Arousal, Sleep and Cardiovascular Responses to Intermittent Hypercapnic Hypoxia in Piglets

Clinical studies have demonstrated an arousal deficit in infants suffering Obstructive Sleep Apnoea (OSA), and that treatment to alleviate the symptoms of OSA appears to reverse the deficit in arousability. Some sudden infant deaths are thought to be contingent upon such an arousal deficit. This research utilised young piglets during early postnatal development, and exposed them to intermittent hypercapnic hypoxia (IHH) as a model of clinical respiratory diseases. Arousal responses of control animals were compared to the animals exposed to IHH. Comparisons were also made between successive exposures on the first and the fourth consecutive days of IHH. Time to arouse after the onset of the respiratory stimulus, and frequency of arousals during recovery, demonstrated that arousal deficits arose after successive exposures and that these were further exacerbated on the fourth study day. After an overnight recovery period, the arousal deficit was apparently dormant, and only triggered by HH exposure. These studies confirm that both acute and chronic deficits can be induced on a background of otherwise normal postnatal development, suggesting that deficits observed in the clinical setting may be a secondary phenomenon

Analysis of rare variants in the C3 gene in patients with age-related macular degeneration

Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15-65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3) gene have been associated with AMD and recently a rare C3 variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the C3 gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated C3 mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (P = 0.04), Arg735Trp (OR = 17.4, 95% CI = 2.2-136; P = 0.0003), and Ser1619Arg (OR = 5.2, 95% CI = 1.0-25; P = 0.05) at the C3 locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Response to anti-VEGF therapy in patients with subretinal fluid and pigment epithelial detachment on spectral-domain optical coherence tomography

Purpose To analyse the long-term functional and morphological response of a specific choroidal neovascular membrane (CNV) phenotype to anti-vascular endothelial growth factor (VEGF) therapy. Methods Data from 30 eyes of 30 consecutive patients with subretinal fluid (SRF) and fibrovascular pigment epithelial detachment (PED) due to CNV on spectral-domain optical coherence tomography (SDOCT) with a follow-up of at least 20 months were retrospectively collected. Main outcome measures included change in visual acuity, quantitative and qualitative parameters on SDOCT [photoreceptor layer, outer nuclear layer (ONL), choroid, PED, SRF] and on fluorescein angiography (CNV activity). Subjects were divided into responders and non-responders based on morphological and functional aspects. Results An average number of 20.23 +/- 9.9 anti-VEGF injections were administered during a mean follow-up of 40.25 +/- 13.5 months. Fourteen eyes were categorized as morphological non-responders, 12 as functional non-responders and eight as complete non-responders. Complete non-responders were significantly younger than complete responders (68.5+4.5 vs 74.3+6.8 years; p < 0.05) and presented thinner baseline ONL values (68.43+15.2 vs103.5+32.8 mu m; p < 0.05). Intermediate or large drusen as typical features for age-related macular degeneration (AMD) were less frequently present in complete non-responders; however, this was not statistically significant (62.5 % vs 91.7 %; p = 0.25). Conclusions Our preliminary findings indicate that eyes with the specific SDOCT phenotype with isolated fibrovascular PED and SRF frequently demonstrate non-response to anti-VEGF therapy, and the underlying disease mechanism may be different from AMD. Larger prospective trials are required to validate those results, and to develop strategies to improve the morphological as well as functional outcome

LONG-TERM ALTERATIONS OF SYSTEMIC VASCULAR ENDOTHELIAL GROWTH FACTOR LEVELS IN PATIENTS TREATED WITH RANIBIZUMAB FOR AGE-RELATED MACULAR DEGENERATION

Purpose: To analyze long-term changes of systemic vascular endothelial growth factor (VEGF) levels in patients treated with ranibizumab for neovascular age-related macular degeneration. Methods: Sixty-one patients with neovascular age-related macular degeneration and 68 age-matched controls were included in the study. Patients were treated with ranibizumab on a pro re nata regimen. Plasma samples were collected before initiation of treatment and after 1 year (30 patients) or 2 years (31 patients) of treatment. Vascular endothelial growth factor was measured by Luminex microbead analysis. Results: At baseline, patients with neovascular age-related macular degeneration and controls did not differ significantly in VEGF levels (P = 0.062). There was a significant decline in systemic VEGF levels of 39.5% after 1 year (34.2 +/- 17.2 pg/mL to 20.7 +/- 14.0 pg/mL; P = 7.50 x 10(-5)) and of 46.7% after 2 years (40.4 +/- 24.1 pg/mL to 21.5 +/- 23.3 pg/mL; P = 2.48 x 10(-4)) of treatment. Patients with persistent activity of choroidal neovascularization showed a significantly smaller decrease of plasma VEGF levels than patients with dry intervals despite the higher number of injections (P = 0.048). Conclusion: In addition to immediate effects limited to days if not hours, ranibizumab also leads to long-term alterations of systemic VEGF to subnormal levels. Patients with persistent choroidal neovascularization activity showed a less pronounced VEGF decrease. Therefore, VEGF levels might be a useful marker for treatment response