Allelic variation in the VMD2 gene in best disease and age-related macular degeneration.

PURPOSE: To assess the allelic variation of the VMD2 gene in patients with Best disease and age-related macular degeneration (AMD). METHODS: Three hundred twenty-one AMD patients, 192 ethnically similar control subjects, 39 unrelated probands with familial Best disease, and 57 unrelated probands with the ophthalmoscopic findings of Best disease but no family history were screened for sequence variations in the VMD2 gene by single-strand conformation polymorphism (SSCP) analysis. Amplimers showing a bandshift were reamplified and sequenced bidirectionally. In addition, the coding regions of the VMD2 gene were completely sequenced in six probands with familial Best disease who showed no SSCP shift. RESULTS: Forty different probable or possible disease-causing mutations were found in one or more Best disease or AMD patients. Twenty-nine of these variations are novel. Of the 39 probands with familial Best disease, mutations were detected in all 39 (33 by SSCP and 6 by DNA sequencing). SSCP screening of the 57 probands with a clinical diagnosis of Best disease but no family history revealed 16 with mutations. Mutations were found in 5 of 321 AMD patients (1.5%), a fraction that was not significantly greater than in control individuals (0/192, 0%). CONCLUSIONS: Patients with the clinical diagnosis of Best disease are significantly more likely to have a mutation in the VMD2 gene if they also have a positive family history. These findings suggest that a small fraction of patients with the clinical diagnosis of AMD may actually have a late-onset variant of Best disease, whereas at the same time, a considerable fraction of isolated patients with the ophthalmoscopic features of Best disease are probably affected with some other macular disease.

Genotype-phenotype correlation of age-related macular degeneration : influence of complement factor H polymorphism

RAPPORT DE SYNTHESE La dégénérescence maculaire liée à l'âge (DMLA) est une maladie très fréquente qui représente la cause principale de cécité légale chez les sujets de plus de 50 ans en Occident. Bien que l'étiologie exacte de cette affection ne soit pas complètement connue, des facteurs environnementaux et génétiques influencent sa survenue et son évolution. A ce sujet, de récentes recherches ont notamment montré une association marquée à une variante du gène CFH, Y402H. Nous ignorons toutefois si le polymorphisme Y402H est associé à un phénotype particulier de la maladie. Cette étude a pour but d'établir si cette variante du gène CFH est associée à certaines caractéristiques phénotypiques précoces. L'étude porte sur quatre cent vingt patients atteints de DMLA qui ont été phénotypés sur la base de photographie du fond d'oeil (International Classification and Grading system for age- related macular degeneration) et génotypés à partir d'ADN leucocytaire à la recherche de la variante Y402H du gène CFH. Ces données ont ensuite fait l'objet d'une analyse statistique de l'association génotype-phénotype (le génotype de 50 sujets-contrôle a été utilisé pour confirmer l'association du polymorphisme avec la DMLA). Les résultats obtenus, corrigés pour l'âge et le sexe, montrent un odds ratio (OR) de développer une DMLA de 2.95 en présence d'au moins un allèle à risque C et de 9.05 pour les homozygotes CC. Par contre, aucune influence n'est observée sur les stades de la maladie (précoce-tardif)? Une association significative entre le génotype CC et la présence de druses périphériques (p=0.028), ainsi que la localisation centrale des druses (p=0,049) a été mise en évidence. Aucune autre tendance n'a été dégagée concernant les critères restants (taille, surface totale recouverte, localisation nasale des druses) ou les changements pigmentaires. Cette étude a permis de confirmer l'association entre la variante Y4G2H et la DMLA dans la population suisse et de conclure que la variante Y402H du gène CFH présente une association géno-phénotypique pour certaines caractéristiques des druses. Il est probable que d'autres facteurs génétiques encore influencent le phénotype de la DMLA. De nouvelles recherches seront nécessaires pour préciser l'influence de ces autres facteurs génétiques ou environnementaux, en vue d'une meilleure compréhension de la pathogenèse de cette affection, et pour développer des mesures thérapeutiques et prophylactiques adaptées.

Characteristics of eyes with secondary loss of visual acuity receiving variable dosing ranibizumab for neovascular age-related macular degeneration.

PURPOSE: The aim of this work is to investigate the characteristics of eyes failing to maintain visual acuity (VA) receiving variable dosing ranibizumab for neovascular age-related macular degeneration (nAMD) after three initial loading doses. METHODS: A consecutive series of patients with nAMD, who, after three loading doses of intravitreal ranibizumab (0.5 mg each), were re-treated for fluid seen on optical coherence tomography. After exclusion of eyes with previous treatment, follow-up less than 12 months, or missed visits, 99 patients were included in the analysis. The influence of baseline characteristics, initial VA response, and central retinal thickness (CRT) fluctuations on the VA stability from month 3 to month 24 were analyzed using subgroups and multiple regression analyses. RESULTS: Mean follow-up duration was 21.3 months (range 12-40 months, 32 patients followed-up for ≥24 months). Secondary loss of VA (loss of five letters or more) after month 3 was seen in 30 patients (mean VA improvement from baseline +5.8 letters at month 3, mean loss from baseline -5.3 letters at month 12 and -9.7 at final visit up to month 24), while 69 patients maintained vision (mean gain +8.9 letters at month 3, +10.4 letters at month 12, and +12.8 letters at final visit up to month 24). Secondary loss of VA was associated with the presence of pigment epithelial detachment (PED) at baseline (p 0.01), but not with baseline fibrosis/atrophy/hemorrhage, CRT fluctuations, or initial VA response. Chart analysis revealed additional individual explanations for the secondary loss of VA, including retinal pigment epithelial tears, progressive fibrosis, and atrophy. CONCLUSIONS: Tissue damage due to degeneration of PED, retinal pigment epithelial tears, progressive fibrosis, progressive atrophy, or massive hemorrhage, appears to be relevant in causing secondary loss of VA despite vascular endothelial growth factor suppression. PED at baseline may represent a risk factor.

Diets based on virgin olive oil or fish oil but not on sunflower oil prevent age-related alveolar bone resorption by mitochondrial-related mechanisms.

BACKGROUND/OBJECTIVES Aging enhances frequency of chronic diseases like cardiovascular diseases or periodontitis. Here we reproduced an age-dependent model of the periodontium, a fully physiological approach to periodontal conditions, to evaluate the impact of dietary fat type on gingival tissue of young (6 months old) and old (24 months old) rats. METHODS/FINDINGS Animals were fed life-long on diets based on monounsaturated fatty acids (MUFA) as virgin olive oil, n-6 polyunsaturated fatty acids (n-6PUFA), as sunflower oil, or n-3PUFA, as fish oil. Age-related alveolar bone loss was higher in n-6PUFA fed rats, probably as a consequence of the ablation of the cell capacity to adapt to aging. Gene expression analysis suggests that MUFA or n-3PUFA allowed mitochondria to maintain an adequate turnover through induction of biogenesis, autophagy and the antioxidant systems, and avoiding mitochondrial electron transport system alterations. CONCLUSIONS The main finding is that the enhanced alveolar bone loss associated to age may be targeted by an appropriate dietary treatment. The mechanisms involved in this phenomenon are related with an ablation of the cell capacity to adapt to aging. Thus, MUFA or n-3PUFA might allow mitochondrial maintaining turnover through biogenesis or autophagy. They might also be able to induce the corresponding antioxidant systems to counteract age-related oxidative stress, and do not inhibit mitochondrial electron transport chain. From the nutritional and clinical point of view, it is noteworthy that the potential treatments to attenuate alveolar bone loss (a feature of periodontal disease) associated to age could be similar to some of the proposed for the prevention and treatment of cardiovascular diseases, a group of pathologies recently associated with age-related periodontitis.

Age-Related Macular Degeneration: Clinical Findings following Treatment with Antiangiogenic Drugs.

Purpose. To survey the management of patients with neovascular age-related macular degeneration (nvAMD) in Spain. Methods. An observational retrospective multicenter study was conducted. The variables analyzed were sociodemographic characteristics, foveal and macular thickness, visual acuity (VA), type of treatment, number of injections, and the initial administration of a loading dose of an antiangiogenic drug. Results. 208 patients were followed up during 23.4 months in average. During the first and second years, patients received a mean of 4.5 ± 1.8 and 1.6 ± 2.1 injections of antiangiogenic drugs, and 5.4 ± 2.8 and 3.6 ± 2.2 follow-up visits were performed, respectively. The highest improvement in VA was observed at 3 months of follow-up, followed by a decrease in the response that stabilized above baseline values until the end of the study. Patients who received an initial loading dose presented greater VA gains than those without. Conclusions. Our results suggest the need for a more standardized approach in the management and diagnosis of nvAMD receiving VEGF inhibitors. To achieve the visual outcomes reported in pivotal trials, an early diagnosis, proactive approach (more treating than follow-up visits), and a close monitoring might be the key to successfully manage nvAMD.

A delphi study to detect deficiencies and propose actions in real life treatment of neovascular age-related macular degeneration.

Purpose. Spanish retina specialists were surveyed in order to propose actions to decrease deficiencies in real-life neovascular age macular degeneration treatment (nv-AMD). Methods. One hundred experts, members of the Spanish Vitreoretinal Society (SERV), were invited to complete an online survey of 52 statements about nv-AMD management with a modified Delphi methodology. Four rounds were performed using a 5-point Linkert scale. Recommendations were developed after analyzing the differences between the results and the SERV guidelines recommendations. Results. Eighty-seven specialists completed all the Delphi rounds. Once major potential deficiencies in real-life nv-AMD treatment were identified, 15 recommendations were developed with a high level of agreement. Consensus statements to reduce the burden of the disease included the use of treat and extend regimen and to reduce the amount of diagnostic tests during the loading phase and training technical staff to perform these tests and reduce the time between relapse detection and reinjection, as well as establishing patient referral protocols to outside general ophthalmology clinics. Conclusion. The level of agreement with the final recommendations for nv-AMD treatment among Spanish retinal specialist was high indicating that some actions could be applied in order to reduce the deficiencies in real-life nv-AMD treatment.

Individualized Therapy with Ranibizumab in Wet Age-Related Macular Degeneration.

Individualized treatment regimens may reduce patient burden with satisfactory patient outcomes in neovascular age-related macular degeneration. Intravitreal anti-VEGF drugs are the current gold standard. Fixed monthly injections offer the best visual outcome but this regimen is not commonly followed outside clinical trials. A PRN regimen requires monthly visits where the patient is treated in the presence of signs of lesion activity. Therefore, an early detection of reactivation of the disease with immediate retreatment is crucial to prevent visual acuity loss. Several trials suggest that "treat and extend" and other proactive regimens provide a reasonable approach. The rationale of the proactive regimens is to perform treatment anticipating relapses or recurrences and therefore avoid drops in vision while individualizing patient followup. Treat and extend study results in significant direct medical cost savings from fewer treatments and office visits compared to monthly treatment. Current data suggest that, for one year, PRN is less expensive, but treat and extend regimen would likely be less expensive for subsequent years. Once a patient is not a candidate to continue with treatment, he/she should be sent to an outpatient unit with adequate resources to follow nAMD patients in order to reduce the burden of specialized ophthalmologist services.

Point Mutations in the Monocarboxylate Transporter SLC16A12 Lead to Juvenile and Age-Related Cataract

Purpose: Previously we reported on a premature termination mutation in SLC16A12 that leads to dominant juvenile cataract and renal glucosuria. To assess the mutation rate and genotype-phenotype correlations of SLC16A12 in juvenile or age-related forms of cataract, we performed a mutation screen in cataract patients. Methods: Clinical data of approximately 660 patients were collected, genomic DNA was isolated and analyzed. Exons 3 to 8 including flanking intron sequences of SLC16A12 were PCR amplified and DNA sequence was determined. Selected mutations were tested by cell culture assays, in silico analysis and RT-PCR. Results: We found sequence alterations at a rate of approximately 1/75 patients. None of them was found in 360 control alleles. Alterations affect splice site and regulatory region but most mutations caused an amino acid substitution. The majority of the coding region mutations maps to trans-membrane domains. One mutation located to the 5'UTR. It affects translational efficiency of SLC16A12. In addition, we identified a cataract-predisposing SNP in the non-coding region that causes allele-specific splicing of the 5'UTR region. Conclusions: Altered translational efficiency of the solute carrier SLC16A12 and its allele-specific splicing strongly support a model of challenged homeostasis to cause various forms of cataract. In addition, the pathogenic property of the here reported sequence alterations is supported by the lack of known sequence variations within the coding region of SLC16A12. Due to the relatively high mutation rate, we suggest to include SLC16A12 in diagnostic cataract screening. Generally, our data recommend the assessment of regulatory sequences for diagnostic purposes.

Reducing the clinical burden of ranibizumab treatment for neovascular age-related macular degeneration using an individually planned regimen.

AIMS: The purpose of this study was to clinically validate an individually planned treatment regimen for neovascular age-related macular degeneration (nAMD), termed, observe and plan. This regimen was based on the predictability of an individual's need for retreatment and aimed to reduce the clinical burden, while obtaining good functional results. METHODS: This was a prospective case series that included 104 patients (115 eyes) with treatment-naive nAMD. Following three loading doses of ranibizumab, monthly observation visits allowed the disease recurrence interval to be determined. The recurrence interval was reduced by 2 weeks to give the retreatment interval for the next three injections. Periodical control visits (at least every 6 months) allowed the effectiveness of the treatment to be assessed and individual intervals adjusted. RESULTS: Mean visual acuity (VA) improved by 8.7 and 9.8 letters in months 3 and 12, respectively. The mean number of injections during the 12-month study was 7.8, while the mean number of ophthalmic examinations between months 3 and 12 was 3.97. The mean treatment interval after the loading doses was 1.97 months. CONCLUSIONS: The observe-and-plan regimen significantly improved VA. This was obtained with fewer clinic visits compared with other regimens, which could ease the burden of nAMD treatment. TRIAL REGISTRATION NUMBER: Commission cantonale (VD) d'éthique de la recherché Clinique, Université de Lausanne, Protocole 351/11.

Age-related differences in the use of guideline-recommended medical and interventional therapies for acute coronary syndromes: a cohort study.

OBJECTIVES: To compare the use of guideline-recommended medical and interventional therapies in older and younger patients with acute coronary syndromes (ACSs). DESIGN: Prospective cohort study. SETTING: Fifty-five hospitals in Switzerland. PARTICIPANTS: Eleven thousand nine hundred thirty-two patients with ACS enrolled between March 1, 2001, and June 30, 2006. ACS definition included ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina pectoris (UA). MEASUREMENTS: Use of medical and interventional therapies was determined after exclusion of patients with contraindications and after adjustment for comorbidities. Multivariate logistic regression models were used to calculate odds ratios (ORs) per year increase in age. RESULTS: Elderly patients were less likely to receive acetylsalicylic acid (OR=0.976, 95% confidence interval (CI)=0.969-0.980) or beta-blockers (OR=0.985, 95% CI=0.981-0.989). No age-dependent difference was found for heparin use. Elderly patients with STEMI were less likely to receive percutaneous coronary intervention (PCI) or thrombolysis (OR=0.955, 95% CI=0.949-0.961). Elderly patients with NSTEMI or UA less often underwent PCI (OR=0.943, 95% CI=0.937-0.949). CONCLUSION: Elderly patients across the whole spectrum of ACS were less likely to receive guideline-recommended therapies, even after adequate adjustment for comorbidities. Prognosis of elderly patients with ACS may be improved by increasing adherence to guideline-recommended medical and interventional therapies.

Intravitreal ranibizumab for age-related macular degeneration : optical coherence tomography guided retreatment intervals and their intra- and inter-individual variability

Purpose: To determine whether the need for retreatment after an initial phase of 3 monthly intravitreal injections of ranibizumab shows an intra-individual regular rhythm and to what degree it varies between different patients. Methods: Prospective study with 42 patients with exudative AMD, treatment naïve. Loading dose of 3 monthly doses of ranibizumab (0,5 mg), followed by a 12 months pro re nata (PRN) regimen according to early exudative signs on HD-OCT Cirrus, Zeiss. The follow-up visits were intensified (week 4, 5, 6, 7, 8, 10, 12, 14, 16, 20, etc after each injection) in order to detect recurrences early, and injection followed within 3 days in cases of subretinal fluid, cysts, or central thickness increase of>50microns. Intervals were calculated between injections for the 12 month follow-up with PRN treatment. Variability was expressed as standard deviation (SD). Results: Visual acuity (VA) improved from a mean ETDRS score of 61.6 (SD 10.8) at baseline to 68.0 (SD 10.2) at month 3 and to 74.7(SD 9.0) at month 12. The 15 patients who have already completed the study showed maintenance of the VA improvement. Central foveal thickness improved from a mean value of 366 microns (baseline) to 253 microns (month 3), well maintained thereafter. Mean number of injections was 8.8 (SD 3.5,range 0-12) per 12 months of follow-up (after 3 doses), with mean individual treatment-recurrence (TR) intervals ranging from 28->365 days (mean 58). Intraindividual variability of TR intervals (SD) was 7.1 days as a mean value (range 1.7¡V22.6). It ranged within 20% of the mean intra-individual interval for 30 (91%) and within 15% for 21 patients (64%). The first interval was within 1 week of the mean intra-individual interval in 64% and within 2 weeks in 89% of patients. Conclusions: The majority of AMD patients showed a relatively stable rhythm for PRN injections of ranibizumab after initial loading phase, associated with excellent functional/anatomical results. The initial interval last loading dose-first recurrence may have a predictive value for further need of treatment, potentially facilitating follow-up and patient care.

Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration.

PURPOSE: To investigate the rhythm and predictability of the need for retreatment with intravitreal injections of ranibizumab for neovascular age-related macular degeneration (nAMD). METHODS: This prospective study enrolled 39 patients with treatment-naïve nAMD. After three loading doses of intravitreal ranibizumab, patients underwent an intensified follow-up for 12 months (initially weekly, then with stepwise increases to every 2 weeks and to monthly after each injection). Patients were retreated on an as-needed basis if any fluid or increased central retinal thickness (CRT) (>50μm) was found on spectral domain optical coherence tomography (OCT). Statistical analysis included patients who received at least two retreatments (five injections). RESULTS: A mean of 7.5 injections (range 0-12) were given between months 3 and 15. The mean visual acuity increased by 13.1 and 12.6 ETDRS letters at months 12 and 15 respectively. Two or more injection-retreatment intervals were found in 31 patients. The variability of their intra-individual intervals up to 14 weeks was small (SD 0-2.13 weeks), revealing a high regularity of the retreatment rhythm. The SD was correlated with the mean interval duration (r = 0.89, p < 0.001). The first interval was a good predictor of the following intervals (regression coefficient =0.81). One retreatment criterion was stable in 97 % of patients (cysts or subretinal fluid). CONCLUSION: The results of this study demonstrate a high intra-individual predictability of retreatment need with ranibizumab injections for nAMD. These findings may be helpful for developing individualized treatment plans for maintained suppression of disease activity with a minimum of injections and visits.