Chronic Systemic Dexamethasone Regulates the Mineralocorticoid/Glucocorticoid Pathways Balance in Rat Ocular Tissues.

Central serous chorioretinopathy (CSCR) is a retinal disease affecting the retinal pigment epithelium (RPE) and the choroid. This is a recognized side-effect of glucocorticoids (GCs), administered through nasal, articular, oral and dermal routes. However, CSCR does not occur after intraocular GCs administration, suggesting that a hypothalamic-pituitary-adrenal axis (HPA) brake could play a role in the mechanistic link between CSCR and GS. The aim of this study was to explore this hypothesis. To induce HPA brake, Lewis rats received a systemic injection of dexamethasone daily for five days. Control rats received saline injections. Baseline levels of corticosterone were measured by Elisa at baseline and at 5 days in the serum and the ocular media and dexamethasone levels were measured at 5 days in the serum and ocular media. The expression of genes encoding glucocorticoid receptor (GR), mineralocorticoid receptors (MR), and the 11 beta hydroxysteroid dehydrogenase (HSD) enzymes 1 and 2 were quantified in the neural retina and in RPE/ choroid. The expression of MR target genes was quantified in the retina (Scnn1A (encoding ENac-α, Kir4.1 and Aqp4) and in the RPE/choroid (Shroom 2, Ngal, Mmp9 and Omg, Ptx3, Plaur and Fosl-1). Only 10% of the corticosterone serum concentration was measured in the ocular media. Corticosterone levels in the serum and in the ocular media dropped after 5 days of dexamethasone systemic treatment, reflecting HPA axis brake. Whilst both GR and MR were downregulated in the retina without MR/GR imbalance, in the RPE/choroid, both MR/GR and 11ß-hsd2/11ß-hsd1 ratio increased, indicating MR pathway activation. MR-target genes were upregulated in the RPE/ choroid but not in the retina. The psychological stress induced by the repeated injection of saline also induced HPA axis brake with a trend towards MR pathway activation in RPE/ choroid. HPA axis brake causes an imbalance of corticoid receptors expression in the RPE/choroid towards overactivation of MR pathway, which could favor the occurrence of CSCR.

Tear inflammatory cytokines and ocular surface changes in patients with active thyroid eye disease treated with high-dose intravenous glucocorticoids.

PURPOSE: To evaluate high-dose intravenous glucocorticoid treatment on tear inflammatory cytokines and ocular surface parameters in patients with active TED. Correlations between tear inflammatory cytokines and clinical parameters were also investigated. METHODS: This prospective pilot study included 15 moderate-to-severe and active TED patients. Control group consist of 15 sex and age-matched healthy subjects. All TED patients were treated with high-dose intravenous methylprednisolone with cumulative dose of 4.5 g during the therapy subdivided into 12 weekly infusions. Tear concentrations of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-17A, tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF) were measured by multiplex bead analysis in TED patients at baseline and 12 weeks after treatment. Ocular surface disease index (OSDI), tear break-up time (TBUT), corneal fluorescent staining, and Schirmer's test were obtained from TED and controls. RESULTS: All baseline cytokine levels except for IL-17A were significantly elevated in active TED patients compared with controls. Concentrations of IL-1ß, IL-6, IL-8, TNF-α, and VEGF were significantly decreased at 12 weeks compared with baseline. OSDI and TBUT showed significant improvement at 6 and 12 weeks. There were significant positive correlations between IL-6, IL-8, and CAS, and negative correlation was found between IL-6 level and TED duration before methylprednisolone treatment. The reduction of IL-6, IL-8, and VEGF were positive correlated with the reduction in CAS at 12 weeks. CONCLUSIONS: High-dose glucocorticoids treatment improved ocular surface symptom, increased the tear film stability, and decreased tear inflammatory cytokines in active TED. The reduction of the inflammatory cytokines is consistent with the improvement of clinical parameters.

Effects of Deepwater Horizon crude oil on ocular development in two estuarine fish species, red drum (Sciaenops ocellatus) and sheepshead minnow (Cyprinodon variegatus).

Polycyclic aromatic hydrocarbons (PAHs) present in crude oil have been shown to cause the dysregulation of genes important in eye development and function, as well as morphological abnormalities of the eye. However, it is not currently understood how these changes in gene expression are manifested as deficits in visual function. Embryonic red drum (Sciaenops ocellatus) and sheepshead minnow (Cyprinodon variegatus) were exposed to water accommodated fractions (WAFs) of weathered crude oil and assessed for visual function using an optomotor response assay in early life-stage larvae, with subsequent samples taken for histological analysis of the eyes. Larvae of both species exposed to increasing concentrations of oil exhibited a reduced optomotor response. The mean diameters of retinal layers, which play an important role in visual function and image processing, were significantly reduced in oil-exposed sheepshead larvae, though not in red drum larvae. The present study provides evidence that weathered crude oil has a significant effect on visual function in early life-stage fishes.

Systemic effects after intravitreal injection of bevacizumab in new born rabbit eyes.

PURPOSE: To determine the systemic impact of intravitreal injection of bevacizumab (IVB), an anti-vascular endothelium growth factor antibody, in newborn rabbits. MATERIALS AND METHODS: We used four groups of rabbits. Group 1 rabbits received a single injection of IVB starting from the age of 6 weeks. Group 2 rabbits received a single injection of balanced salt solution (BSS, 0.025 ml) and served as controls for group 1. Group 3 rabbits received two consecutive injections of IVB at the ages of 6 and 10 weeks. Group 4 rabbits received two consecutive injections of BSS at the ages of 6 and 10 weeks and served as controls for group 3. During the experiment, a complete blood count (CBC), clinical biochemistry, weight gain, food intake, body temperature, blood pressure, pulse, and mortality were measured in the animals. Two months after IVB injection, the animals were sacrificed, and histology of the major organs was checked. Immunohistochemistry was assessed to explore the neurons in the central nervous system (CNS). RESULTS: We found there were no morphological or functional changes in the eyes following IVB injection. Furthermore, there were no differences in CBC, biochemistry, or other measured parameters among the four groups of animals. We checked the histology of the major organs and neurons in the CNS and they did not reveal significant differences among the four groups of animals. CONCLUSIONS: Conclusively, IVB of either one or two injections (0.625 mg) in newborn rabbit eyes is well tolerated and does not cause noticeable systemic organ pathology.

Determination of the toxicity of intravitreal minocycline in rabbit eyes.

PURPOSE: To evaluate the retinal toxicity of intravitreal minocycline in rabbit eyes. METHODS: Intravitreal injection of minocycline with concentrations of 1000, 500, 250, 125 and 62.5 µg in 0.1 ml was performed in 10 New Zealand albino rabbits. Each concentration was injected into two rabbit eyes. For each dose, normal saline was injected in one contralateral eye and the other fellow eye remained non-injected. Electrophysiologic testing was performed before and 4 weeks after injections. The eyes were enucleated 4 weeks after injections and examined using light microscopy. RESULTS: The clinical examination was unremarkable after injections. Electroretinography recordings were significantly affected at all doses in at least one of the a- or b-waves of photopic or scotopic responses. Histopathologic examination revealed marked atrophy and loss of integrity in all retinal layers in all minocycline injected eyes. Contralateral eyes were normal. CONCLUSION: In our study, intravitreal minocycline was toxic to the retina in albino rabbits even at a concentration of 62.5 µg/0.1 ml.

Effects of dopamine receptor blockade on the intensity-response function of electroretinographic b- and d-waves in light-adapted eyes.

The effects of dopamine receptor blockade by sulpiride (D2-class antagonist) and sulpiride plus SCH 23390 (D1-class antagonist) on the V - log I function of the electroretinographic (ERG) b- and d-waves were investigated in light-adapted frog eyes. Sulpiride significantly decreased the absolute sensitivity of the b- and d-waves. The amplitude of the both waves was diminished over the whole intensity range studied. A similar effect on the b-, but not d-wave amplitude was seen during the perfusion with sulpiride plus SCH 23390. The effect on the d-wave amplitude depended on stimulus intensity. The threshold of the d-wave was not significantly altered. The suprathreshold d-wave amplitude was enhanced at the lower stimulus intensities and remained unchanged at the higher ones. The results obtained indicate that the action of endogenous dopamine on the photopic ERG shows clear ON-OFF asymmetry. Participation of different classes of dopamine receptors is probably responsible for this difference.

Correlation of botulinum toxin dose with neurophysiological parameters of efficacy and safety in the glabellar muscles: a double-blind, placebo-controlled, randomized study.

Despite the extensive use of botulinum toxin type A (BoNT-A) in treatments for glabellar frown lines, the dose-response effect in the glabellar muscles remains unknown. The aim of this randomized, double-blind, placebo-controlled prospective study was to characterize the neurophysiological parameters that correlate with the effect of BoNT-A in the glabellar muscles and its diffusion to surrounding ocular muscles. Sixteen healthy women were recruited and randomized to 3 different dose-groups of onabotulinumtoxin A (Vistabel®) or placebo and followed 24 weeks by neuro-physiological examinations. Efficacy of treatment on corrugator supercilii muscles was measured by compound motor action potential (CMAP) and electromyography (EMG). Photographs were used to score glabellar frown lines. Diffusion of the drug to surrounding muscles was assessed by CMAP of the nasalis muscle, EMG and concentric needle electrode jitter analysis (CNE) of the orbicularis oculi muscle. CMAP reduction correlated well with intramuscular BoNT-A dose. Muscle paralysis, measured by EMG, began from 2 weeks and was not entirely reversed at 24 weeks in individuals who received high dose of onabotulinumtoxin. Limited diffusion of orbicularis oculi was detected with CNE. In conclusion, we developed a novel neurophysiological strategy for effect evaluation of BoNT-A in glabellar muscles. CMAP and EMG correlated with given BoNT-A dose and are more defined effect measures than clinical glabellar photo scales.

Comparison of systemic atracurium, retrobulbar lidocaine, and sub-Tenon's lidocaine injections in akinesia and mydriasis in dogs.

OBJECTIVE: To compare the effect of sub-Tenon's lidocaine injections (ST) on akinesia and mydriasis to those of systemic atracurium (AT) and retrobulbar lidocaine injections in dogs. ANIMAL STUDIED: Ten healthy beagle dogs without apparent ocular disease. PROCEDURES: Three treatments were performed on 10 beagle dogs with a minimum 7-day washout period: intravenous injection of AT (0.2 mg/kg, AT group); retrobulbar (RB) injection of 2% lidocaine (2.0 mL, RB group) in one eye; and sub-Tenon's injection of 2% lidocaine (2.0 mL, ST group) in the opposite eye. When the akinesia was not obtained within 10 min, an additional 1 mL of lidocaine was administered in the RB and the ST groups. RESULTS: Onset of akinesia in the AT (1.5 ± 0.9 min) and the ST (3.8 ± 5.8 min) groups was significantly shorter than that in the RB group (9.0 ± 6.5 min). Duration of akinesia in the ST group (116.2 ± 32.8 min) was longer compared to the AT (60.6 ± 23.6 min) and the RB (89.0 ± 52.8 min) groups, even though there was only a significant difference between the AT and the ST groups. Mydriasis was achieved in five eyes in the RB group and nine eyes in the ST group. There was no significant difference in onset (3.6 ± 3.1 and 2.9 ± 2.3 min, respectively) or duration (91.4 ± 31.9 and 102.1 ± 35.8 min, respectively) of mydriasis between the groups. CONCLUSIONS: Sub-Tenon's lidocaine injections provide excellent akinesia and mydriasis compared to systemic AT and retrobulbar lidocaine injections. Therefore, sub-Tenon's anesthesia could be an alternative to the systemic administration of neuromuscular blockers and retrobulbar anesthesia for ophthalmic surgery in dogs.

Recent advances in ocular drug delivery.

Amongst the various routes of drug delivery, the field of ocular drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. Recent research has focused on the characteristic advantages and limitations of the various drug delivery systems, and further research will be required before the ideal system can be developed. Administration of drugs to the ocular region with conventional delivery systems leads to short contact time of the formulations on the epithelium and fast elimination of drugs. This transient residence time involves poor bioavailability of drugs which can be explained by the tear production, non-productive absorption and impermeability of corneal epithelium. Anatomy of the eye is shortly presented and is connected with ophthalmic delivery and bioavailability of drugs. In the present update on ocular dosage forms, chemical delivery systems such as prodrugs, the use of cyclodextrins to increase solubility of various drugs, the concept of penetration enhancers and other ocular drug delivery systems such as polymeric gels, bioadhesive hydrogels, in-situ forming gels with temperature-, pH-, or osmotically induced gelation, combination of polymers and colloidal systems such as liposomes, niosomes, cubosomes, microemulsions, nanoemulsions and nanoparticles are discussed. Novel ophthalmic delivery systems propose the use of many excipients to increase the viscosity or the bioadhesion of the product. New formulations like gels or colloidal systems have been tested with numerous active substances by in vitro and in vivo studies. Sustained drug release and increase in drug bioavailability have been obtained, offering the promise of innovation in drug delivery systems for ocular administration. Combining different properties of pharmaceutical formulations appears to offer a genuine synergy in bioavailability and sustained release. Promising results are obtained with colloidal systems which present very comfortable conditions of use and prolonged action.

Dual effects of ATP on isolated arteries of the bovine eye.

Although the presence of purinoreceptors has been shown in many human and animal arteries, there is few data yet about their role in the arteries of the eye. The purpose of the present study was to evaluate the effects of several agonists of purinoreceptors on isolated arteries of the bovine eye. Responses of isolated preparations of bovine ophthalmic (OA) and posterior ciliary arteries (PCA) to agonists of purinoreceptors (ATP, α,ß-methylene-ATP-α,ß-meATP, 2-methylthioATP-2meSATP, uridine-5'-triphosphate-UTP) as well as agonists of adreno-, cholino-, adenosine and histamine receptors were recorded by a standard organ bath method. ATP induced contractions of the intact vessels but caused relaxation of α,ß-meATP-pretreated arteries. Contractile responses of PCA to high concentrations of ATP and α,ß-meATP were significantly stronger than responses of OA, as well as relaxative responses to ATP and adenosine were significantly stronger in PCA than in OA. We suggest that there are several subtypes of functionally active purinoreceptors in both OA and PCA, although the potency of agonists of purinoreceptors to produce mechanical responses is higher in PCA than in OA. Purinoreceptors can be potential targets for new drugs, treating vascular pathology of the eye.

[Retinal drug targets]. / Cibles rétiniennes d'action des médicaments.

Retinal effects of systemically administered drugs are rare due to the hematoretinal barriers that protect the retina from circulating active principles. However, some compounds may have direct or indirect toxic effects on the retina through direct interaction with a specific receptor or due to their accumulation within pigment of uveal cells. In the latter case, toxicity is dose-dependent and may be observed years after cessation of medication, as observed with antimalarial drugs. Anti-infective and anti-inflammatory agents, particularly glucocorticoids, are currently injected peri- or intraocularly. The mechanisms and the exact toxicity of glucocorticoids on the retina remain poorly understood. More recently, anti-VEGF has been specifically developed for the treatment of retinal diseases. However, the long-term blockade of VEGF on normal retinal physiology should be determined taking into account VEGF and VEGF receptors expression in the normal and pathologic retina. Whilst enormous advances are made in the treatment of retinal diseases, basic research is still required to define more accurately the molecular targets of drugs to improve their benefits and reduce their potential side effects.

The Effects of Topical Timolol and Latanoprost on Calculated Ocular Perfusion Pressure in Nonglaucomatous Volunteers.

Purpose: To characterize the effects of timolol and latanoprost on calculated ocular perfusion pressure (OPP) in a multicenter, prospective, crossover-design study. Methods: Nonglaucomatous volunteers were evaluated at baseline, after 1 week of timolol 0.5% dosed twice daily, and after 1 week of latanoprost 0.005% dosed nightly (randomized treatment order; 6-week washout period). Pneumatonometric intraocular pressure (IOP) and brachial blood pressure (BP) were evaluated at each visit. Using 3 commonly used equations, OPP was calculated based on IOP and BP. The OPPs at each visit were compared by using linear mixed-effects models. Results: This analysis includes 121 participants (242 eyes; 75% female, 87% White, mean age 55 years). Mean OPP (standard deviation) calculated with mean arterial pressure was 46.8 (8.1) mmHg at baseline, 48.5 (7.9) mmHg with timolol (P = 0.005), and 49.6 mmHg (8.2) with latanoprost (P < 0.001). When compared with baseline, OPP calculated with diastolic BP was significantly increased with both timolol (1.3 mmHg) and latanoprost (3.1 mmHg). The OPP calculated with systolic BP was increased with latanoprost (2.8 mmHg) but decreased with timolol (-1.3 mmHg). Timolol reduced systolic BP by 3.2 mmHg. Compared with timolol, latanoprost conferred greater increases in OPP calculated with both systolic and diastolic BP compared with baseline; however, the difference in treatment effects on OPP calculated with mean arterial pressure was not significantly different (P = 0.068). Conclusion: In this crossover study of nonglaucomatous volunteers, latanoprost increased OPP. However, timolol's benefit to OPP may be limited in part because it reduced systolic BP. Clinical Trial Registration number: NCT01677507.

Technical note: Effects of an epinephrine infusion on eye temperature and heart rate variability in bull calves.

Changes in autonomic nervous system (ANS) activity are one of the first phases of a stress response, but they are rarely used to assess the welfare of farm animals. Eye temperature measured using infrared thermography (IRT) is proposed as an indicator of ANS activity because it may reflect changes in blood flow in the capillary beds of the conjunctiva. The aim was to determine whether epinephrine infusion would initiate eye temperature changes in calves. Sixteen 4-mo-old Friesian calves (124±5 kg) were assigned randomly to receive a jugular infusion of either epinephrine (4 µg/kg per min for 5 min) or saline. Eye temperature (°C), heart rate (HR), and HR variability (HRV) were recorded from 15 min before infusion until 10 min after it was completed. Blood samples collected via jugular catheter were assayed for epinephrine, norepinephrine, and cortisol concentrations, and packed cell volume (PCV) was measured. No changes in any variable were observed with the saline infusion. Plasma epinephrine concentrations increased 90-fold with epinephrine infusion, which was associated with a decrease in eye temperature of 1.4±0.05°C. During epinephrine infusion, plasma norepinephrine concentrations decreased by half and HR decreased by 9.3±3.3 beats/min. The HRV measure, the root mean square of successive differences, increased by 49.7±9.2 ms, indicating a compensatory increase in parasympathetic activity. After epinephrine infusion, plasma cortisol concentrations increased by 10.4±1.7 ng/mL and PCV was higher (38 vs. 31±0.1%, epinephrine vs. saline, respectively). These results support the hypothesis that changes in eye temperature are mediated by the sympathetic component of the ANS. Infrared thermography is a noninvasive method to assess ANS activity for evaluating welfare of cattle.

Cationic Emulsion-Based Artificial Tears as a Mimic of Functional Healthy Tear Film for Restoration of Ocular Surface Homeostasis in Dry Eye Disease.

Dry eye disease (DED) is a complex multifactorial disease that affects an increasing number of patients worldwide. Close to 30% of the population has experienced dry eye (DE) symptoms and presented with some signs of the disease during their lifetime. The significant heterogeneity in the medical background of patients with DEs and in their sensitivity to symptoms renders a clear understanding of DED complicated. It has become evident over the past few years that DED results from an impairment of the ocular surface homeostasis. Hence, a holistic treatment approach that concomitantly addresses the different mechanisms that result in the destabilization of the tear film (TF) and the ocular surface would be appropriate. The goal of the present review is to compile the different types of scientific evidence (from in silico modeling to clinical trials) that help explain the mechanism of action of cationic emulsion (CE)-based eye drop technology for the treatment of both the signs and the symptoms of DED. These CE-based artificial tear (AT) eye drops designed to mimic, from a functional point of view, a healthy TF contribute to the restoration of a healthy ocular surface environment and TF that leads to a better management of DE patients. The CE-based AT eye drops help restore the ocular surface homeostasis in patients who have unstable TF or no tears.

Revisiting 35 and 94 GHZ Millimeter Wave Exposure to the Non-Human Primate Eye.

A previous study reported thermal effects resulting from millimeter wave exposures at 35 and 94 GHz on non-human primates, specifically rhesus monkeys' (Macaca mulatta) corneas, but the data exhibited large variations in the observed temperatures and uncertainties in the millimeter wave dosimetry. By incorporating improvements in models and dosimetry, a non-human primate experiment was conducted involving corneal exposures that agreed well with a three-layer, one-dimensional, thermodynamic model to predict the expected surface temperature rise. The new data indicated that the originally reported safety margins for eye exposures were underestimated by 41 ± 20% over the power densities explored. As a result, the expected minimal visible lesion thresholds should be raised to 10.6 ± 1.5 and 7.1 ± 1.0 J cm at 35 and 94 GHz, respectively, provided that the power density is less than 6 W cm for subjects that are unable to blink. If the blink reflex was active, a power density threshold of 20 W cm could be used to protect the eye, although the eyelid could be burned if the exposure was long enough.

Mucus-Penetrating Particles and the Role of Ocular Mucus as a Barrier to Micro- and Nanosuspensions.

The ocular surface is naturally covered with a layer of mucus. Along with other functions, this mucus layer serves to trap and eliminate foreign substances, such as allergens, pathogens, and debris. In playing this pivotal role, mucus can also hinder topical delivery of therapeutics to the eye. Recent studies provide evidence that drugs formulated as traditional micro- or nanoparticles are susceptible to entrapment and rapid clearance by ocular mucus. Mucus-penetrating particles (MPPs) is a nanoparticle technology that emerged over the past decade. With a muco-inert surface and a particle size smaller than the mucus mesh size, MPPs can diffuse in ex vivo mucus essentially freely. Preclinical studies have shown that, compared with particles lacking the mucus-penetrating attributes, MPPs can improve the uniformity of drug particle distribution on mucosal surfaces and enhance drug delivery to ocular tissues.

Probiotic modulation of perfluorobutanesulfonate toxicity in zebrafish: Disturbances in retinoid metabolism and visual physiology.

Perfluorobutanesulfonate (PFBS), an aquatic pollutant of emerging concern, is found to disturb gut microbiota, retinoid metabolism and visual signaling in teleosts, while probiotic supplementation can shape gut microbial community to improve retinoid absorption. However, it remains unknown whether probiotic bacteria can modulate the toxicities of PFBS on retinoid metabolism and visual physiology. In the present study, adult zebrafish were exposed for 28 days to 0, 10 and 100 µg/L PFBS, with or without dietary administration of probiotic Lactobacillus rhamnosus. Interaction between PFBS and probiotic was examined regarding retinoid dynamics (intestine, liver and eye) and visual stimuli transmission. PFBS single exposures remarkably inhibited the absorption of retinyl ester in female intestines, which were, however, restored by probiotic to normal status. Although coexposure scenarios markedly increased the hepatic storage of retinyl ester in females, mobilization of retinol was reduced in livers by single or combined exposures regardless of sex. In the eyes, transport and catalytic conversion of retinol to retinal and retinoic acid were interrupted by PFBS alone, which were efficiently antagonized by probiotic presumably through an indirect action. In response to the availability of retinal chromophore, transcriptions of opsins and arrestin genes were altered adaptively to control visual perception and termination. Neurotransmission across retina circuitry was changed accordingly, centering on epinephrine and norepinephrine. In summary, the present study found the efficient modulation of probiotic on retinoid metabolic disorders of PFBS pollution, which subsequently impacted visual signaling. A future work is warranted to provide mechanistic clues in retinoid interaction.

HLA genotypes and cold medicine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications: a systematic review and meta-analysis.

Serious cutaneous adverse drug reactions [i.e., SJS/TEN with severe ocular complications (SOC)] associated with cold medicine (CM) were reported in several studies. To assess the risks of CM-induced SJS/TEN with SOC, systematic review and meta-analysis were employed. Studies investigating associations between HLA genotypes and CM-induced SJS/TEN with SOC were systematically searched in PubMed, Scopus and the Cochrane Library. Overall odds ratios (ORs) with 95% CIs were calculated using a random-effects model to determine these associations. An initial search of the databases identified 24,011 articles, of which 6 studies met the inclusion criteria. In total from all studies, associations between 81 different HLA genotypes and CM-induced SJS/TEN with SOC (i.e., 22 different HLA-A genotypes, 40 different HLA-B genotypes and 19 different HLA-C genotypes) were investigated. Risk factors to develop SJS/TEN with SOC in patients who used CM were identified from our meta-analysis. HLA-A*0206 (OR = 3.90; 95% CI = 1.96-7.77), HLA-A*3303 (OR = 2.28; 95% CI = 1.31-3.97), HLA-B*4403 (OR = 3.27; 95% CI = 1.52-7.03) and HLA-C*0501 (OR = 2.55; 95% CI = 1.19-5.44) were associated with CM-induced SJS/TEN with SOC. With our results demonstrating a significant association between using of CMs and the severe ADR, a genetic testing can be helpful. However, the CMs are commonly used as an over-the-counter drug in practically almost of people in populations worldwide, the genetic screening prior to use of the CMs might not be cost-effective. Nonetheless, for people with a family history of developing the ADRs with a possible involvement of CMs, a genetic screening may be beneficial.

Drosophila alpha-1,4-glycosyltransferase (alpha-4GT1) inhibits reaper-mediated apoptosis in the eye.

In a genetic screen, alpha-4GT1 has been identified as a potential enhancer of Hairless-mediated cell death in the eye of Drosophila. alpha-4GT1 encodes an alpha-1,4-glycosyltransferase, known to catalyze the fifth step in a series of ceramide glycosylation events. As reported for other enzymes involved in the glycosylation of ceramide, alpha-4GT1 is strongly expressed during oogenesis and is deposited maternally in the egg. Moreover, the protein is enriched at cell membranes. Unexpectedly, overexpression of alpha-4GT1 does not enhance Hairless-mediated cell death; instead, Hairless enhancement is caused by an allele of Scutoid present on the alpha-4GT1 chromosome. Interestingly, the downregulation of alpha-4GT1 during eye development amplifies cell death induction by the pro-apoptotic gene reaper. Accordingly, overexpression of alpha-4GT1 represses reaper-induced cell death. Thus, alpha-4GT1 appears to be an inhibitor of apoptosis, as has previously been observed for other ceramide glycosylating enzymes, suggesting that it likewise contributes to ceramide anchoring in the membrane.

Transient bevacizumab (avastin)-induced alterations in rat eyes.

AIMS: To study the histopathological, biochemical and functional effects of intravitreal bevacizumab on the rat eye, with special emphasis on its immediate pro-inflammatory features eventually associated with cellular oxidative burden. METHODS: Histopathological evaluation was performed 24 h, 1 and 4 weeks after bevacizumab (75 microg/rat eye) or saline intravitreal injection, as well as biochemical analysis of oxidative stress-related markers and electroretinograms. RESULTS: Bevacizumab induces a transient inflammatory reaction together with a modification of the b-wave amplitude and latency of the electroretinogram. No changes were observed in any of the oxidative stress markers studied at any time after injection. CONCLUSION: Intravitreal bevacizumab injection per se generates an immediate, transient and mild inflammation of the rat eye, which is not associated with oxidative stress in ocular tissues.