[Blue light and intraocular lenses (IOLs): Beliefs and realities]. / Lumière bleue et implants intraoculaires : croyances et réalités.

The first intraocular lenses (IOLs) used for cataract surgery transmitted both ultraviolet (UV) radiation and visible light to the retina. Colorless UV-blocking IOLs were introduced and rapidly adopted in the 1980s. Yellow-tinted blue-blocking (also known as blue-filtering) IOLs were marketed in the early 1990s. Blue-blocking IOLs were intended to simulate age-related crystalline lens yellowing to reduce the cyanopsia that some patients experienced after cataract surgery. When blue-filtering IOLs were introduced in North America, however, blue-blocking chromophores were advocated as a way to protect patients from age-related macular degeneration (AMD) despite the lack of evidence that normal environmental light exposure causes AMD. The "blue light hazard" is a term that describes the experimental finding that acute, abnormally intense light exposures are potentially more phototoxic to the retina when short rather than long wavelengths are used. Thus, in brief exposures to intense light sources such as welding arcs, ultraviolet radiation is more hazardous than blue light, which is more hazardous than longer wavelength green or red light. International commissions have cautioned that the blue light hazard does not apply to normal indoor or outdoor light exposures. Nonetheless, the hazard is used for commercial purposes to suggest misleadingly that ambient environmental light can cause acute retinal phototoxicity and increase the risk of AMD. Very large epidemiological studies show that blue-blocking IOLs do not reduce the risk or progression of AMD. Additionally, blue-filtering IOLs or spectacles cannot decrease glare disability, because they decrease image and glare illuminance in the same proportion. Blue light is essential for older adults' scotopic photoreception needed to reduce the risk of nighttime falling and related injuries. It is also critical for circadian photoreception that is essential for good health, sleep and cognitive performance. Unfortunately, age-related pupillary miosis, retinal rod and ganglion cell photoreceptor degeneration and decreased outdoor activity all reduce the amount of healthful blue light available to older adults. Blue-restricting IOLs further reduce the available blue light at a time when older adults need it most. Patients and ophthalmologists are exposed to hypothesis-based advertisements for blue-filtering optical devices that suppress short wavelength light critical for vision in dim lighting and for good physical and mental health. Spectacle and intraocular lens selections should be based on scientific fact, not conjecture. Ideal IOLs should improve photoreception rather than limit it permanently. Practice efficiency, surgical convenience and physician-manufacturer relationships may eliminate a patient's opportunity to choose between colorless blue-transmitting IOLs and yellow-tinted, blue-restricting IOLs. Cataract surgeons ultimately determine whether their patients have the opportunity to make an informed choice about their future photoreception.

[Epigenetics and myopia: Mechanisms and therapeutic targets]. / Épigénétique et myopie : mécanismes et perspectives thérapeutiques.

The development of myopia is influenced by multiple environmental and genetic factors. A third component, epigenetics, may shed light on some of the relationships between environmental and genetic factors. Epigenetics is defined as the study of modulations of gene activity that can be transmitted over cell divisions without involving mutation of the DNA sequence. Methylation is one of the main mechanisms by which gene expression is decreased. In the context of myopia, the study of epigenetic mechanisms also contributes to the understanding of the involvement of candidate genetic variants. The analysis of metabolic and signalling pathways associated with ocular development enables discussion of the biological significance associated with these candidate genes. A better understanding of epigenetic mechanisms would allow individual risk estimations for myopia and probably targeting of therapeutic interventions at a population level. Measuring the level of DNA methylation at candidate gene sites could be used to monitor the effectiveness of myopia prevention measures such as reducing near work and increasing outdoor activity. More specifically, one could consider activating the methylation of myopia promoter genes or, on the contrary, inhibiting the methylation of myopia repressor genes. Finally, the control of metabolic and signalling pathways could be considered by targeting, for example, the regulation of the G protein signalling pathway (RGS 2) with the expression of the adenosine A2a receptor (AdoRs).

How spontaneous pneumothorax is managed in emergency departments: a French multicentre descriptive study.

BACKGROUND: Management of spontaneous pneumothorax (SP) is still subject to debate. Although encouraging results of recent studies about outpatient management with chest drains fitted with a one-way valve, no data exist concerning application of this strategy in real life conditions. We assessed how SP are managed in Emergency departments (EDs), in particular the role of outpatient management, the types of interventions and the specialty of the physicians who perform these interventions. METHODS: From June 2009 to May 2013, all cases of spontaneous primary (PSP) and spontaneous secondary pneumothorax (SSP) from EDs of 14 hospitals in France were retrospectively included. First line treatment (observation, aspiration, thoracic drainage or surgery), type of management (admitted, discharged to home directly from the ED, outpatient management) and the specialty of the physicians were collected from the medical files of the ED. RESULTS: Among 1868 SP included, an outpatient management strategy was chosen in 179 PSP (10%) and 38 SSP (2%), mostly when no intervention was performed. Only 25 PSP (1%) were treated by aspiration and discharged to home after ED admission. Observation was the chosen strategy for 985 patients (53%). In 883 patients with an intervention (47%), it was performed by emergency physicians in 71% of cases and thoracic drainage was the most frequent choice (670 patients, 76%). CONCLUSIONS: Our study showed the low level of implementation of outpatient management for PS in France. Despite encouraging results of studies concerning outpatient management, chest tube drainage and hospitalization remain preponderant in the treatment of SP.

Primary Spontaneous Pneumothorax Admitted in Emergency Unit: Does First Episode Differ from Recurrence? A Cross-Sectional Study.

Introduction. Management of primary spontaneous pneumothorax (PSP) consists of immediate resolution of pleural air, or observation, and prevention of recurrence. The risk factors for recurrence remain debated. Objectives. We aimed to describe and compare the characteristics of patients presenting a first episode of PSP to those of patients presenting a recurrent PSP, in order to identify factors potentially related to recurrence. Methods. We conducted a cross-sectional study including all admissions for PSP in the EDs of fourteen French public hospitals from 2009 to 2013. PSP were classified as a first episode if the patient had no previous history of pneumothorax and as recurrence if a previous episode of spontaneous pneumothorax was documented in the patient's medical records or if a recurrence was identified during the inclusion period. To identify factors potentially associated with recurrence of PSP, multilevel logistic models were fitted. Results. During the study period, 918 (61,6%) first episodes and 573 (38,4%) episodes of recurrent PSP were identified. Clinical presentation, age, gender, smoking habits, and use of cannabis were similar in both groups. No clinical factor associated with recurrence was identified by multivariate analysis. Conclusion. In this large multicenter study, no clinical factor associated with recurrence was highlighted.

[Current uses and indications for indocyanine green angiography]. / Intérêt et indications actuelles de l'angiographie au vert d'indocyanine (ICG).

A full interpretation of indocyanine green angiography images involves not only optical issues but also pharmacokinetic and biochemical aspects. These issues may involve biochemical changes in the fluorescence yield and the affinity of the molecule for lipoproteins and phospholipids. For age related macular degeneration (AMD), the advent of photodynamic therapy and especially anti-VEGF drugs has increased the use of OCT in assessing treatment response and guiding retreatment. The ease and advantages of OCT have become increasingly associated with a decreasing interest in ICG angiography, which is becoming less well suited for the current management of AMD. An aging population, the efficacy of anti-VEGF drugs and the relative rarity of polypoidal choroidal vasculopathy (PCV) in Europe are factors contributing to our proportional increase in AMD patients. However, aside from AMD, the indications for ICG angiography remain little changed over the last decade: it remains important in diagnosing PCV and choroidal hemangiomas, since their prognosis and treatment are specific. Similarly, for certain inflammatory conditions such as Multiple Evanescent White Dot Syndrome (MEWDS) or Birdshot chorioretinitis, the value of ICG angiography remains significant. In addition, for the treatment of chronic Central Serous Chorioretinopathy, ICG angiography helps to find sites of leakage which otherwise might have been missed. The ICG angiographic appearance in this setting may also have prognostic value. Although the indications for ICG angiography are currently decreasing for AMD, these other conditions represent a large enough number of patients to justify the continued use of this original test, which remains complementary to other chorioretinal imaging techniques.

Types of choroidal neovascularisation in newly diagnosed exudative age-related macular degeneration.

AIM: To describe the types and location of choroidal neovascularisation (CNV) in exudative age-related macular degeneration (AMD), including vascularised pigment epithelial detatchments (PED), and most recently described subtypes, such as retinal choroidal anasmostosis, also termed "retinal angiomatous proliferation" (RAP). METHODS: Prospective multicentre consecutive descriptive case series. A total of 207 consecutive cases of newly diagnosed exudative AMD undergoing fluorescein angiography (FA) were recruited by 7 French referral hospital-based or private centres. Indocyanine green angiography (ICG) also was performed, when judged necessary by investigators. Types and location of CNV were classified by two independent experts and adjudicated by a third when discordant. RESULTS: All patients had FA, while ICG was performed in 50% of subjects. A total of 17.6% had classic CNV only, 5.4% and 8.3% had predominantly and minimally classic CNV, respectively. Occult CNV could be classified in occult CNV without PED (32.7%) and occult CNV with PED, ie, vascularised PED (23.9%). RAP was observed in 15.1% of cases, and accounted for 30% of vascularised PED. In 5.8% of the cases there was haemorrhagic AMD and 4.8% had fibrovascular scars. Lesions were mainly subfoveal (80%). Agreement between the centre's ophthalmologist and the final validated expert classification was moderate (kappa = 0.52 for location and 0.59 for type of lesion). CONCLUSION: This study confirms that newly diagnosed cases of exudative AMD are mainly occult and subfoveal. RAP appeared as a common lesion in patients with newly diagnosed exudative AMD.

[Some notions about possible harmlessness and/or toxicity of the antioxidant micronutriments]. / Quelques notions sur l'innocuité et la toxicité éventuelles des supplémentations en micronutriments antioxydants.

Report # 8 of the Age Related Eye Disease Study (AREDS) showed the interest of a cocktail of antioxidant micronutrients for the uni- or bilateral intermediate forms and the unilateral evolved forms of Age related Macular Degeneration. This use of supranutritional amounts aiming at obtaining a therapeutic effect corresponds to the concept of "neutraceuticals" which can be opposed to the concept of nutritional amounts. Although the AREDS was carried out under strict conditions, the evolution of knowledge in micronutrition since its design has led to some criticism of both the amounts of the micronutrients and the composition of the formulation. For example several authors pointed out that beta-carotene used at 3 fold the daily recommendations could have harmful effects, especially among smokers or former smokers. Other authors pointed out that vitamin E, at amounts corresponding to 40 to 60 fold the amounts recommended could be correlated with a lethal risk. We develop here some notions about safety and/or harmlessness of the antioxidant micronutrients.

[Hypothesis on the role of nutritional factors in ocular hypertension and glaucoma]. / Hypothèses sur le rôle des facteurs nutritionnels au cours des hypertonies oculaires et du glaucome.

Recent notions in connection with oxidative stress and the fat balance of long chain polyunsaturated fatty acids (PUFA) families have brought new insight to a probable role of nutritional factors in glaucoma and intraocular hypertony. The modifications of the extracellular matrix of the trabecula could be influenced by oxidative stress. On the one hand, collagen apoptosis and remodeling (associated with an increase in intraocular pressure) are mainly influenced by hydrosoluble antioxidants such as glutathione. On the other hand, elastin apoptosis and remodeling (correlated with the occurrence of optic atrophy) are particularly influenced by liposoluble antioxidants such as vitamin E. In addition, the dietary ratio of omega3/omega6PUFA intake could influence the balance of intraocular pressure. Omega-3 PUFA could influence cyclooxygenase competition. A diet with increased omega-3 and decreased omega-6 could thus favor an increase in intraocular pressure reducing synthesis of PG-F2, leading to a decrease in uveoscleral outflow. The true importance of these factors has not yet been solidly determined and studies are in progress to clarify the real implication of these nutritional factors.

[Nutrition and age-related macular degeneration]. / Nutrition et dégénérescence maculaire liée à l'âge.

The nutritional factors involved in the pathogenesis of age-related macular degeneration (AMD) include antioxidants or antioxidant cofactors: vitamins A, C, etc.; zinc, etc.; anti-free-radicals such as beta-carotene and carotenoids, including lutein and zeaxanthin; micronutrients protecting from blue light such as lutein and zeaxanthin; and finally components of the membranes of the photoreceptors docosahexaenoic acid (DHA). These nutritional factors are closely related to environmental risk factors such as smoking and chronic blue light exposure. Although the experimental and epidemiological data are concordant and coherent, the protective role of these micronutrients is not clearly established, mainly because there are very few clinical studies. However, a first observation study showed positive effects at stages 3 and 4 of AMD. Report #8 of the Age-Related Eye Disease Study (AREDS) provides important results for preventing complications of AMD (secondary prevention), and the cocktail of micronutrients proposed even encourages complementary studies on, for example, lutein and zeaxanthin instead of beta-carotene. The outcome of observation studies including a supplementation of long-chain polyunsaturated fatty acids (PUFA) of the omega-3 family (DHA) is also important, as it addresses primary prevention of the disease. A supplementation of omega-3 PUFAs could be proposed to certain subjects at risk for AMD for primary prevention and a supplementation with an antioxidant cocktail of micronutrients could be proposed to patients presenting AMD at stages 3 or 4 or to subjects with a nutritional imbalance. These conceivable supplementations are compatible with simple dietary advice. The supplements currently proposed could be optimized to increase their advantages. New research and new clinical studies are necessary to definitively validate these formulations in order to grant them an authentic drug status.

[Transpupillary thermotherapy and age-related macular degeneration]. / Thermothérapie transpupillaire et dégénérescence maculaire liée à l'âge.

Transpupillary thermotherapy (TTT) has been proposed over the last a few years for the treatment of subfoveal occult choroidal neovessels resulting from age-related degeneration (AMD) when they are symptomatic and associated with exudation. Several pilot studies have shown how this technique can decrease or slow down the progression of exudation related to choroidal neovessels. Based on these pilot studies, a randomized study (TTT4CNV) is in progress to evaluate the efficacy of TTT. While the inclusion of the patients in this study has come to an end, the therapeutic context of AMD has recently been changed with a permit to market Visudyn for photodynamic therapy (PDT) for some types of subfoveal occult choroidal neovessels. Moreover, the clinical studies in progress on photodynamic therapy and antiangiogenic drugs now make it possible to consider combined treatments possibly including TTT. This paper aims to provide a report on the current place and potential of TTT within the therapeutics available or soon available for subfoveal occult choroidal neovessels of AMD.

Quantitative fluorescein angiography following diode laser retinal photocoagulation.

OBJECTIVE: An in vivo study was done to establish if laser-induced damage of the retina could be quantified using fluorescein angiography. METHOD: This study was carried out on rabbit eyes (n = 6) with an 810 nm diode laser (spot diameter: 500 microm, pulse duration: 1 second, power: 100 mW-400 mW) adapted on a slit lamp. Fluorescence measurements were performed with a fundus camera connected to a fluorescence imaging system. Fluorescence staining of the retina was evaluated by mathematical modeling. Lesions were correlated to laser parameters and to histologic data. RESULTS: Image analysis shows that the laser lesions stained progressively. Fluorescence appears first at the borders of the lesion exhibiting a fluorescent ring. A progressive increase of the fluorescence into the central zone is observed. The maximum fluorescence intensity into the center of the laser spot is obtained after a delay depending on the laser energy. Below 100 +/- 20 mW, lesions are detectable by fluorescence imaging only. A fluorescence plateau appears for a threshold light dose above 200 +/- 20 mW. Mathematical modeling demonstrates that quantitative assessment of laser-induced damage to the retina is feasible using fluorescence imaging. CONCLUSION: The quantification of fluorescence staining in terms of both intensity and time can contribute to a better quantification of laser-induced damage. At last, since laser damage may mimic naturally occurring pathology, this method should also be considered to quantify different types of lesions.

Diode laser-induced thermal damage evaluation on the retina with a liposome dye system.

BACKGROUND AND OBJECTIVES: The aim of the study was to evaluate the feasibility of retinal thermal damage assessment in a rabbit eye model by using laser-induced release of liposome-encapsulated dye. STUDY DESIGN/MATERIALS AND METHODS: After anesthesia, thermosensitive liposomes (DiStearoyl Phosphatidyl Choline: DSPC) loaded with 5,6-carboxyfluorescein were injected intravenously to pigmented rabbits. Retinal photocoagulations were performed with a 810nm diode laser (P=100-400 mW, laser spot=500 microm, 1s) (OcuLight, IRIS Medical Instruments, Mountain View, CA). Fluorescence measurements in the area of the laser exposures were then realized with a digitized angiograph (CF-60UVi, Canon-Europe, The Netherlands; OcuLab, Life Science Resources, UK). RESULTS: Fluorescent spots were observed for power ranging from 100 +/- 5 mW to 400 +/- 5 mW. The fluorescence intensity increased linearly with the power and reached a plateau at 280 +/- 5 mW. The fluorescence intensity was correlated to the maximum temperature at the center of the laser spot with a linear increase from 42 +/- 3 degrees C to 65 +/- 3 degrees C. These results are in agreement with our two previous studies with DSPC liposomes for temperature measurements in a tissue model and then in a vascular model. CONCLUSION: This preliminary study demonstrates the possibility of a laser-induced release of liposome-encapsulated dye for a quantification of diode laser induced thermal damage in ophthalmology. Such a method could be useful for a real-time monitoring of laser photocoagulation for conditions such as choroidal neovascular membranes when a precise thermal damage is required near the foveolar area.

Thermal damage assessment of blood vessels in a hamster skin flap model by fluorescence measurement of a liposome-dye system.

BACKGROUND AND OBJECTIVES: The present study was undertaken to evaluate the feasibility of thermal damage assessment of blood vessels by using laser-induced release of liposome-encapsulated dye. STUDY DESIGN/MATERIALS AND METHODS: Experiments were performed in a hamster skin flap model. Laser irradiation was achieved with a 300 microm fiber connected to a 805 nm diode laser (power = 0.8W, spot diameter = 1.3 mm and pulse exposure time lasting from 1 to 6 s) after potentiation using a specific indocyanine green (ICG) formulation (water and oil emulsion). Liposomes-encapsulated carboxyfluorescein were prepared by the sonication procedure. Carboxyfluorescein (5,6-CF) was loaded at high concentration (100 mM) in order to quench its fluorescence. The measurements were performed after i.v. injection of DSPC liposomes (1.5 ml) and lasted 40 min. Fluorescence emission was measured with an ultra high sensitivity intensified camera. RESULTS: Three different shapes of fluorescent spots were identified depending on target (blood vessel or skin) and energy deposition in tissue: (i) intravascular fluorescence, (ii) transient low fluorescence circular spot, and (iii) persistent high intense fluorescence spot. These images are correlated with histological data. CONCLUSION: Real-time fluorescence imaging seems to be a good tool to estimate in a non-invasive manner the thermal damage induced by a diode laser combined with ICG potentiation.

Selective laser photocoagulation of blood vessels in a hamster skin flap model using a specific ICG formulation.

BACKGROUND AND OBJECTIVE: The present study was undertaken to evaluate the selective laser photocoagulation of blood vessels in a hamster skin flap model using a specific indocyanine green (ICG) formulation. STUDY DESIGN/MATERIALS AND METHODS: Experiments were performed in a hamster skin flap model after injection of ICG in aqueous solution (ICGA), or after injection of a specific formulation of ICG (ICG in emulsion: ICGE). Laser irradiation was achieved 30 minutes after injection with a 300 microns fiber connected to a 805 nm diode laser (power = 0.8W, spot diameter = 1.3 mm and pulse exposure time lasting from 1 to 5 s). Macroscopic observation and acute histology were performed to compare the tissue effects obtained for each ICG formulation and to assess the selectivity of vessel damage. RESULTS: The ICGE clearance process was slowed down as compared to the ICGA process. After 30 minutes, the concentration of ICG in blood is higher (2.27 +/- 0.4, P < 0.003) for ICGE compared to ICGA. With ICGA, vessel coagulation required a minimum fluence of 240 J/cm2, which led to very significant skin damage. Conversely with ICGE, vessel coagulation required a fluence of 120 J/cm2. With such a fluence, no laser effect could be detected on the skin. Histological examination confirmed blood vessels coagulation in depth, whereas epidermis and dermis remained intact. CONCLUSION: The major restrictions of ICG in aqueous solution, which are the very-short half-life of ICG in blood and consequently the lack of selectivity in blood vessels after a few minutes, are alleviated when ICG is used in emulsion. ICG in emulsion increases the circulating half-life of ICG and moreover confines ICG in the vascular compartment. Thanks to this specific property, it is possible to obtain a selective vascular damage 30 minutes after injection.

[Control of photocoagulation intensity by thermo-induced release of a fluorescent marker encapsulated in liposomes: study of an in vivo vascular model]. / Contrôle de l'intensité des photocoagulations par libération thermo-induite d'un marqueur fluorescent encapsulé dans des liposomes: etude d'un modèle vasculaire in vivo.

PURPOSE: To evaluate the feasibility of thermal damage assessment of blood vessels by using laser-induced release of liposome-encapsulated dye. METHODS: A skin flap window model of aluminium was implanted on the loose skin on the back of adults Golden hamsters to expose skin blood vessels in vivo. Thermosensitive liposomes (DSPC) loaded with 5,6-Carboxyfluorescein were injected together with a specific Indocyanine green (ICG) formulation (O/W emulsion) in order to enhance diode laser absorption. Photocoagulations were then performed on the vessels with a diode laser (lambda = 810 nm, P = 0.8W, phi = 1.3 mm, 1 to 6s). Fluorescence measurements were realized with an ultra high sensitivity intensified camera (Hamamatsu Argus 50 imaging system). RESULTS: Two different fluorescence intensity curves corresponding to the variability of absorption of the targets were observed. Variability was related to the amount of ICG. For each curve, 3 zones were identified: (i) for fluences ranging from 60 +/- 20 J/cm2 to 110 +/- 20 J/cm2 a transient intravascular fluorescence was observed only for the loser pulses targeted on the vessels, (ii) for fluences ranging from 110 +/- 20 J/cm2 to 190 +/- 20 J/cm2 a permanent fluorescent spot limited to the vessel was observed for the laser pulses targeted on the vessels; for the laser pulses targeted on the skin a transient low fluorescence circular spot was observed. For this fluence range a selective photocoagulation of a vessel was performed. (iii) for fluences ranging from 190 +/- 20 J/cm2 to 300 +/- 20 J/cm2 persistent intense fluorescence spots were observed on both skin and vessels. This type of fluorescence was related to an overdosage. CONCLUSION: These results are in fair agreement with the data of the literature about liposomes and with the data we obtained in a previous study on a vascular model. This study demonstrates the interest of a laser-induced release of liposome-encapsulated dye for a real-time quantification of thermal damage. Such a method could be useful for laser photocoagulation in ophthalmology for indications such as choroidal neovessels where the production of a precise thermal damage is required.

Fluorescence measurement of 805 nm laser-induced release of 5,6-CF from DSPC liposomes for real-time monitoring of temperature: an in vivo study in rat liver using indocyanine green potentiation.

BACKGROUND AND OBJECTIVE: This in vivo study examines the validity of using fluorescence measurements of laser-induced release of temperature-sensitive, liposome-encapsulated dye for real-time monitoring of temperature and for prediction of tissue thermal damage. STUDY DESIGN/MATERIALS AND METHODS: An in vivo study is performed in rat liver after i.v. injection of liposomes loaded with a fluorescent dye and i.v. injection of indocyanine green (ICG) for diode laser potentiation. Temperature-sensitive liposomes (DSPC: Di-Stearoyl-Phosphatidyl-Choline) are loaded with 5,6-carboxyfluorescein (5,6-CF). These liposomes (1.5 ml solution) and ICG (1.5 ml solution-5mg/kg) are injected in adult male wistar rats. Two hours later, the liver is exposed and irradiated with a 0.8 W diode laser using pulses lasting from 1-6s (fluence ranging from 16-98 J/cm2). Simultaneously, the fluorescence emission is analysed with an ultrahigh sensitivity intensified camera. RESULTS: The fluorescence intensity I(F) increases linearly from 18 J/cm2 up to 75 J/cm2. These fluences correspond to surface temperatures between 42 degrees C and 65 degrees C. The measurements appear to be highly reproducible. In this temperature range, the accuracy is +/- 3 degrees C. The maximum intensity is observed immediately after the laser is switched off. A decrease of the fluorescence intensity (27% in 20 minutes) is observed due to the 5,6-CF clearance. However, the ratio I(F)/I(BCK) (I(BCK): background fluorescence intensity) remains almost stable over this period of time and the determination of the temperature is still possible with good accuracy even 20 minutes after laser irradiation. CONCLUSION: Real-time temperature monitoring by using fluorescence measurement of laser-induced release of liposome-encapsulated dye is clearly demonstrated. This procedure could conceivably prove useful for controlling the thermal coagulation of biological tissues.