Kaleidoscope vortex lasers generated from astigmatic cavities with longitudinal-transverse coupling.

We propose an efficient and robust method to generate the kaleidoscope vortex beam by employing an astigmatic laser cavity with an extra-cavity cylindrical lens. The kaleidoscope vortex beam is arising from the superposition of Laguerre-Gaussian modes with the longitudinal-transverse coupling effect in the laser cavity. The superposed Laguerre-Gaussian mode leads to the formation of complex phase singularities and implies the participation of different optical orbital angular momentum involved in a single kaleidoscope vortex beam. We experimentally demonstrate that a series of kaleidoscope vortex beams with different symmetry are systematically achieved by using a simple setup. The output power of the laser is dependent on the cavity length. This approach is expected to create high-order optical vortex beams and pave the way for optical entanglement.

Alternative delivery of insulin via eye drops.

BACKGROUND: Various insulin delivery systems have been considered for systemic absorption other than injections. Although the ocular route has been suggested, its use is limited by the amount of insulin absorbed systemically via eyes. In order to improve the absorption rate of insulin into systemic circulations, the effects of pH and absorption enhancers were studied with rabbit eyes. METHODS: Insulin eye drops were instilled into eyes of rabbits, and their blood glucose levels were measured with a Glucoscan 200 Meter (Lifescan, Mountain View, CA). RESULTS: Systemic absorption of insulin via the ocular route was much more prominent at higher pH (8.0) than at lower pH (3.5). When absorption enhancers such as glycocholate and fusidic acid were added, the insulin absorption increased further markedly. CONCLUSION: It is feasible to administer insulin through the eyes at pH 8.0 with low concentrations of glycocholate or fusidic acid to achieve the therapeutic efficacy of insulin to lower blood glucose to normal levels.

Comparison of water and lipid content measurements using diffuse optical spectroscopy and MRI in emulsion phantoms.

We present a quantitative comparison of lipid and water signals obtained from broadband Diffuse Optical Spectroscopy (DOS) and Magnetic Resonance Imaging (MRI). DOS and MRI measurements were performed on an identical set of emulsion phantoms that were composed of different water/soybean oil fractions. Absolute concentrations of water and lipid ranging from 35-94% and 63-6%, respectively were calculated from quantitative broadband near-infrared (NIR) absorption spectra (650-1000 nm). MR images of fat and water were separated using the three-point Dixon technique. DOS and MRI measured water and lipid were highly correlated (R(2) = 0.98 and R(2) = 0.99, respectively) suggesting that these techniques are complementary over a broad range of physiologically relevant water and lipid values. In addition, comparison of DOS derived concentrations to the MRI "gold standard" technique validates our quantitation approach and permits estimation of DOS accuracy and sensitivity in vivo.

Effects of nitric oxide donors and nitric oxide synthase substrates on ciliary muscle contracted by carbachol and endothelin for possible use in myopia prevention.

Research has suggested that the development of myopia may possibly be prevented by the use of drugs which facilitate relaxation of the intraocular ciliary muscle. We examined the effects of five nitric oxide-producing agents--two nitric oxide donors, hydralazine and sodium nitrite, and three nitric oxide synthase substrates, L-arginine, L-canavanine, and N-benzoyl-L-arginine ethyl ester--on isolated bovine ciliary muscle maximally contracted with either carbachol or endothelin-1. Of these agents, hydralazine and L-canavanine produced a relaxing effect on endothelin-1-contracted muscle that was significantly greater than relaxing effect on carbachol-contracted muscle. These results indicate that hydralazine and L-canavanine could possibly be used for the prevention of myopia by relaxing the ciliary muscle with few anticholinergic and cycloplegic side effects.

Effects of dopamine antagonists in human eye accommodation.

The purpose of this study was to evaluate the effects of dopamine antagonists in accommodation of the human eye. The dopamine antagonist drugs used in this experiment include 0.5% metoclopramide and 0.25% droperidol. Eighteen healthy subjects were enrolled; they were randomly assigned, in double-masked fashion, to receive topical administration of a single drop of either 0.5% metoclopramide or 0.25% droperidol in one eye, with the fellow eye receiving isotonic saline as control. The accommodative abilities of both eyes were measured before instillation, and also at 3 and 6 hr after instillation of drugs, respectively. We studied the latency of reaction, the rate of accommodation, the average accommodative power, the rate of recovering and the total recovering time as the five parameters for evaluating the accommodative ability of each eye. The results showed that there were significant changes in two parameters: the rate of accommodation and rate of recovering, whereas there were no significant changes in the other three parameters: latency of accommodation, average power of accommodation and total recovering time. In conclusion, the dopamine antagonists may have some effects on the rate of accommodation but not the degree of accommodation. Further studies with higher concentrations of these dopamine antagonists on dose-response relationships are needed before exact drug efficacy can be drawn.

Review: effects of nitric oxide on eye diseases and their treatment.

Both underproduction and overproduction of nitric oxide (NO) could lead to various eye diseases. It is known that endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are activated in normal tissues to produce NO for physiological functions. Thus, underproduction of NO results in various eye diseases which could be corrected by providing NOS substrates or NO donors to lower the intraocular pressure, increase ocular blood flow, relax ciliary muscle, etc. On the other hand, immunological NOS (iNOS) is inducible only in pathological conditions by endotoxins, inflammation, and certain cytokines, such as interleukin-1 (IL-1), IL-6, TNF (tumor necrosis factor) and the like. Once induced, iNOS will produce large amounts of NO for long periods of time, so that NO is converted into NO2, nitrite, peroxynitrite and free radicals to induce pathophysiological actions, such as optic nerve degeneration and posterior retinal degeneration lesion, which lead to glaucoma, retinopathy, age-related macular degeneration (AMD), myopia, cataracts and uveitis. To treat/prevent these eye diseases, inhibitors of iNOS activity and/or iNOS induction could be tried.

Effects of N-nitropyrazoles on ocular blood flow of rabbits and retinal function recovery of rat eyes after ischemic insults.

Twelve compounds of N-nitropyrazoles were studied for their effects on ocular blood flow in rabbits and retinal function recovery in rat eyes after ischemic insults. Of the twelve N-nitropyrazoles examined, nine increased choroidal blood flow while five increased retinal blood flow significantly. On the other hand, all twelve compounds increased blood flow in iris and ciliary muscle without exception. As for retinal function recovery after ischemic insult in rat eyes, eight out of the twelve compounds showed more significant facilitation than the control. The structure activity relationship of the N-nitropyrazoles to increase ocular blood flow and to facilitate retinal function recovery after ischemic insults were discussed.

Inhibition of interleukin-1-induced uveitis and corneal fibroblast proliferation by interleukin-1 blockers.

Interleukin-1 (IL-1) is known to trigger induction of inducible nitric oxide synthase (iNOS) to persistently mass produce nitric oxide (NO) to induce various diseases such as cancer, inflammation, Alzheimer's disease and eye diseases, including uveitis, retinopathy, age-related macular degeneration, glaucoma and myopia. Therefore, IL-1 blockers could become an important class of drugs to fight numerous diseases. Among the many compounds studied so far, 1-methyl hydrazino analogs are among the most promising agents to be developed. A minor structural change of 1-methyl hydrazino group into 1-methyl thiosemicarbazido group enhanced their anti-inflammatory activity but reduced their antiproliferation activity on corneal fibroblast cell growth.

Contribution of circulating acetylcholine to sensory nerve conduction augmentation.

We previously discovered that sensory nerve action potential amplitudes increased during isometric muscle contraction and that this response could be blocked with tourniquet isolation of the contraction source. The hypothesis for this study was that a circulating factor was responsible for this effect. In this prospective study, baseline and post intravenous injection of serial sural nerve action potential recordings were made in the leg of 8 rabbits. The sequence of the injections was randomized: 1) normal saline placebo, 2) 0.01 mg/kg acetylcholine (ACh) 3) 200 mg/kg Na acetate, 4) 260 mg/kg Na lactate, and 5) 20 mg/kg choline. Results showed there was a 3.8 microV increase in the sural nerve response 6 min after ACh injection compared to baseline at rest (p = .01, power = .9, analysis of variance (ANOVA), repeated measures). There were no significant changes in the amplitudes of the sural nerve after injection of the remaining agents or placebo (p = .33 to .81, ANOVA, repeated measures). In conclusion, circulating ACh is the only agent tested thus far that appears to be responsible for this effect. In addition, the amplitude and temporal curve of this response is similar to that seen after exercise in human subjects. The clinical importance of this study is that ACh plays a role in this newly discovered sensory regulatory mechanism controlled by the motor system.

Effects of interleukin-1 blockers on corneal fibroblast proliferation in vitro and ocular inflammation in vivo.

The success of keratorefractive surgical procedures is limited by the wound healing process in the corneal stroma. The proliferation and matrix synthesis of corneal stromal fibroblasts is the central element of the wound healing process that is triggered by an initial inflammation. In order to develop new therapeutic strategies to reduce wound healing intensity, we investigated the effect of newly synthesized interleukin-1 (IL-1) blockers on the proliferation of cultured rabbit corneal fibroblasts and the ocular inflammation induced by IL-1. It was found that the addition of IL-1 blockers, such as CK-135 to CK-145, led to a dose-dependent inhibition of cell proliferation after 24, 48 and 72 hr of incubation. The isotope incorporation study showed that the syntheses ofDNA and mRNA were suppressed whereas that of protein was enhanced or unaffected. These compounds also demonstrated a potent anti-inflammation action in the rat uveitis model. Our results indicate that CK (Chiou-Kumamoto) compounds may be valuable therapeutic agents for the prevention of postoperative complications after corneal keratorefractive surgical procedures.

Effects of nitric oxide donors on the retinal function measured with electroretinography.

It has been reported that nitric oxide raises c-GMP in the vascular muscle to cause vasodilation and to improve blood flow in the retina. Consequently, a diverse group of potential nitric oxide (NO) donors were synthesized and evaluated for their effectiveness in improving the retinal function after ischemic insult. These compounds include an NO carrier, N-acetyl-S-nitrosoglutathione (RVC-593), several NO donors such as N-nitropyrazole derivatives (RVC-595, RVC-596, RVC-597, RVC-598, and RVC-599) and two fused N-heterocycles, 4H-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxides, (RVC-600 and RVC-601). Most of the compounds demonstrated the pharmacological activity in the ophthalmic model, except the pyrazole derivatives (RVC-595, RVC-596 and RVC-599) that bear bulky aromatic substituents at the R2-position.

Transient retinal ischemia-reperfusion in rats.

OBJECTIVE: To investigate the effect of transient ischemia-reperfusion on the retina in rats. METHODS: Retinal ischemia-reperfusion was induced in rats by increasing the intraocular pressure. After 1 or 5 minutes of ischemia, retinal neuronal cell death at different periods of reperfusion was studied using the TdT-deoxynucleotide terminal nick-end labeling (TUNEL) method and light microscopy. Retinal IL-1 beta and TNF alpha were quantified by an enzyme-linked immunosorbent assay (ELISA). RESULTS: A few migrating leukocytes were noticed in the retina after transient retinal ischemia-reperfusion. Rare TUNEL-positive (T+) cells were noticed in the outer granular layer or the rod and cone layer, and not in ganglion cell layer in control eyes, but they were significantly increased in the outer granular layer, the inner granular layer, and ganglion cell layer in the eyes treated with 1 or 5 minutes of retinal ischemia-reperfusion (P < 0.05). Retinal IL-1 beta was significantly increased at 6 hours after reperfusion in the eyes treated with 1 or 5 minutes ischemia over the control eyes (P < 0.05), but retinal TNF alpha was not significantly increased (P > 0.05). CONCLUSION: Transient retinal ischemia-reperfusion for only 1 or 5 minutes of ischemia can induce the upregulation of retinal IL-1 beta and apoptosis of retinal neuronal cells. This kind of apoptosis in individual cells, however, was not sufficient to affect the whole retinal function.

[Effects of synthetic interleukin-1 blockers on uveitis in rats].

OBJECTIVE: To investigate the therapeutic action of synthetic interleukin-1 blockers on uveitis in rats. METHOD: Experiments were performed on 18 Spraque-Dawley rats (36 eyes), and the retinal interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) were quantified by an enzyme-linked immunoabsorbent assay (ELISA) before and after the rats with uveitis treated by synthetic interleukin-1 blockers. RESULT: The retinal IL-1 beta and TNF-alpha in rats with uveitis treated by synthetic IL-1 blockers (CK-138, 139) were significantly decreased than those treated by contrasting design. CONCLUSION: Synthetic IL-1 blockers (CK-138, 139) are effective in treatment of IL-1 alpha induced uveitis in the rat.

Suppression of interleukin-1alpha-induced uveitis and inhibition of fibroblast-like cell proliferation by synthetic interleukin-1 blockers.

To treat uveitis and prolong the functional life of filtration surgery on glaucomatous eyes, some interleukin-1 (IL-1) blockers were used to inhibit IL-1-induced uveitis in rat eyes and to suppress proliferation of fibroblast-like corneal and conjunctival cells in the cell cultures, respectively. It was found in this research that the blood-aqueous barrier can be broken by IL-1alpha to allow fluorescein to enter the eyeballs and to be detected by fluorotron. The uveitis was effectively blocked by the IL-1 blockers studied in this research. It was also noted that the proliferation of fibroblast-like corneal and conjunctival cells was effectively inhibited by IL-1 blockers. The inhibition of cell growth seems to be caused primarily by the inhibition of RNA synthesis. There was a significant difference in the potency of IL-1 blockers to inhibit corneal vs. conjunctival cells. It was noted that conjunctival cells were more easily inhibited by IL-1 blockers than corneal cells. These results indicate that IL-1 blockers can suppress the proliferation of conjunctival cells at dose levels which do not affect the normal cell growth of corneal cells.

Improvement of ocular blood flow and retinal functions with puerarin analogs.

Ischemic retinopathy and, particularly, age-related macular degeneration (AMD) are difficult eye diseases to treat. Since the etiology of these diseases is inadequate blood circulation in the retina and choroid, drugs which can improve blood circulation to these tissues should be beneficial to these diseases. Since fovea is avascular, AMD is closely related to choroidal vascular abnormalities, and drugs which show strong effects to increase choroidal blood flow would be particularly useful. Puerarin and all its derivatives, except ET (puerarin disubstituted with -CH2CH2OH), showed marked increase of choroidal blood flow at various time periods. Even ET showed a tendency to increase choroidal blood flow, though it was not statistically significant. As for b wave recovery, all puerarin analogs showed strong recovery of retinal function after ischemic insult for 30 min. These results indicate that puerarin analogs could be used for the treatment of ischemic retinopathy, and AMD in particular.

Effects of some N-nitropyrazole derivatives on ocular blood flow and retinal function recovery after ischemic insult.

Ocular blood flow and retinal function were determined in this study with colored microspheres and b-wave amplitude of electroretinography, respectively. It was found that N-nitropyrazole analogs can facilitate the retinal function recovery efficiently after ischemic insult primarily through increase of choroidal blood flow specifically. Since age-related macular degeneration (AMD) is caused mainly by the choroidal vascular abnormality and/or insufficiency, these N-nitropyrazole analogs are of potential use in the treatment of AMD.

Effects of crocin analogs on ocular blood flow and retinal function.

Ischemic retinopathy and age-related macular degeneration are the leading ocular diseases that cause blindness. The etiology of these diseases is due in part to the reduction of blood flow in the retina and/or choroid. Crocin analogs isolated from Crocus sativus L. were found to significantly increase the blood flow in the retina and choroid and to facilitate retinal function recovery. Increased blood flow due to vasodilation presumably improves oxygenation and nutrient supply of retinal structures. These results indicated that crocin analogs could be used to treat ischemic retinopathy and/or age-related macular degeneration. It was noted that disaccharide analogs of crocin, such as crocin-1 and crocin-2, were less potent than monosaccharide analogs of crocin, such as crocin-3 and crocin-4, constituting an interesting structure-activity relationship.

Systemic anti-inflammation by synthetic interleukin-1 blockers.

AIM: To study the systemic anti-inflammatory actions of interleukin-1 (IL-1) blockers, OB-101 and OB-186. METHODS: Prevention of palm swelling induced by carrageenin injection was used as an animal model of systemic anti-inflammation efficacy. RESULTS: Both OB-101 and OB-186 (10-30 mg.kg-1) were approximately 10-30-fold more potent than aspirin (300 mg.kg-1) to inhibit carrageenin-induced systemic inflammation. The LD50 of OB-101 and OB-186 were at least 20 g.kg-1 i.g., indicating that they were extremely safe agents with a therapeutic index (LD50/ED50) of at least 2000. CONCLUSION: These IL-1 blockers are extremely safe systemically and are useable for the treatment of systemic inflammation such as rheumatoid arthritis.

Anti-inflammation and antifibroblastic actions of interleukin-1 blockers.

Interleukin-1 (IL-1) blockers, CK 127 and CK 129, were found to inhibit IL-1-induced posterior uveitis very effectively at 3-10 mg/kg i.p. and were more potent than prednisolone which required at least 20 mg/kg i.p. to achieve the same level of anti-uveitis action. CK 127 and CK 129 were also found to be effective in inhibiting fibroblast-like corneal cells at 30-300 micrograms/ml and conjunctival cells at 0.3-10 micrograms/ml. These results indicate that IL-1 blockers are more potent in inhibiting the cell growth of conjunctival cells than that of corneal cells. From in vitro cell culture experiments, it was found that inhibition of cell growth could be due primarily to the inhibition of DNA. Although the inhibition of cell growth was due mainly to the inhibition of DNA synthesis, mRNA synthesis was also markedly inhibited. In both cells, the protein synthesis was unaffected in a few cases and markedly stimulated in most cases.

Antiuveitis and inhibition of fibroblast-like corneal and conjunctival cell cultures by interleukin-1 blockers, CK 125, CK 126 and CK 128.

Three new interleukin-1 (IL-1) blockers, CK 125, CK 126 and CK 128, were studied for their effects on IL-1-induced uveitis in rat eyes. They were more potent (at 3-10 mg/kg t.i.d.) than prednisolone (20 mg/kg t.i.d.) in effectively inhibiting posterior uveitis. They were also found to inhibit fibroblast-like corneal cells at 10-300 micrograms/ml concentrations and conjunctival cells at 1-30 micrograms/ml levels. The incorporation of leucine into corneal and conjunctival cells was either stimulated or unaffected by CK 126, indicating that the inhibition of cell growth has nothing to do with the protein synthesis. However, the incorporation of uridine into corneal and conjunctival cells was markedly inhibited by CK 126 at 3-30 micrograms/ml concentrations whereas the incorporation of thymidine into the cells was inhibited at a lesser extent than that of uridine. These results indicate that cell inhibition by CK 126 could be related mainly to the synthesis of mRNA and, to a lesser extent, to DNA synthesis.