Hypoxia-Induced Retinal Angiogenesis in Zebrafish as a Model to Study Retinopathy

Mechanistic understanding and defining novel therapeutic targets of diabetic retinopathy and age-related macular degeneration (AMD) have been hampered by a lack of appropriate adult animal models. Here we describe a simple and highly reproducible adult fli-EGFP transgenic zebrafish model to study retinal angiogenesis. The retinal vasculature in the adult zebrafish is highly organized and hypoxia-induced neovascularization occurs in a predictable area of capillary plexuses. New retinal vessels and vascular sprouts can be accurately measured and quantified. Orally active anti-VEGF agents including sunitinib and ZM323881 effectively block hypoxia-induced retinal neovascularization. Intriguingly, blockage of the Notch signaling pathway by the inhibitor DAPT under hypoxia, results in a high density of arterial sprouting in all optical arteries. The Notch suppression-induced arterial sprouting is dependent on tissue hypoxia. However, in the presence of DAPT substantial endothelial tip cell formation was detected only in optic capillary plexuses under normoxia. These findings suggest that hypoxia shifts the vascular targets of Notch inhibitors. Our findings for the first time show a clinically relevant retinal angiogenesis model in adult zebrafish, which might serve as a platform for studying mechanisms of retinal angiogenesis, for defining novel therapeutic targets, and for screening of novel antiangiogenic drugs

Coccidian Infection Causes Oxidative Damage in Greenfinches

The main tenet of immunoecology is that individual variation in immune responsiveness is caused by the costs of immune responses to the hosts. Oxidative damage resulting from the excessive production of reactive oxygen species during immune response is hypothesized to form one of such costs. We tested this hypothesis in experimental coccidian infection model in greenfinches Carduelis chloris. Administration of isosporan coccidians to experimental birds did not affect indices of antioxidant protection (TAC and OXY), plasma triglyceride and carotenoid levels or body mass, indicating that pathological consequences of infection were generally mild. Infected birds had on average 8% higher levels of plasma malondialdehyde (MDA, a toxic end-product of lipid peroxidation) than un-infected birds. The birds that had highest MDA levels subsequent to experimental infection experienced the highest decrease in infection intensity. This observation is consistent with the idea that oxidative stress is a causative agent in the control of coccidiosis and supports the concept of oxidative costs of immune responses and parasite resistance. The finding that oxidative damage accompanies even the mild infection with a common parasite highlights the relevance of oxidative stress biology for the immunoecological research

Oxidative Stress Mediates Physiological Costs of Begging in Magpie (Pica pica) Nestlings

[Background] Theoretical models predict that a cost is necessary to guarantee honesty in begging displays given by offspring to solicit food from their parents. There is evidence for begging costs in the form of a reduced growth rate and immunocompetence. Moreover, begging implies vigorous physical activity and attentiveness, which should increase metabolism and thus the releasing of pro-oxidant substances. Consequently, we predict that soliciting offspring incur a cost in terms of oxidative stress, and growth rate and immune response (processes that generate pro-oxidants substances) are reduced in order to maintain oxidative balance. [Methodology/Principal Findings] We test whether magpie (Pica pica) nestlings incur a cost in terms of oxidative stress when experimentally forced to beg intensively, and whether oxidative balance is maintained by reducing growth rate and immune response. Our results show that begging provokes oxidative stress, and that nestlings begging for longer bouts reduce growth and immune response, thereby maintaining their oxidative status. [Conclusions/Significance] These findings help explaining the physiological link between begging and its associated growth and immunocompetence costs, which seems to be mediated by oxidative stress. Our study is a unique example of the complex relationships between the intensity of a communicative display (begging), oxidative stress, and life-history traits directly linked to viability.GM-R was supported by the Spanish Government (Ministerio de Ciencia y Tecnología, “Juan de la Cierva” program), and TR was supported by the Consejo Superior de Investigaciones Científicas (CSIC; Proyectos Intramurales Especiales)

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand

OBJECTIVE: To describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: 1094 children initiating an NNRTI- or boosted PI-based regimen aged 1 to 10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using 3 parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (World Health Organisation references) at ART initiation. Multivariate regression explored characteristics associated with these 3 parameters. RESULTS: At ART initiation median age and HAZ was 6.4[IQR:2.8,9.0] years and -1.2[-2.3,-0.2], respectively. Median follow-up was 9.1[6.9,11.4] years. In females, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% CI 0.20,0.62) years later in children starting ART age 6-<11 years compared to 1-<3 years and 1.50 (1.21,1.78) years later in those starting with HAZ<-3 compared to HAZ≥-1. Later growth spurts in females resulted in continued height growth into later adolescence. In males starting ART with HAZ<-1, growth spurts were later in children starting ART in the oldest age group, but for HAZ≥-1 there was no association with age. Males and females who initiated ART with HAZ≥-1 maintained a similar height to the WHO reference mean. CONCLUSIONS: Stunting at ART initiation was associated with later growth spurts in females. Children with HAZ≥-1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches

Surgical resection followed by radiotherapy and temozolomide in newly diagnosed glioblastoma can prolong survival, but it is not curative. For patients with disease progression after frontline therapy, there is no standard of care, although further surgery, chemotherapy, and radiotherapy may be used. Antiangiogenic therapies may be appropriate for treating glioblastomas because angiogenesis is critical to tumor growth. In a large, noncomparative phase II trial, bevacizumab was evaluated alone and with irinotecan in patients with recurrent glioblastoma; combination treatment was associated with an estimated 6-month progression-free survival (PFS) rate of 50.3%, a median overall survival of 8.9 months, and a response rate of 37.8%. Single-agent bevacizumab also exceeded the predetermined threshold of activity for salvage chemotherapy (6-month PFS rate, 15%), achieving a 6-month PFS rate of 42.6% (p < 0.0001). On the basis of these results and those from another phase II trial, the US Food and Drug Administration granted accelerated approval of single-agent bevacizumab for the treatment of glioblastoma that has progressed following prior therapy. Potential antiangiogenic agents-such as cilengitide and XL184-also show evidence of single-agent activity in recurrent glioblastoma. Moreover, the use of antiangiogenic agents with radiation at disease progression may improve the therapeutic ratio of single-modality approaches. Overall, these agents appear to be well tolerated, with adverse event profiles similar to those reported in studies of other solid tumors. Further research is needed to determine the role of antiangiogenic therapy in frontline treatment and to identify the optimal schedule and partnering agents for use in combination therapy

Optimal timing of antiretroviral treatment initiation in HIV-positive children and adolescents: a multiregional analysis from Southern Africa, West Africa and Europe

BACKGROUND: There is limited knowledge about the optimal timing of antiretroviral treatment initiation in older children and adolescents. METHODS: A total of 20 576 antiretroviral treatment (ART)-naïve patients, aged 1-16 years at enrolment, from 19 cohorts in Europe, Southern Africa and West Africa, were included. We compared mortality and growth outcomes for different ART initiation criteria, aligned with previous and recent World Health Organization criteria, for 5 years of follow-up, adjusting for all measured baseline and time-dependent confounders using the g-formula. RESULTS: Median (1st;3rd percentile) CD4 count at baseline was 676 cells/mm(3) (394; 1037) (children aged ≥ 1 and 10 years at enrolment we did not find any difference in mortality or growth with immediate ART initiation, with estimated differences of -0.1% (-0.2%; 0.6%) and -0.03 (-0.05; 0.00), respectively. Growth differences in children aged < 10 years persisted for treatment thresholds using higher CD4 values. Regular follow-up led to better height and mortality outcomes. CONCLUSIONS: Immediate ART is associated with lower mortality and better growth for up to 5 years in children < 10 years old. Our results on adolescents were inconclusive

Predictors of faster virological suppression in early treated infants with perinatal HIV from Europe and Thailand

OBJECTIVE: To identify predictors of faster time to virological suppression among infants starting combination antiretroviral therapy (cART) early in infancy. DESIGN: Cohort study of infants from Europe and Thailand included in studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC). METHODS: Infants with perinatal HIV starting cART aged <6 months with ≥1 viral load (VL) measurement within 15 months of cART initiation were included. Multivariable interval-censored flexible parametric proportional hazards models were used to assess predictors of faster virological suppression, with timing of suppression assumed to lie in the interval between last VL≥400 and first VL<400copies/ml. RESULTS: Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% UK/Ireland, 15% Eastern Europe and 3% Thailand; 46% and 54% started a boosted protease inhibitor- or non-nucleoside reverse transcriptase inhibitor- based regimen, respectively. At cART initiation, the median age, CD4% and VL were 2.9 (IQR:1.4-4.1) months, 34 (IQR:24-45)% and 5.5 (IQR:4.5-6.0) log10copies/ml, respectively. Overall, an estimated 89% (95%CI:86-92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age (aHR:0.84 per month older; P < 0.001), higher CD4% (aHR:1.11 per 10% higher; P = 0.010) and lower log10 VL (aHR:0.85 per log10 higher; P < 0.001) at cART initiation independently predicted faster virological suppression. CONCLUSION: We observed a significant independent effect of age at cART initiation, even within a narrow 6 months window from birth. These findings support the earliest feasible cART initiation in infants and suggest that early therapy influences key virological and immunological parameters that could have important consequences for long term health