Corrigendum to "Activation of Melanocortin Receptors MC1 and MC5 Attenuates Retinal Damage in Experimental Diabetic Retinopathy".

[This corrects the article DOI: 10.1155/2016/7368389.].

Autosomal-dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation.

We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.

Wide-band polarization controller for Si photonic integrated circuits.

A circuit for the management of any arbitrary polarization state of light is demonstrated on an integrated silicon (Si) photonics platform. This circuit allows us to adapt any polarization into the standard fundamental TE mode of a Si waveguide and, conversely, to control the polarization and set it to any arbitrary polarization state. In addition, the integrated thermal tuning allows kilohertz speed which can be used to perform a polarization scrambler. The circuit was used in a WDM link and successfully used to adapt four channels into a standard Si photonic integrated circuit.

Activation of Melanocortin Receptors MC 1 and MC 5 Attenuates Retinal Damage in Experimental Diabetic Retinopathy.

We hypothesize that melanocortin receptors (MC) could activate tissue protective circuit in a model of streptozotocin- (STZ-) induced diabetic retinopathy (DR) in mice. At 12-16 weeks after diabetes induction, fluorescein angiography (FAG) revealed an approximate incidence of 80% microvascular changes, typical of DR, in the animals, without signs of vascular leakage. Occludin progressively decreased in the retina of mice developing retinopathy. qPCR of murine retina revealed expression of two MC receptors, Mc1r and Mc5r. The intravitreal injection (5 µL) of the selective MC1 small molecule agonist BMS-470539 (33 µmol) and the MC5 peptidomimetic agonist PG-901 (7.32 nM) elicited significant protection with regular course and caliber of retinal vessels, as quantified at weeks 12 and 16 after diabetes induction. Mouse retina homogenate settings indicated an augmented release of IL-1α, IL-1ß, IL-6, MIP-1α, MIP-2α, MIP-3α, and VEGF from diabetic compared to nondiabetic mice. Application of PG20N or AGRP and MC5 and MC1 antagonist, respectively, augmented the release of cytokines, while the agonists BMS-470539 and PG-901 almost restored normal pattern of these mediators back to nondiabetic values. Similar changes were quantified with respect to Ki-67 staining. Finally, application of MC3-MC4 agonist/antagonists resulted to be inactive with respect to all parameters under assessment.

Interplay between Intravitreal RvD1 and Local Endogenous Sirtuin-1 in the Protection from Endotoxin-Induced Uveitis in Rats.

Rat endotoxin-induced uveitis (EIU) is a well-established model of human uveitis. In this model, intravitreal injection of resolvin D1 (RvD1, 10-100-1000 ng/kg) 1 hour after subcutaneous treatment of Sprague-Dawley rats with lipopolysaccharide (LPS, 200 µg/rat) significantly prevented the development of uveitis into the eye. RvD1 dose-dependently increased the expression of sirtuin-1 (SIRT1) within the eye, while it decreased the expression of acetyl-p53 and acetyl-FOXO1. These effects were accompanied by local downregulation of some microRNAs related to the expression and activity of SIRT1. These were miR-195-5p, miR-200a-3p, miR-34a-5p, and miR-145-5p. An increase of manganese superoxide dismutase and decrease of caspase 3 were evident after RvD1 treatment. In another set of experiments, the protective effects of RvD1 (1000 ng/kg) were partly abolished by the pretreatment of the rats with EX527 (10 mg/kg/day, i.p.), a specific inhibitor of SIRT1 activity, for 7 days prior to the induction of EIU in rats. Similarly, the effects of RvD1 (1000 ng/kg) on the SIRT1 protein expression were abolished by Boc2, N-t-butoxycarbonyl-PLPLP, a specific formyl-peptide receptor type 2/lipoxin A receptor antagonist. Therefore, an interplay of the SIRT1 activity on the RvD1 mediated resolution of EIU is argued.

A pilot study for development of a novel tool for clinical decision making to identify fallers among ophthalmic patients.

BACKGROUND: Falls in the elderly is a major problem. Although falls have a multifactorial etiology, a commonly cited cause of falls in older people is poor vision. This study proposes a method to discriminate fallers and non-fallers among ophthalmic patients, based on data-mining algorithms applied to health and socio-demographic information. METHODS: A group of 150 subjects aged 55 years and older, recruited at the Eye Clinic of the Second University of Naples, underwent a baseline ophthalmic examination and a standardized questionnaire, including lifestyles, general health, social engagement and eyesight problems. A subject who reported at least one fall within one year was considered as faller, otherwise as non-faller. Different tree-based data-mining algorithms (i.e., C4.5, Adaboost and Random Forest) were used to develop automatic classifiers and their performances were evaluated by assessing the receiver-operator characteristics curve estimated with the 10-fold-crossvalidation approach. RESULTS: The best predictive model, based on Random Forest, enabled to identify fallers with a sensitivity and specificity rate of 72.6% and 77.9%, respectively. The most informative variables were: intraocular pressure, best corrected visual acuity and the answers to the total difficulty score of the Activities of Daily Vision Scale (a questionnaire for the measurement of visual disability). CONCLUSIONS: The current study confirmed that some ophthalmic features (i.e. cataract surgery, lower intraocular pressure values) could be associated with a lower fall risk among visually impaired subjects. Finally, automatic analysis of a combination of visual function parameters (either self-evaluated either by ophthalmological tests) and other health information, by data-mining algorithms, could be a feasible tool for identifying fallers among ophthalmic patients.

Efficacy of vaccination on Staphylococcus aureus and coagulase-negative staphylococci intramammary infection dynamics in 2 dairy herds.

The aim of this study was to evaluate vaccine efficacy of a commercial vaccine (Startvac, Hipra Spain) aimed at reducing intramammary infections (IMI) with Staphylococcus aureus and coagulase-negative staphylococci under field conditions. During the 21-mo duration of the study, 1,156 lactations from 809 cows were enrolled in 2 herds. During the first phase of the trial, all cows that were due to calve were vaccinated until approximately 50% of cows in the milking herd were vaccinated (at ~6mo). At that point, when 50% vaccination coverage was reached, cows that were due to calve were randomly assigned to be vaccinated or left as negative controls. Cure rate, rate of new infection, prevalence, and duration of infections were analyzed. Vaccination resulted in a moderate reduction in incidence of new staphylococcal IMI and a more pronounced reduction in duration of IMI associated with reduction of the basic reproduction ratio of Staph. aureus by approximately 45% and of coagulase-negative staphylococci by approximately 35%. The utilization of vaccine in combination with other infection-control procedures, such as excellent milking procedures, treatment, segregation, and culling of known infected cattle, will result in an important reduction in incidence and duration of intramammary staphylococcal infections.

Clinical presentation, echocardiographic findings, treatment strategies, and prognosis of dogs with myxomatous mitral valve disease presented with pericardial effusion due to suspected left atrial tear: a retrospective case-control study.

INTRODUCTION/OBJECTIVES: Left atrial tear (LAT) is a life-threatening complication in dogs with myxomatous mitral valve disease (MMVD). The study objective was to describe clinical presentation, echocardiographic findings, treatment strategies, and survival in dogs with LAT compared to a control group of dogs with a similar stage of MMVD but no LAT. ANIMALS AND MATERIALS AND METHODS: Two-center retrospective case-controlled study including 15 dogs with and 15 dogs without LAT was conducted. Clinical and echocardiographic data were reviewed, and survival information were collected. RESULTS: Nine dogs in each group were in stage C of MMVD, while the remaining were in stage B2. No differences between groups were found regarding age, body weight, sex, kidney values, and echocardiography-derived cardiac dimensions. Most reported clinical signs associated with LAT included weakness, respiratory signs, and syncope. Treatment varied and was mainly focused on the management of congestive heart failure. Three dogs with LAT received a pericardiocentesis. All 15 dogs with LAT had died of cardiac causes, five dogs during the first seven days after admission. The median survival time for all 15 dogs with LAT was 52 days compared to 336 days in the control group (P=0.103). When excluding five dogs with LAT that died during the first seven days, the median survival increased to 407 days, not different compared to the control group (P=0.549). CONCLUSIONS: Dogs with MMVD and LAT have a high short-term mortality; however, when surviving the acute phase, the long-term prognosis may not differ from dogs with a similarly advanced degree of MMVD but without LAT.

Muscle atonia index during multiple sleep latency test: A possible marker to differentiate narcolepsy from other hypersomnias.

OBJECTIVE: The complexity and delay of the diagnosis of narcolepsy require several diagnostic tests and invasive procedures such as lumbar puncture. Our study aimed to determine the changes in muscle tone (atonia index, AI) at different levels of vigilance during the entire multiple sleep latency test (MSLT) and each nap in people with narcolepsy type 1 (NT1) and 2 (NT2) compared with other hypersomnias and its potential diagnostic value. METHODS: Twenty-nine patients with NT1 (11 M 18F, mean age 34.9 years, SD 16.8) and sixteen with NT2 (10 M 6F, mean age 39 years, SD 11.8) and 20 controls with other hypersomnias (10 M, 10F mean age 45.1 years, SD 15.1) were recruited. AI was evaluated at different levels of vigilance (Wake and REM sleep) in each nap and throughout the MSLT of each group. The validity of AI in identifying patients with narcolepsy (NT1 and NT2) was analyzed using receiver operating characteristic (ROC) curves. RESULTS: AI during wakefulness (WAI) was significantly higher in the narcolepsy groups (NT1 and NT2 p < 0.001) compared to the hypersomniac group. AI during REM sleep (RAI) (p = 0.03) and WAI in nap with sudden onsets of REM sleep periods (SOREMP) (p = 0.001) were lower in NT1 than in NT2. The ROC curves showed high AUC values for WAI (NT1 0.88; Best Cut-off > 0.57, Sensitivity 79.3 % Specificity 90 %; NT2 0.89 Best Cut-off > 0.67 Sensitivity 87.5 % Specificity 95 %; NT1 and NT2 0.88 Best Cut-off > 0.57 Sensitivity 82.2 % Specificity 90 %) in discriminating subjects suffering from other hypersomnias. RAI and WAI in nap with SOREMP showed a poor AUC value (RAI AUC: 0.7 Best cutoff 0.7 Sensitivity 50 % Specificity 87.5 %; WAI in nap before SOREMP AUC: 0.66, Best cut-off < 0.82 sensitivity 61.9 % and specificity 67.35 %) differentiating NT1 and NT2. CONCLUSIONS: WAI may represent an encouraging electrophysiological marker of narcolepsy and suggests a vulnerable tendency to dissociative wake / sleep dysregulation lacking in other forms of hypersomnia. SIGNIFICANCE: AI during wakefulness may help distinguish between narcolepsy and other hypersomnias.

Suspected sequential left atrial ruptures in a dog with myxomatous mitral valve disease.

An 11-year-old mixed breed dog was presented with exercise intolerance and syncope. At admission, transthoracic echocardiography revealed myxomatous mitral valve disease (MMVD) associated with severe left atrial (LA) enlargement and moderate anechoic pericardial effusion with a hyperechoic density suggestive of a thrombus. Rupture of the LA free wall secondary to MMVD was suspected, and medical therapy with furosemide and pimobendan was initiated. After one month, recheck echocardiography showed mild anechoic pericardial effusion and an acquired atrial septal defect with a left-to-right intracardiac shunting flow. In light of the dog's history, the latter finding was suspected to be secondary to a further rupture of the LA wall due to MMVD, this time affecting the interatrial septum. The images described here allow us to suspect that sequential LA wall ruptures developed over time in the same subject affected by MMVD, a clinical presentation not previously described in veterinary medicine.

The canine T wave: a retrospective analysis on qualitative and quantitative T wave variables obtained in 129 healthy dogs and proposed reference intervals.

INTRODUCTION/OBJECTIVE: The T wave is a poorly characterized electrocardiographic variable in small animals. Therefore, this study aimed to describe T wave features in a large population of healthy dogs. ANIMALS, MATERIALS, AND METHODS: Medical records were reviewed to identify healthy dogs ≥one-year-olds that underwent an electrocardiogram. T wave qualitative (morphology, polarity, and concordance between R and T waves) and quantitative (duration, amplitude, mean electrical axis, ratio between T and R waves amplitudes, interval from the peak to the end of the T wave, and ratio between the duration of the latter interval and that of the QT) variables were evaluated. Continuous and categorical variables were compared between dogs of distinct sex, body weight (BW), age and somatotype using the Mann-Whitney U test and χ2 test, respectively. Spearman's correlation coefficients between quantitative variables and age and BW were calculated. Reference intervals of quantitative variables were determined in the overall population. RESULTS: One hundred and twenty-nine dogs were enrolled. Concerning morphology, the asymmetrical (slow/fast) pattern occurred more frequently than the symmetrical and biphasic ones. Concerning polarity, positive T waves occurred more frequently than negative and neutral ones. T and R waves were predominantly concordant. No meaningful differences were found when comparing qualitative and quantitative variables between dogs of distinct sex, BW, age and somatotype. No significant correlations were found between quantitative variables and age and BW. Reference intervals of quantitative variables are provided. CONCLUSIONS: Canine T wave features were addressed and statistically reliable reference intervals made available for clinical use.

Retrospective evaluation of the ST segment electrocardiographic features in 180 healthy dogs.

OBJECTIVES: Normal features of the ST segment are poorly characterised in dogs. This study aimed to describe ST segment characteristics in a population of healthy dogs. MATERIALS AND METHODS: Medical records were reviewed to identify healthy dogs that underwent an electrocardiogram. Several ST segment qualitative parameters were evaluated: presence/absence of deviation, type of deviation (depression/elevation) and morphological patterns of depression (horizontal, downsloping, upsloping and sagging) and elevation (horizontal, concave and convex). Moreover, the amplitude of ST segment depression/elevation was measured. The potential effect of sex, bodyweight, age and somatotype on the presence/absence of ST segment deviation was evaluated through binary logistic regression. RESULTS: One hundred and eighty dogs were enrolled. The deviation was evident in 43 of 180 dogs (23.9%), among which 36 showed depression and seven showed elevation. The median depression amplitude was 0.1 (range 0.05 to 0.3) mV. The mean elevation amplitude was 0.136 ±0.055 mV. Concerning depression morphology, the horizontal pattern was overrepresented, followed by the downsloping and upsloping ones. Concerning elevation morphology, all dogs showed a concave pattern. No meaningful effect of sex, bodyweight, age and somatotype on the presence/absence of ST segment deviation was documented. CLINICAL SIGNIFICANCE: Normal features of canine ST segment were described and made available for clinical use.

AAV-mediated photoreceptor transduction of the pig cone-enriched retina.

Recent success in clinical trials supports the use of adeno-associated viral (AAV) vectors for gene therapy of retinal diseases caused by defects in the retinal pigment epithelium (RPE). In contrast, evidence of the efficacy of AAV-mediated gene transfer to retinal photoreceptors, the major site of inherited retinal diseases, is less robust. In addition, although AAV-mediated RPE transduction appears efficient, independently of the serotype used and species treated, AAV-mediated photoreceptor gene transfer has not been systematically investigated thus so far in large animal models, which also may allow identifying relevant species-specific differences in AAV-mediated retinal transduction. In the present study, we used the porcine retina, which has a high cone/rod ratio. This feature allows to properly evaluate both cone and rod photoreceptors transduction and compare the transduction characteristics of AAV2/5 and 2/8, the two most efficient AAV vector serotypes for photoreceptor targeting. Here we show that AAV2/5 and 2/8 transduces both RPE and photoreceptors. AAV2/8 infects and transduces photoreceptor more efficiently than AAV2/5, similarly to what we have observed in the murine retina. The use of the photoreceptor-specific rhodopsin promoter restricts transgene expression to porcine rods and cones, and results in photoreceptor transduction levels similar to those obtained with the ubiquitous promoters tested. Finally, immunological, toxicological and biodistribution studies support the safety of AAV subretinal administration to the large porcine retina. The data presented here on AAV-mediated transduction of the cone-enriched porcine retina may affect the development of gene-based therapies for rare and common severe photoreceptor diseases.

Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age related macular degeneration in an Italian population.

AIMS: To evaluate the complement factor H (CFH) p.402Y>H polymorphism as a risk factor in age related macular degeneration (AMD) in an Italian population. METHODS: 104 unrelated Italian AMD patients and 131 unrelated controls were screened for the CFH polymorphism p.402Y>H (c.1277 T>C), which has been associated with AMD. Retinography was obtained for patients and controls; the AMD diagnosis was confirmed by fluorescein angiograms. The c.1277 T>C polymorphism was genotyped with the TaqMan real time polymerase chain reaction single nucleotide polymorphism assay. RESULTS: The frequency of c.1277C allele was higher in AMD patients than in controls (57.2% v 39.3%; p<0.001). The odds ratio (OR; logistic regression analysis) for AMD was 3.9 (95% confidence interval (CI): 1.9 to 8.2) for CC homozygotes. The CC genotype conferred a higher risk for sporadic (OR 4.6; CI: 2.0 to 10.5) than for familial AMD (OR 2.9; CI: 1.0 to 8.4). Genotypes were not related to either age at AMD diagnosis or to AMD phenotype. However, geographic atrophy and choroidal neovascularisation were more frequent in sporadic than in familial AMD (p = 0.027). Overall, the percentage of population attributable risk for the CC genotype was 28% (95% CI:18% to 33%). CONCLUSION: The association between the p.402Y>H (c.1277T>C) polymorphism and AMD applies to the Italian population and the CC genotype is more frequent in sporadic than in familial AMD cases.

Molecular genetics of autosomal dominant retinitis pigmentosa (ADRP): a comprehensive study of 43 Italian families.

Retinitis pigmentosa is the most common form of retinal degeneration and is heterogeneous both clinically and genetically. The autosomal dominant forms (ADRP) can be caused by mutations in 12 different genes. This report describes the first simultaneous mutation analysis of all the known ADRP genes in the same population, represented by 43 Italian families. This analysis allowed the identification of causative mutations in 12 of the families (28% of the total). Seven different mutations were identified, two of which are novel (458delC and 6901C-->T (P2301S), in the CRX and PRPF8 genes, respectively). Several novel polymorphisms leading to amino acid changes in the FSCN2, NRL, IMPDH1, and RP1 genes were also identified. Analysis of gene prevalences indicates that the relative involvement of the RHO and the RDS genes in the pathogenesis of ADRP is less in Italy than in US and UK populations. As causative mutations were not found in over 70% of the families analysed, this study suggests the presence of further novel genes or sequence elements involved in the pathogenesis of ADRP.

Clinical phenotype of an Italian family with a new mutation in the PRPF8 gene.

PURPOSE: To report the clinical and functional characteristics of an autosomal dominant retinitis pigmentosa (ADRP) family with a novel point mutation (P2301S) in the PRPF8 gene. METHODS: PRPF8 gene analysis and complete ophthalmologic examination in an ADRP family. RESULTS: Clinical examination revealed the typical RP phenotype in all family members. Electroretinography showed preserved ERG photopic responses. Genetic analysis showed that the P2301S missense mutation segregated with the disease in all subjects. CONCLUSIONS: Unlike previously reported families, the PRPF8 gene mutation in our family is associated with a mild phenotype in which cone function is partially preserved.