Propofol: del blanco al verde / Propofol: From white to green

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Effect of Kynurenic Acid on Pupae Viability of Drosophila melanogaster cinnabar and cardinal Eye Color Mutants with Altered Tryptophan-Kynurenine Metabolism.

Kynurenic acid (KYNA) is one of the metabolites of evolutionary conserved tryptophan (Trp)/kynurenine (Kyn) metabolic pathway. Elevation of KYNA contributes to development of psychosis in schizophrenia but attenuates neurodegeneration in Drosophila model of Huntington's disease. We have reported that KYNA increased lethality of pupae of wild-type flies, but not of vermilion (v) mutants with impaired formation of Kyn from Trp, suggesting that KYNA toxicity depends on its interaction with downstream Kyn metabolites [i.e., 3-hydroxykynurenine (3-HK) and/or xanthurenic acid (XA)]. The present study aimed to further explore the mechanisms of KYNA-induced lethality by the assessment of KYNA effect on pupae of two Drosophila mutants: cinnabar (cn), characterized by higher KYNA and lower 3-HK production, and cardinal (cd), characterized by higher 3-HK and XA levels compared to wild-type flies. Our microarray datamining revealed that the gene expression pattern of enzymes forming Trp/Kyn pathway stands in line with previously reported developmental changes in KYNA, 3-HK, and XA concentrations in wild-type and mutant flies. Administration of KYNA increased pupae lethality in cd, but not in cn mutants. Present data suggest that toxic effect of exogenous KYNA depends on the presence of 3-HK and/or XA. This is further supported by our finding that early stages of Drosophila development are associated with a positive expression pattern of genes encoding sulfotransferases, enzymes that are inhibited by KYNA and are involved in detoxification of XA. Alternatively, the toxic effect of KYNA might depend on anti-proliferative effects of KYNA.

A Clinical Randomized Trial Comparing the Cycloplegic Effect of Cyclopentolate Drops Applied to Closed Eyelids Versus Open Eyelids.

BACKGROUND AND PURPOSE: Adequate cycloplegia and dilation are required for refraction and fundus exam in children. Standard practice is to instill cycloplegic drops in the inferior cul-de-sac, and this is often traumatic for children. Our study assesses the use of cyclopentolate on closed lids as a method of instillation for ensuring complete cycloplegia. PATIENTS AND METHOD: Ninety children presenting for annual refraction were enrolled. Three were excluded as they did not finish the testing. One drop of Alcaine® and one drop of cyclopentolate HCL 1% were used in each eye. Cyclopentolate drops were placed on the inner canthus near the lid margin on the closed eye and directly onto the conjunctiva of the fellow eye. RESULTS: Overall, 145/174 eyes (83%) were fully cyclopleged with one drop. The methods of instillation were equally successful (seventy-two indirect vs. seventy-three direct). Age, eye color, spherical refractive error, astigmatic refractive error, and presence of amblyopia on the study visit played no role in the success of either method. Dark irises where the pupil margin was clinically indistinguishable had the largest number of failures (n = 17/44) in comparison to light irises (12/130), but had an equal amount of failures for both direct and indirect methods. CONCLUSION: Placing one drop of cyclopentolate HCL 1% on a closed eyelid had a success rate for complete cycloplegia that was equivalent to placing one drop directly on the cornea.

Induction of homologous recombination following in utero exposure to DNA-damaging agents.

Much of our understanding of homologous recombination, as well as the development of the working models for these processes, has been derived from extensive work in model organisms, such as yeast and fruit flies, and mammalian systems by studying the repair of induced double strand breaks or repair following exposure to genotoxic agents in vitro. We therefore set out to expand this in vitro work to ask whether DNA-damaging agents with varying modes of action could induce somatic change in an in vivo mouse model of homologous recombination. We exposed pregnant dams to DNA-damaging agents, conferring a variety of lesions at a specific time in embryo development. To monitor homologous recombination frequency, we used the well-established retinal pigment epithelium pink-eyed unstable assay. Homologous recombination resulting in the deletion of a duplicated 70 kb fragment in the coding region of the Oca2 gene renders this gene functional and can be visualized as a pigmented eyespot in the retinal pigment epithelium. We observed an increased frequency of pigmented eyespots in resultant litters following exposure to cisplatin, methyl methanesulfonate, ethyl methanesulfonate, 3-aminobenzamide, bleomycin, and etoposide with a contrasting decrease in the frequency of detectable reversion events following camptothecin and hydroxyurea exposure. The somatic genomic rearrangements that result from such a wide variety of differently acting damaging agents implies long-term potential effects from even short-term in utero exposures.

Protective effects of new medicinal mushroom, Grifola gargal singer (higher Basidiomycetes), on induced DNA damage in somatic cells of Drosophila melanogaster.

Grifola gargal is an edible mushroom with attributed antioxidant properties. Different sources of G. gargal materials, i.e., fruit bodies and mycelia grown in liquid or solid media, were used to study its potential protective capacity when somatic mutation and recombination is induced in Drosophila melanogaster using DMBA (7-12-dimethyl-benz(α)anthracene) as promutagen. Heterozygote larvae (white/white+) were grown in media with different concentrations of DMBA. Grifola gargal fruit bodies (GgFB) or mycelia from liquid culture (GgLC) or from solid culture (GgWG), i.e., biotransformed wheat kernel flour, were added to the culture media in combined treatments with DMBA. Water, DMBA solvent, or wheat flour (WF) plus DMBA solvent were used as negative controls. Larval mortality increased from 9% to 11% in negative controls to 31% to 36% in DMBA treatments. The addition of GgFB, GgLC, or GgWG materials produced a protective effect on 25 µmol/vial DMBA-induced mortality. Mutations observed in SMART, as light spots per 100 eyes (LS/100 eyes), increased with increasing doses of DMBA; this was also true when considering the mutation incidence expressed as percentage of eyes exhibiting light spots (% eyes with LS). Interestingly, mycelia from GgFB, GgLC, or GgWG, in the presence of 25 µmol/vial DMBA, showed lower values in SMART of both the total LS/100 eyes and the percentage of eyes with LS. Thus, Grifola gargal materials were not only nontoxic, but in combination with 25 µmol/vial DMBA lowered the mortality induced by the promutagen and showed antimutagenic effects. Protective effects of G. gargal against DMBA are discussed in terms of the onset of desmutagenic and/or bioantimutagenic mechanisms of detoxification in the host organism, probably due to some bioactive compounds known to occur in higher mushrooms.

Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism.

Oculocutaneous albinism (OCA) is a group of genetic disorders characterized by hypopigmentation of the skin, hair, and eyes. Affected individuals experience reduced visual acuity and substantially increased skin cancer risk. There are four major types of OCA (OCA1-OCA4) that result from disruption in production of melanin from tyrosine. Current treatment options for individuals with OCA are limited to attempts to correct visual problems and counseling to promote use of sun protective measures. However, Onojafe et al., reporting in this issue of the JCI, provide hope for a new treatment approach for OCA, as they demonstrate that treating mice that model OCA-1b with nitisinone, which is FDA approved for treating hereditary tyrosinemia type 1, elevates plasma tyrosine levels, and increases eye and hair pigmentation.

Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism.

Mutation of the tyrosinase gene (TYR) causes oculocutaneous albinism, type 1 (OCA1), a condition characterized by reduced skin and eye melanin pigmentation and by vision loss. The retinal pigment epithelium influences postnatal visual development. Therefore, increasing ocular pigmentation in patients with OCA1 might enhance visual function. There are 2 forms of OCA1, OCA-1A and OCA-1B. Individuals with the former lack functional tyrosinase and therefore lack melanin, while individuals with the latter produce some melanin. We hypothesized that increasing plasma tyrosine concentrations using nitisinone, an FDA-approved inhibitor of tyrosine degradation, could stabilize tyrosinase and improve pigmentation in individuals with OCA1. Here, we tested this hypothesis in mice homozygous for either the Tyrc-2J null allele or the Tyrc-h allele, which model OCA-1A and OCA-1B, respectively. Only nitisinone-treated Tyrc-h/c-h mice manifested increased pigmentation in their fur and irides and had more pigmented melanosomes. High levels of tyrosine improved the stability and enzymatic function of the Tyrc-h protein and also increased overall melanin levels in melanocytes from a human with OCA-1B. These results suggest that the use of nitisinone in OCA-1B patients could improve their pigmentation and potentially ameliorate vision loss.

Subconjunctival bevacizumab injection in treatment of pterygium.

This study determined the clinical effect of subconjunctival administration of bevacizumab in patients with primary and recurrent pterygium. The study was an off-label, single-dosing, interventional case series involving 22 patients with primary and recurrent pterygium. They received subconjunctival bevacizumab (0.2 cc). Pterygium vascularity and thickness was graded. The size of the pterygium (measured by surface area in cm2) was recorded from baseline to 12 weeks, after injection. Treatment-related complications and adverse events were reported. The main outcome of measurements was the change in size, vascularity, thickness, color intensity. There were 15 males (68.2%) and 7 females (31.8%) of 22 patients with a mean age of 45.5 years (SD 11.68 years). One cases didn't cooperate, and excluded. There was a significant difference in the mean surface area of pterygium at different intervals (P < 0.05) and the size of pterygium was reduced. On comparison of the mean pterygium size, there was no significant difference between men and women (P >0.05). There was a significant reduction in the mean pterygium size of patients younger than 45 years in comparison to those older than 45 years after three month (P =0.037), but after 6 months, this difference was not significant (P = 0.338). Average changes in pterygium size for both eyes were not different. The reduction of color intensity in both eyes was significant (P =0.031). Subconjuctival bevacizumab injection is useful in management of patients with primary and recurrent pterygium without significant local or systemic adverse effects.

Five-year, multicenter safety study of fixed-combination latanoprost/timolol (Xalacom) for open-angle glaucoma and ocular hypertension.

PURPOSE: To evaluate the safety of fixed-combination latanoprost/timolol (Xalacom) in patients requiring additional intraocular pressure (IOP) reduction over 5 years. METHODS: This phase 3b, open-label, multicenter study included prostaglandin-naive participants with open-angle glaucoma or ocular hypertension insufficiently responsive to ß-blockers and requiring additional IOP reduction. Participants were evaluated at eleven 6-month visits. A masked assessor evaluated iris/eyelash changes at baseline and 12, 36, and 60 months. Increased iris pigmentation incidence was compared with a historic control from a similarly designed study evaluating latanoprost. Ocular and systemic adverse events were recorded. RESULTS: Among 828/974 treated participants with assessable iris photographs, 233 (28.1%) developed increased iris pigmentation versus 127/380 (33.4%) in the historic controls. Participants with mixed eye colors exhibited greater susceptibility to overall increased iris pigmentation (85.8% in both studies). In this study, most participants (80.3%) with increased iris pigmentation developed only a weak increase. Eyelash changes were seen in 58.1% of participants and darkening of the eyelids in 5-6%; 14.1% experienced a serious adverse event. Adverse events resulted in treatment withdrawal in 133 (13.7%) participants. Most were nonserious ocular adverse events, about half of them ocular irritation. Only 3 of 13 serious systemic adverse events were considered to be drug related by the investigator. Mean IOP reductions were stable over 5 years. CONCLUSIONS: After 5 years, more than 70% of participants treated with fixed-combination latanoprost/timolol had no increased iris pigmentation. The fixed combination is safe and well tolerated for long-term treatment in patients with open-angle glaucoma or ocular hypertension.

Eyelash growth from application of bimatoprost in gel suspension to the base of the eyelashes.

OBJECTIVE: To determine whether bimatoprost (Lumigan, Allergan Inc., Irvine, CA) causes increased lash length when used in gel suspension applied to the base of the eyelashes. DESIGN: Randomized controlled trial. PARTICIPANTS: Nineteen subjects were enrolled. METHODS: Subjects recruited from the Bascom Palmer Eye Institute were screened, and those who met inclusion criteria were enrolled. Each participant received 2 vials of gel suspension, which contained bimatoprost and normal saline, respectively, each mixed 1:1 with Gonak gel (Akorn Inc., Lake Forest, IL) and labeled "right eye" and "left eye" according to randomization. The suspension was applied to the upper eyelid eyelashes every evening on the designated eye for 6 weeks. MAIN OUTCOME MEASURES: Lash length was measured with a caliper at enrollment, at weekly intervals during the application of the gel, and at 1 and 3 months after discontinuation of its use. Visual acuity, ocular symptoms, intraocular pressure, and photographs were documented at these same intervals. RESULTS: The mean eyelash growth from baseline in the bimatoprost group was 2.0 mm versus a mean of 1.1 mm in the placebo group, which was a statistically significant difference (P=0.009). The average intraocular pressure decreased equally in both groups (2 mmHg). No change in visual acuity or iris discoloration was noted in any of the subjects. CONCLUSIONS: Our data showed an increase in eyelash length with the use of bimatoprost in gel suspension, suggesting the product's eyelash-lengthening properties.

Effects of latanoprost in iris bioidentification.

PURPOSE: Bioidentification is becoming increasingly important in everyday life. One of the most widespread methods of bioidentification is based on the structure of the iris. Iris photography has several advantages as an identification method: it is relatively simple and effective; it is non-invasive, and it is comparatively inexpensive. However, some medical conditions may change the appearance of the iris. This paper discusses the effects of latanoprost-induced pigmentation changes in iris bioidentification. METHODS: The study is based on four extreme cases of latanoprost-induced pigmentation changes. Iris photographs in these patients during treatment are compared with pretreatment photographs. The comparison is carried out with iris recognition software developed by our research group based on the principles of Daugman's well-known IrisCode. The system was evaluated with 595 iris comparisons. RESULTS: Iris photographs showing latanoprost-induced pigmentation changes were correctly matched with pretreatment photographs of the same irises with an error probability similar to that for matching equivalent pairs of photographs in intact eyes. CONCLUSIONS: Our results indicate that the pigmentation changes studied do not seem to have a significant effect on the standard identification algorithm.

Increased iridial pigmentation in Chinese eyes after use of travoprost 0.004%.

PURPOSE: To investigate the topical use of travoprost [Trademark: Travatan (Alcon laboratories Inc, TX)] and the incidence of iridial pigmentation change in the brown irises of Chinese eyes. DESIGN: Prospective, masked, observational study. Enrolled in the study were 37 Chinese subjects (73 eyes) with primary open-angle glaucoma who were being treated for the first time with travoprost eye drops (patient-group). Twenty-one Chinese volunteers with normal eyes (42 eyes) served as the control-group. To evaluate iris pigmentation, photographs were taken of the control-group's irises using a slit-lamp biomicroscope with attached digital camera. Before the start of travoprost treatment and 3 months after the start of travoprost treatment, photographs of the irises of the patient-group were taken using the same photographic methods. Five glaucoma specialists independently read the series of photographs to determine if there was an increase in iris pigmentation. Three of the 5 observers had to be in agreement that there was an increase from the baseline. "Picture Color Analyzer" computer software was also used to calculate the color value of each iris picture. RESULTS: Observation with eyes: Twenty-six eyes (35.6%) in the patient-group developed an increase in iris pigmentation compared with zero subjects (0%) in the control-group (P=0.000, chi(2) test). Results with Picture Color Analyzer software: On the basis of the threshold value that was obtained from the control-group, 22 eyes (30.1%, n=73) in the patient-group were shown to have developed an increase in iris pigmentation. CONCLUSIONS: Contrary to the previous studies that noted that the percentage of iris hyperpigmentation caused by travoprost in homochromic brown eyes was very low, our study showed that 35.6% iris hyperpigmentation did occur, which is a considerably higher percentage than that reported in whites.

Prostanoids for the management of glaucoma.

BACKGROUND: Prostanoids are the newest pharmacologic group of ocular hypotensive drugs for clinical management of glaucoma. The group includes four chemical compounds structurally derived from naturally-occurring prostaglandin (PG) F(2). Prostanoids have been divided into PG analogues (unoprostone, latanoprost and travoprost) and prostamides (bimatoprost) because of differences in molecular structures. The drugs share a novel mechanism of action that produces a potent ocular hypotensive effect and a novel local adverse effect of increased iridial pigmentation. OBJECTIVE: To summarise the pharmacologic and clinical data regarding the effectiveness and safety of prostanoids in clinical glaucoma management. METHODS: The review was supported by a literature search of peer-reviewed publications, based on medical information available in databases such as PubMed. RESULTS/CONCLUSION: The prostanoids began a treatment revolution not only because of their novel mechanism of action but also as a result of a new local side effect.

The clinical impact and incidence of periocular pigmentation associated with either latanoprost or bimatoprost therapy.

PURPOSE: To evaluate the incidence and characteristics of periocular pigmentation with latanoprost versus bimatoprost. METHODS: A retrospective, active-controlled comparison of consecutive patients treated with latanoprost or bimatoprost for 12 months evaluating patients to determine the incidence, characteristics, and reversibility of periocular pigmentation. RESULTS: Periocular pigmentation was found in 1% patients treated with latanoprost and 6% patients treated with bimatoprost within 12 months of beginning treatment (p = 0.004). CONCLUSIONS: This study suggests that periocular pigmentation may develop after treatment with latanoprost or bimatoprost.

Monte Carlo simulation of latanoprost induced iris darkening.

The aim of this study was to provide numerical evidence that latanoprost induced iris darkening (LIID) can be caused by changes to the melanin granule size distribution in the anterior segment of the iris. Iridectomies from two patients were used, where both had undergone unilateral treatment with latanoprost and had exhibited LIID. The untreated eye provided the comparative control. Micrographs from the iris samples were analysed to determine the number and size of the mature melanin granules. Monte Carlo (MC) simulation of light propagation in the iris was performed to examine the changes in reflectance and absorption with varying particle size and density. The reflected intensity of light was obtained as a function of wavelength. CIE colour theory was employed in order to estimate a perceived colour from the reflectance data. MC simulations showed that the reflectance was reduced for the LIID irises compared to the control irises for both subjects and for all wavelengths of light. The MC simulated colours were in good agreement with the in vivo photography of the eye colour. Hence, we have demonstrated that increases in melanin granule size causes iris darkening, and can explain LIID.