In vivo and in vitro IL-18 production during uveitis associated with Behçet disease: effect of glucocorticoid therapy.

Uveitis represents one of the major diagnostic criteria in Behçet's disease. It is most prevalent in the countries of the Mediterranean area, including Algeria, and along the Silk Road. Clinical features include oral and genital ulcers, ocular and skin lesions, as well as central nervous system, joint, vascular, gastrointestinal, or pulmonary manifestations. Many studies have reported that Th1 immune responses are involved in the physiopathology. We have previously studied the production of IL-12 and IFN-γ, cytokine markers in the Th1 pathway involved in Behçet's disease. In our study, we investigate in vivo and in vitro IL-18 production in Algerian patients with Behçet's disease with ocular manifestations in various stages of the disease. We examined the effect of glucocorticoids on IL-18 production during the active stage of the disease. Our results suggest that IL-18 could be a good biomarker for monitoring disease activity and its regression, demonstrating the effectiveness of treatment on the underlying immunopathologic process.

[Frequency and risk factors for diabetic macular edema in the wilaya of Constantine (Algeria)]. / Fréquence et facteurs de risque de l'œdème maculaire diabétique dans la wilaya de Constantine (Algérie).

We conducted an exhaustive cross-sectional descriptive study, in 2009, on type 1 diabetics residing in the wilaya of Constantine. Our objective was to assess the frequency and risk factors associated with diabetic macular edema (DME) by mydriatic non-stereoscopic fundus photographs of nine retinal fields. The frequency of DME was 8.7%. There was no gender influence on the frequency of macular edema. There were as many men (46.4%) as women (53.6%) with ME (P = 0.8). On bivariate analysis, the duration of diabetes (P = 0.001), age (P = 0.0001), hypertension (P = 0.00001), renal involvement (P = 0.00001) and hypercholesterolemia (P = 0.01) were risk factors for DME.

[Cilioretinal artery occlusion and central retinal vein occlusion complicating hyperhomocysteinemia: a case report]. / Occlusion mixte : de l'artère ciliorétinienne et de la veine centrale de la rétine par hyperhomocystéinémie (à propos d'un cas).

INTRODUCTION: Hyperhomocysteinemia is known to be a risk factor in both retinal artery and retinal vein occlusions. We report the case of a young patient with combined occlusion of the cilioretinal artery and the central retinal vein due to hyperhomocysteinemia. PATIENTS AND METHODS: A 23-year-old patient without significant medical history, presented for sudden, painless visual loss in the right eye. Ophthalmologic examination revealed best-corrected visual acuity of the right eye 8/10 P2, and 10/10 P2 on the left. Anterior segment exam was normal in both eyes, while the right fundus revealed white, ischemic edema, centered around a cilioretinal artery, sparing the fovea, with some hemorrhagic spots and disc edema. Fluorescein angiography confirmed delayed filling of the right cilioretinal artery and revealed a normal disc on the left. Two weeks later, the clinical picture had evolved into a right ischemic CRVO, confirmed by a second angiogram, with a decrease in visual acuity to 3/10. RESULTS: A work-up was performed, including: a full lipid profile, serum electrolytes, ESR, CRP, a complete blood count (leukocytes, platelets, hemoglobin were normal), a coagulation work-up (PT, PTT, protein C, protein S, antithrombin III, factor V Leiden were normal), ANCA, antiphospholipid antibodies and antinuclear antibodies were negative, and finally cardiology studies (cardiac echo, carotid Doppler) and neurology (brain MRI) were ordered and came back normal. Otherwise, plasma homocysteine was moderately high on two samples, at 18.3 µmol/L and 17.78 µmol/L. Thyroid and renal work-ups were ordered. Urgent PRP was performed, and vitamin therapy (vitB12, vitB6, folic acid) was instituted. The subsequent course was remarkable for recovery of visual acuity to 10/10, P2 with persistence of an inferior altitudinal central scotoma. MTHFR C677T polymorphism was negative. DISCUSSION: Retinal vascular occlusions (RVO) are serious events, which require investigation for underlying systemic disease, which can be life-threatening. The clinical picture is variable depending on the location of the occlusion, the extent of the ischemic area and the degree of macular involvement. The etiologies of RVO are varied, requiring a thorough biological assessment in young subjects. The association between hyperhomocysteinemia and RVO is proven, while this association with the MTHFR C677T polymorphism was not found. Vitamin therapy reduces plasma levels of homocysteine by 25% but its role in the treatment and prevention of RVO remains to be demonstrated. CONCLUSION: Several cases of occlusion of the central retinal vein or one of its branches have been published. Combined occlusion of the central retinal vein and cilioretinal artery secondary to hyperhomocysteinemia does not appear to have been published, which would make our case unique.

[Effects of peroxynitrite derived from nitric oxide on cultured bovine ocular explants]. / Effets du peroxynitrite dérivé du monoxyde d'azote sur des explants oculaires bovins en culture.

INTRODUCTION: Several studies have reported a significant production of nitric oxide (NO) with peroxynitrite formation in the setting of intraocular inflammation. In a previous study, we showed the cytotoxic effect of nitrites and nitrates, stable metabolites of NO, on the various tissues forming the layers of the eye, with variable degrees of tissue sensitivity. This study aims to investigate the effect of peroxynitrite on whole ocular bovine explants in culture. METHODS: Healthy ocular bovine eyes, obtained immediately upon enucleation, were dissected and samples were taken from the anterior and posterior segments, and then cultured in DMEM supplemented with 10% fetal bovine serum, 2mM L-glutamine and antibiotics. Cultures were treated with 3-morpholino-sydonimin N-ethyl-carbamide (SIN-1) (molecule which produces NO and superoxide anion O(2)(.-)) at varying concentrations (100 to 500 µM) over 24 hours. After incubation, the explants were fixed in 10% buffered formalin, and histological study was performed. RESULTS: Most of the structures showed changes on tissue and cellular levels after incubation with the peroxynitrite donor and various responses depending on the concentration used. These observations reflect variable concentration-dependent tissue sensitivity. The epithelia (cornea, iris and ciliary process) showed high sensitivity in comparison with sclera, which developed greater resistance. CONCLUSION: In all, our results indicate a deleterious effect of peroxynitrite on bovine ocular structures in vitro. This effect is proportional to the concentration used. These results corroborate those reported by other teams and suggest the role of peroxynitrite derived from NO in the ocular lesions observed in the setting of uveitis.

Early involvement of nitric oxide in mechanisms of pathogenesis of experimental autoimmune uveitis induced by interphotoreceptor retinoid-binding protein (IRBP).

INTRODUCTION: Autoimmune uveitis is a group of HLA-associated inflammatory diseases of the eye, prevalent worldwide, that may cause blindness. It can be limited to the eye, or associated with a systemic syndrome. Furthermore, patients suffering from uveitis exhibit high serum and local nitric oxide (NO) levels as a consequence of cellular responses to immunologically privileged antigens within the eye such as interphotoreceptor retinoid binding protein (IRBP). To investigate NO production kinetics in autoimmune uveitis and its implication in mechanisms of ocular pathogenesis, we first attempted to develop an experimental model of autoimmune uveitis (EAU) on the Wistar rat, using the whole bovine retinal interphotoreceptor matrix extract (IPMe) and isolated IRBP. MATERIAL AND METHODS: Female Wistar rats (n=24) were divided into three experimental groups: "control rats" (n=3) consisting of non-immunized animals, "IRBP-immunized rats" (n=12) and "IPMe-immunized rats" (n=9), which received a subcutaneous injection, respectively, of 13 µg IRBP and 100 µg IPMe emulsified in complete Freund's adjuvant. On days 7, 14 and 21 post immunization, the rats were sacrificed. Nitrites were assessed in plasma and in homogenate of eyes using the Griess reaction. Meanwhile, eyes were collected for histological studies. RESULTS: Our results show the sensitivity of the Wistar strain to both IPMe and IRBP-induced EAU. In fact, we observed histological disorders affecting the retinal tissue in both models of EAU. On the other hand, a significantly increased production of NO in plasma and homogenate of eyes was also observed in comparison to the control group. Moreover, we noted with interest that maximal production of NO occurs prior to the alteration of retinal tissue. CONCLUSION: In summary, our results suggest the early involvement of NO in the mechanisms of pathogenesis of EAU. NO can be considered as a key bio-marker of poor prognosis in ocular autoimmune inflammation.

[Nitric oxide, biomarker of experimental autoimmune uveitis induced by S antigen]. / Le monoxyde d'azote, bio-marqueur de l'uvéite auto-immune expérimentale induite par l'antigène S.

INTRODUCTION: uveitis is an intraocular inflammation and one of the most severe and frequent manifestations of Behçet disease. S antigen (S Ag) is a highly conserved retinal protein implicated in the mechanism of the physiopathology in Behçet disease. This autoantigen is used in different animal models for experimental autoimmune uveitis (EAU) development, particularly in Behçet uveitis. Nitric oxide (NO) production has been reported in this disease by several groups and mainly by our team. MATERIALS AND METHODS: in this study, we investigated the development of Behçet uveitis in an experimental model using the Wistar rat after treatment with S antigen. This antigen was isolated and purified from bovine retina by gel filtration chromatography using Sephadex G-200. The rats were immunized with 10µg of S Ag. We evaluated the changes in nitric oxide metabolite production in plasma using the Griess reaction, during the 7th, 14th, and 21st days post-immunization. Furthermore, deleterious effects by S antigen on retinal tissue were assessed in a histological study. RESULTS: the results showed a significant increase in NO production in Wistar rats treated with S Ag in comparison with controls. We noted with interest that the clinical stages of EAU correlated with NO production. Furthermore, S Ag had several deleterious effects on Wistar rat retina. CONCLUSION: this study indicated in vivo elevation of NO levels, which was observed before retinal tissue damage. Nitric oxide appears to be a good marker for a poor prognosis in this experimental model. Moreover, oxidative stress can be considered the primary step in pathogenesis inducing the destruction of retinal photoreceptors. Collectively, our data could be helpful in the development of strategies for diagnosing patients with Behçet uveitis.

[Deleterious effects of stable nitric oxide derivatives, a uveitis inflammatory marker, on cultured bovine ocular layers]. / Effets délétères des dérivés stables du monoxyde d'azote, marqueur inflammatoire des uvéites, sur les différentes tuniques de l'oeil de boeuf en culture.

INTRODUCTION: Uveitis is an intraocular inflammation affecting various eye segments. This disease is characterized by a high level of nitric oxide production. It is estimated via the quantification of its end products: nitrites and nitrates. In a previous study, we showed the cytotoxic effect of these molecules on bovine retina in vitro. In this study, we investigated the effect of these two molecules on cultured ocular explants in vitro. METHODS: After clinical examination, healthy bovine eyes were obtained immediately after enucleation and were transported to the laboratory at +4 degrees C. After dissection, ocular explants from anterior and posterior segments were cultured in DMEM supplemented with 10% of FBS, 2mM glutamine, 100UI penicillin, and 100UI/ml streptomycin. Cultures were treated with either nitrites or nitrates at different concentrations (300-500 microM). After culture incubation (24-48h), ocular explants were fixed in buffered formalin and the histological study was performed. RESULTS: All structures showed structural alterations in relation with culture duration and molecule concentrations. The different structures showed different degrees of sensitivity depending on the type and concentration of the metabolite used. Sclerotic analysis showed very little response to the two molecules, whereas the cornea and ciliary process epithelia showed the highest sensitivity. CONCLUSION: Our results showed a cytotoxic effect of nitrites and nitrates on ocular structures in vitro. This effect was correlated with molecule concentration and duration of exposure. The structural alterations observed suggest that nitric oxide, via its products, is implicated in the ocular lesions observed during uveitis.

[Intra-annual and seasonal allergic conjunctivitis treatment: comparison of two therapeutic protocols]. / Traitement de la conjonctivite allergique per-annuelle et saisonnière: comparaison de deux protocoles thérapeutiques.

INTRODUCTION: Allergic conjunctivitis is the most common form of conjunctivitis encountered in daily ophthalmological practice. Its therapy can be problematic: it must be simple, free of complications, and adaptable to everyday life. PATIENTS AND METHODS: We conducted a randomized prospective single-center survey on 102 patients between 4 and 80 years of age who presented moderate allergic conjunctivitis. Patients were divided into two groups, one treated in monotherapy with N-acetyl-aspartyl glutamic acid (NAAGA) over 4 weeks and the other treated with bi-therapy (NAAGA and Levocabastine during the first week and NAAGA only for the next 3 weeks), with evaluation of the sum of the scores of the cardinal signs of allergic conjunctivitis at D0, D7 and D28. RESULTS: The two populations were homogeneous at inclusion: the majority of the patients had a history of allergies, with a nonspecific disrupted allergy workup (IgE and eosinophils) and a higher initial score for the children included in the study. The scores decreased sharply at D7 (50% reduction) and at D28 (bordering 1) with no significant difference between the two groups. Tolerance to the treatment judged by unusual sensations upon instillation was better for the NAAGA treatment (80.8% of the cases). Clinical and functional signs disappeared without recourse to corticoids. CONCLUSION: In the moderate forms of seasonal and intra-annual allergic conjunctivitis, NAAGA treatment alone is sufficient. The association with Levocabastine is necessary only in cases of highly bothersome functional signs. The use of corticoids should be reserved for the serious forms.

[Effect of corticotherapy on interleukin-8 and -12 and nitric oxide production during Behçet and idiopathic uveitis]. / Effet de la corticothérapie sur la production des interleukines 8, 12 et du monoxyde d'azote au cours des uvéites Behçet et idiopathique.

OBJECTIVES: To investigate the effect of corticotherapy on IL-8, IL-12, and nitric oxide (NO) production during idiopathic and Behçet active uveitis. METHODS: Peripheral venous blood was drawn from 70 patients with active uveitis before and during corticotherapy (32 with Behçet uveitis and 38 with idiopathic uveitis) and from 30 controls. Plasma was collected and peripheral blood mononuclear cells were separated immediately and cultured with or without Concanavaline A. IL-8 and IL-12 levels in plasma and culture supernatants were measured by specific enzyme-linked immunosorbent assay (ELISA). Nitric oxide levels were evaluated using a modified Griess method. RESULTS: Before therapy, the two groups of patients showed highly significant elevation of IL-8, IL-12, and NO levels compared to control subjects. During therapy, IL-8 and nitric oxide levels were significantly lower in active idiopathic and Behçet active uveitis both in vivo and in vitro. This effect was correlated with therapy duration. In contrast, while significant reduction of IL-12 levels was observed both in vivo and in vitro in idiopathic active uveitis during therapy, this effect was observed in vitro in Behçet active uveitis but not in vivo. CONCLUSION: Our results suggest that IL-8, IL-12, and NO are involved in the physiopathological mechanisms of idiopathic and Behçet uveitis. These three molecules showed different degrees of sensitivity to the inhibitory effect of corticoids, reflecting their different regulation by corticotherapy during active phases of the two diseases. According to our study, IL-8 can serve as a marker of inflammatory responses, while IL-12 should be used as a marker of the specific immune responses during active uveitis.

[Production of Th1/Th2 cytokines and nitric oxide in Behçet's uveitis and idiopathic uveitis]. / Production des cytokines Th1/Th2 et du monoxyde d'azote au cours de l'uvéite "Behçet" et de l'uvéite "idiopathique".

INTRODUCTION: The aim of this study was to investigate the role of Th1 (IFN-gamma and IL-12), Th2 (IL-10) cytokines and nitric oxide (NO) in the immunopathologic mechanisms of uveitis related to Behçet's disease and isolated idiopathic uveitis. PATIENTS AND METHOD: This study was conducted on 24 patients with Behçet's syndrome who had active uveitis, ten of whom showed isolated uveitis classified as idiopathic uveitis, and 13 healthy controls. The levels of IFN-gamma, IL-12 and IL-10 in sera and supernatants of PBMC cultures stimulated by PHA were estimated using immunoenzymatic dosage (ELISA sandwich according to the methods recommended by Immunotech France). The production of NO was measured in vivo and in vitro for the same patients using the modified Griess method. RESULTS: The induction of IFN-gamma and IL-12 was higher in the two groups of patients than in the controls (P<0.001). Significant IL-10 levels were recorded in 56.5% of patients with Behçet's disease presenting uveitis versus 30% of patients with idiopathic uveitis. NO production was more pronounced in idiopathic uveitis than in Behçet's syndrome (P<0.02). CONCLUSION: The predominance of the Th1 profile was associated with high production of NO in idiopathic uveitis. A Th1/Th2 profile with a moderated increase in NO production was observed in Behçet's disease. Our data have a clinical impact. The observation of combined Th1/Th2 cytokines and NO elevation in both in vivo an in vitro experiments could have a predictive value in characterizing uveitis associated with Behçet's disease.

[Effect of nitrites and nitrates on bovine retina in vitro]. / Effet des nitrites et des nitrates sur les rétines de boeuf in vitro.

BACKGROUND/AIM: Uveitis is an endocular inflammation that forms one of the most serious manifestations of Behçet disease. Nitric oxide (NO) is a molecule that expresses important immunoinflammatory properties and is produced by NO synthases (NOS). In previous studies, we showed an elevated production of endogenous NO during Behçet's and idiopathic uveitis. These results led us to investigate the effect of nitrites (NO2-) and nitrates (NO3-) (physiologically stable metabolites of NO) on fragments of bovine retina in order to determine the role of nitric oxide (NO) in the genesis of retinal lesions during uveitis. MATERIAL AND METHODS: Retinas were removed from freshly enucleated bovine eyes and cultured in DMEM, 10% CFS in presence of nitrites (NaNO2) or nitrates (NaNO3) at different concentrations. The cultures were processed at 37 degrees C, 5% CO2 in a humidified chamber. Cultured retinas were observed by inverse microscopy and then fixed in formaldehyde. Histological studies were conducted after H & E staining. RESULTS: Cultured retina showed alterations when exposed to concentrations of nitrites and nitrates higher than 200 microM and 250 microM, respectively. These alterations were dose-dependent and affected the cellular and tissular structures. Morphological and histological studies suggested that the toxic effect is apoptotic and/or necrotic for both effectors. CONCLUSION: Our investigations showed that nitrites and nitrates, two physiologically stable metabolites of NO, have a deleterious effect on cultured retina. NO, produced in inflammatory processes during uveitis may be implicated in the genesis of the retinal lesions observed during the exacerbation phase of the disease.

[Pseudo-exfoliative fibrillopathy in eastern Algeria. Epidemiologic and statistical study]. / La fibrillopathie pseudo-exfoliative dans l'est algérien. Enquête épidémiologique et étude statistique.

The systematic examination of 1440 patients of more than 40 years old divided into two groups of 607 hospitalised patients and 833 consultants has revealed the exceptionally high frequency of the pseudo-exfoliative disease in the East of Algeria. In fact this syndrome is find in 25% of the cases. The analysis relates the different epidemiology criteria: age, topography, geographic factors and biomicroscopic characters. The association to the glaucoma of this syndrome forms the subjects of a study which details particularly its frequency, its different clinical forms, the factors of the intraocular pressure and the evolution under treatment. The authors have compared this study to those wHich have been described in literature.

[Surgical treatment of sequelae of oculomotor paralysis of the 4th, 6th, and 3d cranial nerves]. / Traitement chirurgical des paralysies oculomotrices séquellaires des IV, VI, III.

The writers analyse the operative results of 43 cases of oculo-motor paralysis aftermaths of the 4th, 6th and 3rd cranial pairs treated since 1985. The applying of muscular puckering, associated with a controlled or kept tenotomy, of muscular transplant, of "Fadenoperation" and of oblique surgery, allowed to obtain good results with suppression of diplopia, at least in the facing and in the lower glance, attenuation of ocular torticollis, disappearing of the ocular deviation, and restitution of a fusion area in primary position, within a more or less extended zone of space.

[Ophtalmic involvement in cutaneous leishmaniasis (author's transl)]. / Manifestations ophtalmologiques des leishmanioses cutanées.

In stricto sensu cutaneous leishmaniasis from 2 to 5 p. 100 of the facial lesions are localized on the eye-lids, most often on the external corner. The pathologic pattern is comparable to what can be observed on the rest of the skin but the fragility of eye-lid gives a special risk of local spreading. The most common aspect is chalazion-like but ulcerous, phagedenic and cancer-like forms may be observed. Lacrymal ducts are sometimes involved. In muco-cutaneous leishmaniasis the lesions are more destructive and may lead to eye loss. The authors consider the diagnosis and the appropriate treatment.