Aflibercept in wet AMD: specific role and optimal use.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a naturally occurring glycoprotein in the body that acts as a growth factor for endothelial cells. It regulates angiogenesis, enhances vascular permeability, and plays a major role in wet age-related macular degeneration. The consistent association between choroidal neovascularization and increased VEGF expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of this disorder. Blockade of VEGF activity is currently the most effective strategy for arresting choroidal angiogenesis and reducing vascular permeability, which is frequently the main cause of visual acuity deterioration. In recent years, a number of other molecules have been developed to increase the efficacy and to prolong the durability of the anti-VEGF effect. Aflibercept (EYLEA®; Regeneron Pharmaceutical Inc and Bayer), also named VEGF Trap-eye, is the most recent member of the anti-VEGF armamentarium that was approved by the US Food and Drug Administration in November 2011. Because of its high binding affinity and long duration of action, this drug is considered to be a promising clinically proven anti-VEGF agent for the treatment of wet maculopathy. OBJECTIVE: This article reviews the current literature and clinical trial data regarding the efficacy and the pharmacological properties of VEGF-Trap eye and describes the possible advantages of its use over the currently used "older" anti-VEGF drugs. METHODS: For this review, a search of PubMed from January 1989 to May 2013 was performed using the following terms (or combination of terms): vascular endothelial growth factors, VEGF, age-related macular degeneration, VEGF-Trap eye in wet AMD, VEGF-Trap eye in diabetic retinopathy, VEGF-Trap eye in retinal vein occlusions, aflibercept. Studies were limited to those published in English. RESULTS AND CONCLUSION: Two Phase III clinical trials, VEGF Trap-eye Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2, comparing VEGF Trap-eye to ranibizumab demonstrated the noninferiority of this novel compound. The clinical equivalence of this compound against ranibizumab is maintained even when the injections are administered at 8-week intervals, which indicates the potential to reduce the risk of monthly intravitreal injections and the burden of monthly monitoring.

Ruthenium-106 eye plaque brachytherapy in the conservative treatment of uveal melanoma: a mono-institutional experience.

BACKGROUND: Traditional treatment for uveal melanoma is the enucleation of the eye with outcomes cosmetically unacceptable and loss of useful vision. Plaque brachytherapy, compared to enucleation, had the advantage to preserve the eye with outcomes cosmetically acceptable and preservation of vision. PATIENTS AND METHODS: From July 1990 to December 2009 one hundred forty-two (142) patients (51 males and 91 females) with small to medium uveal melanoma were treated with 106Ru plaque brachytherapy. The patients underwent a complete staging before brachytherapy with indirect ophthalmoscopy and ultrasounds. Mean tumour thickness was 3.26 mm (1.6-6 mm). The dose scheduled was 80-100 Gy to the apex with a maximum dose of 800 Gy to the sclera. RESULTS: One hundred forty-two have been treated, nine patients had lost the follow-up and drop out; 133 patients were assessed. Mean follow-up was 7.7 years (6 months-18 years). The overall survival at 5, 10 and 15 years was 92%, 85% and 78% respectively. Cancer fee survival was 95%, 90% and 83%, respectively at 5, 10 and 15 year. Radiation-induced toxicity was represented in 47 patients with a 5 year actuarial survival rate free from complications of 54%. CONCLUSIONS: 106Ru plaque brachytherapy is a valid approach for treatment of uveal melanoma. This technique is efficacy and safe, with a low toxicity profile.

Administration of sulpiride or domperidone for advancing the first ovulation in deep anestrous mares.

Since results with using sulpiride and domperidone are conflicting and since both have not been tested at the same time, the aim of this study was to compare the efficacy of these substances for the induction of ovulation in deep anestrous mares in the same experimental conditions and to determine their fertility after artificial insemination (AI) at the induced estrus. Twenty-six non-pregnant, non-lactating standardbred anestrous mares were randomly assigned to three groups and treated daily for 25 days (from February 3rd to February 28th) with either sulpiride (1mg/kg of body weight im SID, n=10), or domperidone (1mg/kg po SID, n=10); 6 animals were used as control. The beginning of the transition period and the first ovulation were hastened in sulpiride (16.4+/-0.8 days) but not in domperidone (46.0+/-3.3 days) treated mares (P<0.05). The diameter of the largest follicle was affected by treatment, time and interaction of treatment-by-day (P<0.05) and significantly increased in the sulpiride group (P<0.05). Although a main effect of treatment on plasma LH concentration was not observed (P=0.06), time and interaction of treatment-by-day were statistically significant (P<0.05). The interval from the beginning of treatment to first ovulation was shorter (P<0.05) in the sulpiride group (36.9+/-2.5 days) than in the domperidone (74.7+/-3.3 days) and control (81.4+/-3.1) groups. The establishment of pregnancy was significantly (P<0.05) hastened in sulpiride (61.0+/-35.2 days) but not in domperidone (83.0+/-44.0 days) treated mares. Treated mares not pregnant after the first AI, showed normal estrous cycles with regular interovulatory intervals (P>0.05). It was concluded that sulpiride is effective in advancing the beginning of transition period and the first ovulation whereas domperidone is successful only in some mares.

Verteporfin photodynamic therapy for subfoveal choroidal neovascularization in pathologic myopia: a 12-month retrospective review.

PURPOSE: To evaluate the visual outcome of patients with subfoveal choroidal neovascularization (CNV) secondary to pathologic myopia treated with verteporfin photodynamic therapy (PDT-V) and to verify the predictive role of visual and angiographic parameters. METHODS: This is a retrospective, interventional, consecutive case series study of subjects with subfoveal CNV secondary to pathologic myopia. All patients received PDT-V according to VIP guidelines. A complete ophthalmologic evaluation was performed on all patients and included best-corrected visual acuity (BCVA), fundus examination, and fluorescein angiography (FA, IMAGEnet System, Topcon Corp., Japan). CNV size (mm2) was directly measured on the early phase of the angiogram using the software included with the IMAGEnet package. All checks were scheduled at 3-month intervals for a period of 1 year. A review of medical and angiographic records was performed and assessed throughout a 12-month follow-up period. RESULTS: A total of 62 patients (62 eyes) were examined. Best-corrected visual acuity (BCVA) moderately decreased without reaching a statistically noticeable level throughout the followup; reduction in lesion size reached a significant level at the second checkup. A significant correlation between higher baseline BCVA and better final visual outcome was detected. CONCLUSIONS: Standardized PDT-V minimizes central vision deterioration in patients with CNV secondary to pathologic myopia. Better BCVA at presentation represents a good predictive sign.

Tyrosine83 is essential for the activity of E. coli galactoside transacetylase.

The gene (lacA) coding for Escherichia coli galactoside transacetylase was cloned into the pTrcHisB plasmid, and the corresponding hexahistidine-tagged enzyme was over-expressed and purified. The kinetic constants of the tagged protein were determined, yielding values in excellent agreement with previous observations reported for the natural enzyme. LacA Tyrosine83 was then substituted with a Valine: by comparing the K(m) and k(cat) values observed for wild type and mutant enzymes using isopropyl-thio-beta-d-galactopyranoside or p-nitrophenyl-beta-d-galactopyranoside as substrates, Tyrosine83 was identified as an essential residue for the catalytic activity of E. coli galactoside transacetylase.

Macular coloboma in siblings affected by different phenotypes of retinitis pigmentosa.

Purpose To report the clinical association between macular coloboma (early-onset macular dystrophies/atrophic changes) and different phenotypes of retinitis pigmentosa (RP). Methods Three young-adult siblings, two males and one female, were retrospectively studied. These patients underwent two complete ophthalmologic examinations (27-month follow-up), including orthoptic evaluation, colour vision test, visual field, corneal topography, electronystagmography, fluorescein angiography, and electroretinography. Eye check, automated visual field test, and complete electroretinographic study were also conducted on other asymptomatic members of the same family. Results All symptomatic siblings were affected by manifest congenital nystagmus, poor visual acuity, and progressive visual field impairment in both eyes, bilaterally presenting macular coloboma associated with three different RP patterns: classic RP; mild dystrophy of the retinal pigment epithelium, associated with subnormal electroretinographic findings (subclinical form of RP); and sector RP. The ophthalmologic reports regarding their deceased father documented that he had suffered from the same alterations of ocular movements and visual performances diagnosing, in both eyes, extensive atrophic changes of the macular area completely surrounded by pigmented bone spicules (RP-type tapeto-retinal dystrophy). The other investigated relatives did not show any specific and/or significant ocular disorder. Conclusions In these three adult members of the same family, the concomitance between macular coloboma and different intrafamilial RP phenotypes is described. This association represents an autosomal dominant clinical entity, hitherto observed only in non familial sporadic cases.Eye (2004) 18, 421-428. doi:10.1038/sj.eye.6700689

Quantitative evaluation of the retinal venous tortuosity in chronic anaemic patients affected by beta-thalassaemia major.

AIMS: Retinal venous tortuosity (RVT) is a common finding in patients affected by different forms of chronic anaemia. The aims of this study were to quantify RVT in anaemic patients with beta-thalassaemia major and to verify whether it is related to some of the following parameters: patient's age, ferritin plasma level, and Desferrioxamine (DFX) daily dosage. METHODS: A retrospective study was carried out. In total, 36 consecutive thalassaemic patients, treated with polytransfusion regimen and DFX, were age- and sex-matched with a control group of 36 normal subjects. All subjects bilaterally underwent red-free fundus photography, centred on the optic disc. The four main retinal veins were measured with a computer-assisted method. RESULTS: Mean venous length in the thalassaemic group was significantly greater than that observed in the control group (P <0.001). In thalassaemic patients, no significant correlations between retinal venous length and, respectively, plasma ferritin level and DFX daily dosage were documented. Statistical analysis demonstrated a very significant association between patient's age and increased RVT only in thalassaemic patients (P <0.001). CONCLUSIONS: Our findings demonstrate that patients with beta-thalassaemia major have increased RVT, as compared to normal subjects. In this selected anaemic population, patient's age, closely related to anaemia duration, is the only variable responsible for the RVT increment. This clinical sign indicates a long-standing duration of anaemia.

Management of incontinentia pigmenti: a case of monolateral preretinal fibrovascular proliferations adjacent to snail-track degeneration areas.

PURPOSE: To report a case of monolateral preretinal fibrovascularproliferations in a young adult woman, who had suffered from incontinentia pigmenti (IP) during her first month of life. METHODS: Case report. RESULTS: Circumscribed preretinal fibrovascular proliferations, adjacent to a mid-peripheral area of snail track degeneration, were occasionally diagnosed in the left eye of an asymptomatic 18-year-old white female. Careful ocular examination did not reveal any cause of the monolateral vascular abnormalities observed in the posterior segment. A detailed medical history brought to light that the patient has suffered infantile IP, like four other females in her family. The patient did not present any evident malformation of teeth, nails, skeleton or hair. A cytogenetic linkage study documented a chromosomal aberration in the Xq28 band, which confirmed the diagnosis of familial IP (type 2). The fluorescein angiography findings clearly illustrated the minimal retinal involvement in the course of IP. CONCLUSIONS: This case shows that a wide range of etiologies must be considered in patients presenting monolateral preretinal fibrovascular proliferations. To correctly manage these uncommon, inherited or acquired, retinal diseases it is better to do a mid-term follow-up, rather than operate immediately, and this enabled us to observe the natural course of the lesion, while awaiting a definitive diagnosis.

Bilateral central serous chorioretinopathy in a patient treated with systemic cortico-steroids for non-Hodgkin lymphoma.

PURPOSE: To describe the concomitant occurrence of systemic cortico-steroid treatment and the development of bilateral central serous chorioretinopathy (CSC), which promptly regressed after the reduction of the drug dosage, up to its scheduled withdrawal. METHODS: Case report. RESULTS: A 46-year-old white male, with a history of monolateral CSC, had a non-Hodgkin lymphoma on his right cheek. Soon after surgical excision of the tumoral lesion, he received a standard post-operative regimen of decreasing intramuscular betamethasone for 25 days, followed by 10 day's withdrawal, then cycles of intravenous cyclophosphamide and vincristine, followed by 7-day oral prednisone, repeated monthly for three months. Fluorescein angiographies at the end of the first oral cortico-steroid cycle and before starting the second, documented the occurrence of bilateral CSC and its regression, which were chronologically related respectively to the cortico-steroid administration and withdrawal. CONCLUSIONS: This case further demonstrates that systemic cortico-steroids can be responsible for the occurrence of CSC. The patient's history should always be checked for any previous CSC episodes. In these subjects, periodical ophthalmoscopic examination is essential to discover early or asymptomatic steroid-related CSC patterns, to prevent complications of the disease.

Recurrent central retinal vein occlusion in a young thrombophilic patient with factor V Leiden mutation.

PURPOSE: To investigate the cause of recurrent central retinal vein occlusion in a 26-year-old white woman. METHODS: Case report. Complete blood analyses were done, including HLA tissue typing, immunoserologic and coagulation tests, with cardiovascular and capillaroscopy investigations. Factor V:R506Q and prothrombin 20210 GIA mutations were checked by polymerase chain reaction and restriction enzyme analysis. RESULTS: DNA analysis showed the patient to be heterozygous for factor V:R506Q mutation. During a follow-up of 18-months, after starting anticoagulant therapy, the patient had not suffered from any other ocular or systemic occlusive vascular accident. CONCLUSIONS: The R506Q factor V gene mutation may be associated with recurrent central retinal vein occlusions. Genetic investigation should be promptly recommended in thrombotic patients to establish a specific preventive treatment.

The heterozygous 20210 G/A genotype prevalence in patients affected by central and branch retinal vein occlusion: a pilot study.

BACKGROUND: Several inherited conditions have been associated with an increased or decreased incidence of retinal vein occlusion (RVO). The A allele in the 20210 G/A prothrombin gene has been found to be associated with systemic venous thrombosis. The aim of this study has been to verify the prevalence of this mutation in patients affected by central RVO (CRVO) or branch RVO (BRVO). METHODS: A retrospective study was carried out on 100 consecutive patients suffering from RVO, more than 50 years old, unaffected by systemic diseases known to be associated with markedly increased RVO occurrence. We determined the frequency of this mutation by performing mutagenised amplification of exon 14 followed by restriction analysis of the amplified DNA fragment. RESULTS: The overall frequency of prothrombin 20210A allele in RVO patients was 6.0%. All heterozygous patients had suffered from CRVO. In this study subgroup, the frequency of the 20210 G/A prothrombin heterozygosis was 12.0%. The difference in the frequency of this the genetic variant between the CRVO and BRVO groups was statistically significant. None of the conventional RVO risk factors were statistically related to the occurrence of the disease in either the CRVO or the BRVO subgroup. CONCLUSION: The prevalence of the prothrombin 20210A mutation observed in CRVO patients is significantly higher than in the normal Italian population. Moreover, the prevalence is significantly greater in CRVO than in BRVO patients. These results raise the possibility that the prothrombin 20210A variant may be considered as a risk factor for CRVO.

Ocular surface changes induced by topical application of latanoprost and timolol: a short-term study in glaucomatous patients with and without allergic conjunctivitis.

BACKGROUND: This study evaluated the conjunctival effects of latanoprost and timolol, both of which contain benzalkonium chloride, in patients with primary open-angle glaucoma (POAG), with and without a history of allergic conjunctivitis (AC). METHODS: Two groups of 25 patients with and without a positive history for AC were studied. After a 21-day wash-out period patients were randomized to 14 days treatment with latanoprost or with timolol, in a cross-over fashion. The following parameters were evaluated on days 0 and 14: number of white blood cells, ferning test, conjunctival impression cytology, subjective symptoms, and objective ocular changes. RESULTS: Latanoprost caused: (a) an increase in eosinophils in both groups and reduction in lymphocytes only in the group with a history of AC; (b) alterations in ferning test and impression cytology only in AC patients; and (c) development of subjective symptoms and objective signs only in non-AC glaucomatous subjects. Timolol therapy was responsible only for the occurrence of subjective symptoms and objective signs in non-AC patients. CONCLUSION: Latanoprost treatment induces ocular surface changes which are more evident in POAG patients who are also affected by AC. These findings are probably related to the very high latanoprost concentration of benzalkonium chloride and to its bedtime administration, which further amplifies the toxicity.

Idiopathic multiple serous detachments of the retinal pigment epithelium followed by bilateral central serous chorioretinopathy: a case report.

An uncommon case of a 25-year-old woman affected by bilateral idiopathic multiple serous detachments of the macular retinal pigment epithelium is described. During the fluorescein angiography follow-up, in either macular area one of these detachments resulted in a typical central serous chorioretinopathy active leakage point. These findings detail that idiopathic serous detachments of the retinal pigment epithelium may represent predisposing changes for the development of macular neurosensory retinal detachment.

Local and systemic inoculation of DNA or protein gB1s-based vaccines induce a protective immunity against rabbit ocular HSV-1 infection.

A secreted form of gB1 (gB1s), previously shown to protect rabbits against HSV-1 ocular infection when inoculated systemically, was delivered to rabbit periocular area to evaluate its vaccine efficacy upon local administration. The efficacy of local or systemic inoculation of a gB1s-DNA-based vaccine in the rabbit model of ocular HSV-1 infection was assessed in parallel flow. Rabbits received four inoculations of the different immunogens, then immune responses and clinical symptoms were evaluated. Both the local protein and the systemic DNA administration elicited a neutralizing antibody response, reduced ocular symptoms with respect to controls (P<0.01), and completely prevented the death of rabbits from encephalitis. Conversely, local DNA vaccination did not induce any detectable antibody response, and could only partially protect rabbits from the development of encephalitis and severe ocular infection.

Idiopathic central retinal vein occlusion in a thrombophilic patient with the heterozygous 20210 G/A prothrombin genotype.

PURPOSE: To report the occurrence of monolateral central retinal vein occlusion in a patient with heterozygous 20210 G/A prothrombin genotype, known to be associated with high thrombophilic risk. METHODS: A monolateral central retinal vein occlusion was diagnosed in a 71-year-old woman, who had suffered from a deep vein thrombosis in her left leg at the age of 36 years. Mutations of the genes involved in the coagulation process were investigated by DNA polymerase chain reaction. RESULT: DNA analysis showed the patient to be heterozygous for the prothrombin 20210 G/A genetic variation. CONCLUSION: The 20210 G/A prothrombin gene mutation may be associated with central retinal vein occlusion.

Prevalence of retinopathy in diabetic thalassaemic patients.

Thalassaemic patients with diabetes mellitus are at risk of developing retinopathy. To evaluate the prevalence and the characteristics of diabetic retinopathy in thalassaemics we examined 46 patients with beta-thalassaemia major and insulin-dependent diabetes by fluorescein angiography. The study group was matched for sex, age and diabetes duration with a control group of 46 type 1 diabetic patients. Diabetic retinopathy was detected in 26% (12/46) of thalassaemics and in 50% (23/46) of the controls. In thalassaemics the diabetic retinopathy was significantly less severe than in controls (P < 0.0001). The influence of risk factors for diabetic retinopathy (duration of diabetes and metabolic control) was confirmed in the control group. In thalassaemic patients we found no significant correlation between these risk variables and the presence of diabetic retinopathy. Various factors may protect thalassaemics from diabetic retinopathy: heterogeneity of pancreatic functions; high incidence of hypogonadism; contemporary dysfunction of GH and/or glucagon secretion.

Effects of the passive transfer of anti-gB antibodies in a rabbit model of HSV-1-induced keratitis.

The effectiveness of passively transferred antibodies directed against the secretory form of herpes simplex virus type 1 (HSV-1) glycoprotein B (gB1-s) was tested in a rabbit model of ocular HSV-1 infection. The animals were passively immunized through the intramuscular injection of a homologous polyclonal anti-gB1-s antiserum at different times from the viral ocular challenge (i.e. at -24, 0, +24 and +48 h from infection). The effects observed in this trial were compared with those obtained in an active immunization trial, in which the animals were vaccinated with gB1-s before the ocular infection with HSV-1 (large variant). The results have shown that passive immunization appears quite effective in prophylactic utilization, whereas it is less effective when performed at 24 or 48 h after inoculation. By contrast, active immunization of rabbits proved to be highly effective both in preventing the development of fatal encephalitis and in reducing the severity of corneal lesions.