomy rates ranging from 20.3% to 33.4% were noted with four relatively older designs (high incidence of implantation between 1988 and the early 1990s). Four modern foldable lOLs manufactured from silicone and acrylic materials had significantly lower Nd:YAG laser posterior capsulotomy rates ranging from 0.9% (Alcon Acrysof) to 17.1%. The difference in Nd:YAG rates among the eight IOL designs was found to be significant (P < 0.0001, chi-square test). Comparing foldable versus rigid designs, the foldable IOLs were associated with a much lower Nd:YAG laser posterior capsulotomy rate (14.1% vs. 31.1%). CONCLUSIONS: By use of the six factors regarding surgical technique and IOL choice described in this article, we strongly believe that the overall incidence of PCO and hence the incidence of Nd:YAG laser posterior capsulotomy is now rapidly decreasing from rates as high as 50% in the 1980s to early 1990s. Surgical tools and IOLs are now available to bring these rates down to single digits. Careful application and use of these tools by surgeons can genuinely lead in the direction of virtual eradication of secondary cataract, the second most common cause of visual loss worldwide.

Multimodality imaging probe for positron emission tomography and fluorescence imaging studies.

Our goal is to develop multimodality imaging agents for use in cell tracking studies by positron emission tomography (PET) and optical imaging (OI). For this purpose, bovine serum albumin (BSA) was complexed with biotin (histologic studies), 5(6)-carboxyfluorescein, succinimidyl ester (FAM SE) (OI studies), and diethylenetriamine pentaacetic acid (DTPA) for chelating gallium 68 (PET studies). For synthesis of BSA-biotin-FAM-DTPA, BSA was coupled to (+)-biotin N-hydroxysuccinimide ester (biotin-NHSI). BSA-biotin was treated with DTPA-anhydride and biotin-BSA-DTPA was reacted with FAM. The biotin-BSA-DTPA-FAM was reacted with gallium chloride 3 to 5 mCi eluted from the generator using 0.1 N HCl and was passed through basic resin (AG 11 A8) and 150 µCi (100 µL, pH 7-8) was incubated with 0.1 mg of FAM conjugate (100 µL) at room temperature for 15 minutes to give 68Ga-BSA-biotin-DTPA-FAM. A shaved C57 black mouse was injected with FAM conjugate (50 µL) at one flank and FAM-68Ga (50 µL, 30 µCi) at the other. Immediately after injection, the mouse was placed in a fluorescence imaging system (Kodak In-Vivo F, Bruker Biospin Co., Woodbridge, CT) and imaged (λex: 465 nm, λem: 535 nm, time: 8 seconds, Xenon Light Source, Kodak). The same mouse was then placed under an Inveon microPET scanner (Siemens Medical Solutions, Knoxville, TN) injected (intravenously) with 25 µCi of 18F and after a half-hour (to allow sufficient bone uptake) was imaged for 30 minutes. Molecular weight determined using matrix-associated laser desorption ionization (MALDI) for the BSA sample was 66,485 Da and for biotin-BSA was 67,116 Da, indicating two biotin moieties per BSA molecule; for biotin-BSA-DTPA was 81,584 Da, indicating an average of 30 DTPA moieties per BSA molecule; and for FAM conjugate was 82,383 Da, indicating an average of 1.7 fluorescent moieties per BSA molecule. Fluorescence imaging clearly showed localization of FAM conjugate and FAM-68Ga at respective flanks of the mouse, whereas only a hot spot at the expected flank (FAM-68Ga injection site) was observed in microPET imaging. Our results suggest that BSA-biotin-DTPA-FAM may function as a multiprobe for PET and fluorescence imaging. Experiments are currently in progress to demonstrate cell tracking using both optical and nuclear imaging.

Evaluation of serotonin 5-HT(1A) receptors in rodent models using [¹8F]mefway PET.

INTRODUCTION: Serotonin 5-HT(1A) receptors have been investigated in various CNS disorders, including epilepsy, mood disorders, and neurodegeneration. [¹8F]Mefway (N-{2-[4-(2'-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(cis/trans-4'-[¹8F]fluoromethylcyclohexane)-carboxamide) has been developed as a suitable positron emission tomography (PET) imaging agent for these receptors. We have now evaluated the suitability of [¹8F]trans-mefway in rat and mouse models using PET and computerized tomography (CT) imaging and corroborated with ex vivo and in vitro autoradiographic studies. METHODS: Normal Sprague-Dawley rats and Balb/C mice were used for PET/CT imaging using intravenously injected [¹8F]trans-mefway. Brain PET data were coregistered with rat and mouse magnetic resonance imaging template and regional distribution of radioactivity was quantitated. Selected animals were used for ex vivo autoradiographic studies to confirm regional brain distribution and quantitative measures of binding, using brain region to cerebellum ratios. Binding affinity of trans-mefway and WAY-100635 was measured in rat brain homogenates. Distribution of [¹8F]trans-4-fluoromethylcyclohexane carboxylate ([¹8F]FMCHA), a major metabolite of [¹8F] trans-mefway, was assessed in the rat by PET/CT. RESULTS: The inhibition constant, K(i) for trans-mefway was 0.84 nM and that for WAY-100635 was 1.07 nM. Rapid brain uptake of [¹8F]trans-mefway was observed in all rat brain regions and clearance from cerebellum was fast and was used as a reference region in all studies. Distribution of [¹8F]trans-mefway in various brain regions was consistent in PET and in vitro studies. The dorsal raphe was visualized and quantified in the rat PET but identification in the mouse was difficult. The rank order of binding to the various brain regions was hippocampus > frontal cortex > anterior cingulate cortex > lateral septal nuclei > dorsal raphe nuclei. CONCLUSION: [¹8F]trans-Mefway appears to be an effective 5-HT(1A) receptor imaging agent in rodents for studies of various disease models.

All optical modulation in vertically coupled indium tin oxide ring resonator employing epsilon near zero state.

We present an innovative approach to achieve all-optical modulation within an ITO-based vertically coupled ring resonator. This method leverages the material's enhanced nonlinear response in the near-infrared wavelengths, particularly within the epsilon-near-zero (ENZ) state. To enhance the interaction between light and the material while minimizing scattering losses, our approach employs an ITO-based vertically connected ring resonator. The vertical arrangement eliminates the need for etching fine gaps to separate the ring and bus waveguide. The novel waveguide design addresses the necessity of high sensitivity, non-linear effects and compact size opening the possibilities for all-optical signal processing. This unique resonator structure effectively facilitates the coupling of a high-intensity pump wavelength into the ITO-based micro-ring resonator. Consequently, this optical pumping induces electron heating within the ITO material, leading to a significant increase in its nonlinear optical properties. This, in turn, results in a noteworthy alteration of ITO's refractive index, specifically in the unity order, thereby modifying the complex effective index of the optical beam propagating at 1550 nm. Our experimental findings demonstrate an impressive extinction ratio of 18 dB for a 30 µm long device, which highlights the efficiency of our approach in achieving all-optical modulation through the optical pumping of an ITO-based vertically coupled ring resonator. The proposed all-optical modulator has outperformed as compared to conventional waveguide-based modulators in terms of extinction ratio and footprint. This novel technique holds immense potential for advancing high-speed data communication systems in the future. As the demand for advanced processing capabilities, such as artificial intelligence, continues to grow, all-optical modulation emerges as a groundbreaking technology poised to revolutionize the next generation of computing and communication systems.

Nicotinic acetylcholine receptors in rat forebrain that bind ¹8F-nifene: relating PET imaging, autoradiography, and behavior.

Nicotinic acetylcholine receptors (nAChRs) in the brain are important for cognitive function; however, their specific role in relevant brain regions remains unclear. In this study, we used the novel compound ¹8F-nifene to examine the distribution of nAChRs in the rat forebrain, and for individual animals related the results to behavioral performance on an auditory-cognitive task. We first show negligible binding of ¹8F-nifene in mice lacking the ß2 nAChR subunit, consistent with previous findings that ¹8F-nifene binds to α4ß2* nAChRs. We then examined the distribution of ¹8F-nifene in rat using three methods: in vivo PET, ex vivo PET and autoradiography. Generally, ¹8F-nifene labeled forebrain regions known to contain nAChRs, and the three methods produced similar relative binding among regions. Importantly, ¹8F-nifene also labeled some white matter (myelinated axon) tracts, most prominently in the temporal subcortical region that contains the auditory thalamocortical pathway. Finally, we related ¹8F-nifene binding in several forebrain regions to each animal's performance on an auditory-cued, active avoidance task. The strongest correlations with performance after 14 days training were found for ¹8F-nifene binding in the temporal subcortical white matter, subiculum, and medial frontal cortex (correlation coefficients, r > 0.8); there was no correlation with binding in the auditory thalamus or auditory cortex. These findings suggest that individual performance is linked to nicotinic functions in specific brain regions, and further support a role for nAChRs in sensory-cognitive function.

Synthesis and evaluation of 3-¹²³I-iodo-5-[2-(S)-3-pyrrolinylmethoxy]-pyridine (niodene) as a potential nicotinic α4ß2 receptor imaging agent.

Nicotinic acetylcholine receptors (nAChRs) are downregulated in disease conditions such as Alzheimer's and substance abuse. Presently, (123)I-5-IA-85380 is used in human studies and requires over 6h of scanning time, thus increases patient discomfort. We have designed and synthesized 3-iodo-5-[2-(S)-3-pyrrolinylmethoxy]pyridine (niodene) with the aim to have faster binding kinetics compared to (123)I-5-IA-85380, which may reduce scanning time and help in imaging studies. Binding affinity K(i) of niodene for rat brain α4ß2 receptors in brain homogenate assays using (3)H-cytisine was 0.27 nM. Niodene, 10nM displaced >95% of (18)F-nifene bound to α4ß2 receptors in rat brain slices. By using the iododestannylation method, (123)I-niodene was obtained in high radiochemical purity (>95%) but with low radiochemical yield (<5%) and low specific activity (∼100 Ci/mmol). Autoradiograms show (123)I-niodene localized in the thalamus and cortex, which was displaced by nicotine (thalamus to cerebellum ratio=4; cortex to cerebellum ratio=1.6). Methods of radioiodination need to be further evaluated in order to obtain (123)I-niodene in higher radiochemical yields and higher specific activity of this potentially useful new SPECT imaging agent.

Conjugation of cRGD peptide to chlorophyll a based photosensitizer (HPPH) alters its pharmacokinetics with enhanced tumor-imaging and photosensitizing (PDT) efficacy.

The α(v)ß(3) integrin receptor plays an important role in human metastasis and tumor-induced angiogenesis. Cyclic Arg-Gly-Asp (cRGD) peptide represents a selective α(v)ß(3) integrin ligand that has been extensively used for research, therapy, and diagnosis of neoangiogenesis. For developing photosensitizers with enhanced PDT efficacy, we here report the synthesis of a series of bifunctional agents in which the 3-(1'-hexyloxyethyl)-3-devinylpyropheophorbide a (HPPH), a chlorophyll-based photosensitizer, was conjugated to cRGD and the related analogues. The cell uptake and in vitro PDT efficacy of the conjugates were studied in α(v)ß(3) integrin overexpressing U87 and 4T1 cell lines whereas the in vivo PDT efficacy and fluorescence-imaging potential of the conjugates were compared with the corresponding nonconjugated photosensitizer HPPH in 4T1 tumors. Compared to HPPH, the HPPH-cRGD conjugate in which the arginine and aspartic acid moieties were available for binding to two subunits of α(v)ß(3) integrin showed faster clearance, enhanced tumor imaging and enhanced PDT efficacy at 2-4 h postinjection. Molecular modeling studies also confirmed that the presence of the HPPH moiety in HPPH-cRGD conjugate does not interfere with specific recognition of cRGD by α(v)ß(3) integrin. Compared to U87 and 4T1 cells the HPPH-cRGD showed significantly low photosensitizing efficacy in A431 (α(v)ß(3) negative) tumor cells, suggesting possible target specificity of the conjugate.

J Donald M Gass MD: father of macular diseases, and one of the ten most influential ophthalmologists of the 20th century.

John Donald MacIntyre Gass, MD was one of the most significant figures to emerge in ophthalmology in the last 100 years. There could be few ophthalmologists who cannot attribute part of their increase in understanding of retinal disease to the influence of Don Gass. His insights opened up opportunities for many new effective therapies. He has influenced ophthalmic thought worldwide, if not by his presence as a visitor, then through his scientific publications, his outstanding books and the international fellows he trained. Like many distinguished physicians, Don Gass's clinical acumen was well grounded in his understanding of ocular pathology. This experience was gained under the mentorship of Lorenz E Zimmerman, MD, who trained a number of distinguished ophthalmologists, who subsequently became professors. Professor Gass passed away on February 26, 2005 at the age of 76 years from pancreatic carcinoma. With the demise of Don Gass, the world of ophthalmology has lost an extraordinary physician of great talent, commonsense and humility. On the other hand it has gained a generation of young ophthalmologists inspired by his example.

Substrate affinity of photosensitizers derived from chlorophyll-a: the ABCG2 transporter affects the phototoxic response of side population stem cell-like cancer cells to photodynamic therapy.

Photosensitizers (PS) synthesized with the aim of optimizing photodynamic therapy (PDT) of tumors do not always fulfill their potential when tested in vitro and in vivo in different tumor models. The ATP-dependent transporter ABCG2, a multidrug resistant pump expressed at variable levels in cancerous cells, can bind and efflux a wide range of structurally different classes of compounds including several PS used preclinically and clinically such as porphyrins and chlorins. ABCG2 may lower intracellular levels of substrate PS below the threshold for cell death in tumors treated by PDT, leaving resistant cells to repopulate the tumor. To determine some of the structural factors that affect substrate affinity of PS for ABCG2, we used an ABCG2-expressing cell line (HEK 293 482R) and its nonexpressing counterpart, and tyrosine kinase ABCG2 inhibitors in a simple flow cytometric assay to identify PS effluxed by the ABCG2 pump. We tested a series of conjugates of substrate PS with different groups attached at different positions on the tetrapyrrole macrocycle to examine whether a change in affinity for the pump occurred and whether such changes depended on the position or the structure/type of the attached group. PS without substitutions including pyropheophorbides and purpurinimides were generally substrates for ABCG2, but carbohydrate groups conjugated at positions 8, 12, 13, and 17 but not at position 3 abrogated ABCG2 affinity regardless of structure or linking moiety. At position 3, affinity was retained with the addition of iodobenzene, alkyl chains and monosaccharides, but not with disaccharides. This suggests that structural characteristics at position 3 may offer important contributions to requirements for binding to ABCG2. We examined several tumor cell lines for ABCG2 activity, and found that although some cell lines had negligible ABCG2 activity in bulk, they contained a small ABCG2-expressing side population (SP) thought to contain cells which are responsible for initiating tumor regrowth. We examined the relevance of the SP to PDT resistance with ABCG2 substrates in vitro and in vivo in the murine mammary tumor 4T1. We show for the first time in vivo that the substrate PS HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) but not the nonsubstrate PS HPPH-Gal (a galactose conjugate of HPPH) selectively preserved the SP which was primarily responsible for regrowth in vitro. The SP could be targeted by addition of imatinib mesylate, a tyrosine kinase inhibitor which inhibits the ATPase activity of ABCG2, and prevents efflux of substrates. A PDT resistant SP may be responsible for recurrences observed both preclinically and clinically. To prevent ABCG2 mediated resistance, choosing nonsubstrate PS or administering an ABCG2 inhibitor alongside a substrate PS might be advantageous when treating ABCG2-expressing tumors with PDT.

Compared to purpurinimides, the pyropheophorbide containing an iodobenzyl group showed enhanced PDT efficacy and tumor imaging (124I-PET) ability.

Two positional isomers of purpurinimide, 3-[1'-(3-iodobenzyloxyethyl)] purpurin-18-N-hexylimide methyl ester 4, in which the iodobenzyl group is present at the top half of the molecule (position-3), and a 3-(1'-hexyloxyethy)purpurin-18-N-(3-iodo-benzylimide)] methyl ester 5, where the iodobenzyl group is introduced at the bottom half (N-substitued cyclicimide) of the molecule, were derived from chlorophyll-a. The tumor uptake and phototherapeutic abilities of these isomers were compared with the pyropheophorbide analogue 1 (lead compound). These compounds were then converted into the corresponding 124I-labeled PET imaging agents with specific activity >1 Ci/micromol. Among the positional isomers 4 and 5, purpurinimide 5 showed enhanced imaging and therapeutic potential. However, the lead compound 1 derived from pyropheophorbide-a exhibited the best PET imaging and PDT efficacy. For investigating the overall lipophilicity of the molecule, the 3-O-hexyl ether group present at position-3 of purpurinimide 5 was replaced with a methyl ether substituent, and the resulting product 10 showed improved tumor uptake, but due to its significantly higher uptake in the liver, spleen, and other organs, a poor tumor contrast in whole-body tumor imaging was observed.

Robotics and ophthalmology: Are we there yet?

Ophthalmology is a field that is now seeing the integration of robotics in its surgical procedures and interventions. Assistance facilitated by robots offers substantial improvements in terms of movement control, tremor cancellation, enhanced visualization, and distance sensing. Robotic technology has only recently been integrated into ophthalmology; hence, the progression is only in its initial stages. Robotic technologies such as da Vinci Surgical System are integrated into the field of ophthalmology and are assisting surgeons in complex eye surgeries. Ophthalmic surgeries require high accuracy and precision to execute tissue manipulation, and some complex ocular surgery may take few hours to complete the procedures that may predispose high-volume ophthalmic surgeons to work-related musculoskeletal disorders. A complete paradigm shift has been achieved in this particular field through the integration of advanced robotic technology, resulting in easier and more efficient procedures. Where robotic technology assists the surgeons and improves the overall quality of care, it also projects several challenges including limited availability, training, and the high cost of the robotic system. Although considerable studies and trials have been conducted for various robotic systems, only a few of them have made it to the commercial stage and ophthalmology, on its own, has a long way to go in robotics technology.

Histochemical analysis of bandage contact lens precipitates.

Contact lens deposits have been reported previously with extended wear of soft contact lenses, with proteins, lipids, mucous, and various salts such as chloride, potassium and calcium being deposited on the lens surface [1]. We report an unusual case of precipitates on the surface of a bandage contact lens (BCL) following intensive treatment with topical preservative free artificial tears. Evaluation included microscopic and histochemical analysis of the BCL. We have also reviewed the literature for previous reports of contact lens precipitates.

Zepto-rhexis: A new surgical technique of capsulorhexis using precision nano-pulse technology in difficult cataract cases.

Several techniques are used to make a capsulorhexis in white mature cataract cases as needle cystotome, Utrata capsulorhexis forceps, microincision capsulorhexis forceps, femtosecond Laser, etc. Zepto precision nano-pulse capsulotomy device (Mynosys Cellular Devices; Fremont, CA, USA) is Food and Drug Administration approved, a disposable capsulotomy device that uses low-energy pulses to create a precise central capsulorhexis, independent of pupil size, corneal clarity, or lens density. In this article, the authors report their experience of performing anterior circular curvilinear capsulorhexis with Zepto precision nano-pulse capsulotomy device in challenging cataract cases done at our center. The Zepto handpiece device was inserted through 2.8 mm clear corneal incision. Results of our study in 3 cataract cases (intumescent cataract, morgagnian cataract, and cataract with small pupil) revealed that the precision pulse capsulotomy technology mechanically and simultaneously cleaves all 360° of the apposed capsule of without cauterizing it, creating CCC of 5.2 mm size.

Irregularities on the surface of single-piece AcrySof SA60AT intraocular lenses.

PURPOSE: To report a case series of what initially appeared to be macroscopic biomaterial deposits and irregularities on the surface of AcrySof SA60AT intraocular lenses (IOLs) (Alcon Inc.) SETTING: Department of Ophthalmology and Somerset Hospital, Taunton, United Kingdom; Department of Ophthalmology and Visual Sciences, John A Moran Eye Center, University of Utah, Salt Lake City, Utah, USA; and Intraocular Implant Unit, Sydney Eye Hospital, University of Sydney, Sydney, Australia. METHODS: Twelve AcrySof SA60AT IOLs were initially thought to have irregularities on their surfaces when examined under the operating microscope before implantation in the capsular bag during cataract surgery. The IOLs were sent for further analysis, including gross examination and light and scanning electron microscopy, to John A. Moran Eye Center, Salt Lake City, Utah, USA, and to Alcon Laboratories, Hemel Hempstead, United Kingdom. RESULTS: Light microscopy revealed the presence of irregular fine lesions on the IOLs' optics and haptics. The lesions consisted of elevations and depressions of the IOL surface that were present on both the anterior and the posterior surfaces of the IOLs. Scanning electron microscopy confirmed the presence of physical/mechanical damage to the IOLs, which was thought to originate from the packaging. The manufacturer believed this to have resulted from compression of the IOL between the container and its cover. CONCLUSIONS: Implantation of an imperfect IOL remains a potentially serious occurrence. Faults still occur in modern IOLs, and some defects can be detected by examining the IOL under the operating microscope before implantation into the eye.