Higher prolactin and vasoinhibin serum levels associated with incidence and progression of retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is a potentially blinding, retinal neovascular disease. Systemic prolactin accesses the retina to regulate blood vessels. Prolactin is proangiogenic and can be cleaved to antiangiogenic vasoinhibins. We investigated whether circulating prolactin and vasoinhibins associate with incidence and progression of ROP. METHODS: A prospective, longitudinal, case-control study covering postnatal weeks 1 to 9 measured serum prolactin, vasoinhibins, and vascular endothelial growth factor (VEGF) weekly in 90 premature infants diagnosed as ROP or control. RESULTS: Prolactin levels were higher in ROP than in control patients before (106.2 ± 11.3 (SEM) vs. 64.7 ± 4.9 ng/ml, postnatal week 1) and during (120.6 ± 10 vs. 84.7 ± 7.5ng/ml, postnatal week 5) ROP diagnosis. Prolactin, but not gestational age, birth weight, Apgar score, sepsis, or ventilation time, correlated with ROP. The relative risk (RR) of developing ROP increased if Prolactin (PRL) levels were higher than thresholds of 80 ng/ml (RR = 1.55, 95% CI: 1.06-2.28), 100 ng/ml (RR = 1.63, 95% CI: 1.14-2.34), or 120 ng/ml (RR = 1.95, 95% CI: 1.41-2.68). Vasoinhibin levels were 39.7% higher (95% CI: 4.5-77.5) in the circulation of ROP than in control patients at postnatal week 1 and similar thereafter, whereas VEGF serum levels were always similar. CONCLUSION: High serum prolactin and vasoinhibin levels predict and may impact ROP progression.

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1.

Adeno-associated virus (AAV) vector-mediated delivery of inhibitors of blood-retinal barrier breakdown (BRBB) offers promise for the treatment of diabetic macular edema. Here, we demonstrated a reversal of blood-retinal barrier pathology mediated by AAV type 2 (AAV2) vectors encoding vasoinhibin or soluble VEGF receptor 1 (sFlt-1) when administered intravitreally to diabetic rats. Efficacy and safety of the AAV2 vasoinhibin vector were tested by monitoring its effect on diabetes-induced changes in the retinal vascular bed and thickness, and in the electroretinogram (ERG). Also, the transduction of AAV2 vectors and expression of AAV2 receptors and co-receptors were compared between the diabetic and the non-diabetic rat retinas. AAV2 vasoinhibin or AAV2 sFlt-1 vectors were injected intravitreally before or after enhanced BRBB due to diabetes induced by streptozotocin. The BRBB was examined by the Evans blue method, the vascular bed by fluorescein angiography, expression of the AAV2 EGFP reporter vector by confocal microscopy, and the AAV2 genome, expression of transgenes, receptors, and co-receptors by quantitative PCR. AAV2 vasoinhibin and sFlt-1 vectors inhibited the diabetes-mediated increase in BRBB when injected after, but not before, diabetes was induced. The AAV2 vasoinhibin vector decreased retinal microvascular abnormalities and the diabetes-induced reduction of the B-wave of the ERG, but it had no effect in non-diabetic controls. Also, retinal thickness was not altered by diabetes or by the AAV2 vasoinhibin vector. The AAV2 genome, vasoinhibin and sFlt-1 transgenes, and EGFP levels were higher in the retinas from diabetic rats and were associated with an elevated expression of AAV2 receptors (syndecan, glypican, and perlecan) and co-receptors (fibroblast growth factor receptor 1, αvß5 integrin, and hepatocyte growth factor receptor). We conclude that retinal transduction and efficacy of AAV2 vectors are enhanced in diabetes, possibly due to their elevated cell entry. AAV2 vectors encoding vasoinhibin and sFlt-1 may be desirable gene therapeutics to target diabetic retinopathy and macular edema.

High Prolactin Excretion in Patients with Diabetes Mellitus and Impaired Renal Function.

BACKGROUND: The metabolic clearance of prolactin (PRL) is partially executed by the kidney. Here, we investigate the urine excretion of PRL in patients with Diabetes Mellitus and renal impairment. METHODS: Serum and urine samples were collected from male, mestizo patients in central Mexico employing a cross-sectional study design. Ninety-eight individuals had either no diabetes and normal renal function (control), diabetes and normal renal function, or diabetes with impaired renal function. PRL was determined by a chemiluminescent immunometric assay; protein, albumin, and creatinine were evaluated using quantitative colorimetric assays. The results were analyzed using ANOVA-testing. RESULTS: Patients with Diabetes Mellitus and renal impairment had significantly higher urine PRL levels than patients with Diabetes Mellitus and normal renal function and control patients. Higher urine PRL levels were associated with lower glomerular filtration rates, higher serum creatinine, and higher urinary albumin-to-creatinine ratios (UACR). Urine PRL levels correlated positively with UACR. Serum PRL levels were similar among groups. CONCLUSIONS: Patients with Diabetes Mellitus and impaired renal function demonstrate a high urinary PRL excretion. Urinary PRL excretion in the context of proteinuria could contribute to PRL dysregulation in renal impairment.

Effectiveness of the Use of Three-Dose Intravitreal Ziv-Aflibercept in the Management of Diabetic Macular Edema in a Real-Life Setting.

Purpose: It has been reported that intravitreal Ziv-aflibercept is a safe and effective drug for the treatment of diabetes macular edema (DME). The objective of this study was to evaluate in a real-life setting, the efficacy of intravitreal Ziv-aflibercept in the treatment of DME after the administration of three consecutive monthly doses. Methods: A single arm, prospective cohort study. We included patients with DME who received three doses of intravitreal Ziv-aflibercept. Data such as best corrected visual acuity (BCVA) and tomographic biomarkers before treatment and a month after the third dose were collected. DME was staged using the Panozzo classification. Results: Thirty-eight patients participated for a total of 53 eyes. The mean age was 59 ± 8.1 years. We observed significant changes after the third dose in the parameters studied (BCVA in LogMAR pre-treatment (0.6 ± 0.33) and post-treatment (0.4 ± 0.29) [p<0.001], macular thickness pre-treatment (501 ± 167 µm) and post-treatment (324 ± 114 µm) [p<0.001], macular volume pre-treatment 10.8 (7.5-17.8) mm3 and post-treatment 9.3 (0-13.6) mm3 [p<0.005]). And 73.6% of the patients presented an advanced severe stage during their pre-treatment evaluation and after post-treatment, 64.2% of the patients no longer presented edema. No systemic or ocular adverse events occurred. Conclusion: The use of three consecutive monthly doses of intravitreal Ziv-aflibercept in a real-life setting is effective and safe in the management of diabetic macular edema.

Prolactin stimulates the vascularisation of the retina in newborn mice under hyperoxia conditions.

The hormone prolactin (PRL) is emerging as an important regulator of ocular blood vessels. PRL is pro-angiogenic and acquires anti-angiogenic properties after undergoing proteolytic cleavage to the PRL fragment, vasoinhibin. The vascularisation of the rodent retina develops after birth when it rapidly expands until completion at the end of the first postnatal week. Exposure of newborn mice to high oxygen levels lowers the rate of blood vessel growth. In the present study, we investigated whether PRL treatment modifies the vascularisation of the retina in newborn mice exposed to high oxygen or to normoxia and whether the retinal conversion of PRL to vasoinhibin may be altered in the neonate. Newborn mice and their nursing mothers were subjected to 75% oxygen or to normoxia from postnatal day (P) 6 to P8 (group 1) or from P2 to P5 (group 2). PRL (2 µg g-1 , i.p., twice a day) or vehicle was injected from P5 to P8 in group 1 and from P1 to P5 in group 2. PRL treatment reduced the retinal inhibition of blood vessel growth and the increase in vascular regression induced by hyperoxia as revealed by immunofluorescence staining of blood vessels and the expression of angiogenesis and apoptosis markers. The pro-angiogenic effect may involve a reduced conversion of PRL to vasoinhibin. Incubation of PRL with retinal extracts showed reduced activity of the PRL-cleaving protease, cathepsin D, in the neonate vs the adult retina that was further reduced under hyperoxia. PRL and the PRL receptor mRNA were expressed at higher levels in the retina at P8 than in the adult, whereas endogenous PRL was undetectable in the circulation at P8. We conclude that PRL has a pro-angiogenic effect in the neonate retina as a result of its reduced conversion to vasoinhibin and that PRL produced by the retina may help promote physiological vascularisation after birth.

Accuracy of trained rural ophthalmologists versus non-medical image graders in the diagnosis of diabetic retinopathy in rural China.

BACKGROUND/AIMS: To determine the diagnostic accuracy of trained rural ophthalmologists and non-medical image graders in the assessment of diabetic retinopathy (DR) in rural China. METHODS: Consecutive patients with diabetes mellitus were examined from January 2014 to December 2015 at 10 county-level facilities in rural Southern China. Trained rural ophthalmologists performed a complete eye examination, recording diagnoses using the UK National Diabetic Eye Screening Programme (NDESP) classification system. Two field, mydriatic, 45° digital photographs were made by nurses using NDESP protocols and graded by trained graders with no medical background using the NDESP system. A fellowship-trained retina specialist graded all images in masked fashion and served as reference standard. RESULTS: Altogether, 375 participants (mean age 60±10 years, 48% men) were examined and 1277 images were graded. Grader sensitivity (0.82-0.94 (median 0.88)) and specificity (0.91-0.99 (median 0.98)), reached or exceeded NDESP standards (sensitivity 80%, specificity 95%) in all domains except specificity detecting any DR. Rural ophthalmologists' sensitivity was 0.65-0.95 (median 0.66) and specificity 0.59-0.95 (median 0.91). There was strong agreement between graders and the reference standard (kappa=0.84-0.87, p<0.001) and weak to moderate agreement between rural doctors and the reference (kappa=0.48-0.64, p<0.001). CONCLUSION: This is the first study of diagnostic accuracy in DR grading among non-medical graders or ophthalmologists in low-income and middle-income countries. Non-medical graders can achieve high levels of accuracy, whereas accuracy of trained rural ophthalmologists is not optimal.