Ann Hellström

Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis.

Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of ω-3- and ω-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy. We show that increasing ω-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive ω-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of ω-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-α. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of ω-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in ω-3-PUFA, and premature infants lack the important transfer from the mother to the infant of ω-3-PUFA that normally occurs in the third trimester of pregnancy. Supplementing ω-3-PUFA intake may be of benefit in preventing retinopathy.

Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: Direct correlation with clinical retinopathy of prematurity

Retinopathy of prematurity is a blinding disease, initiated by lack of retinal vascular growth after premature birth. We show that lack of insulin-like growth factor I (IGF-I) in knockout mice prevents normal retinal vascular growth, despite the presence of vascular endothelial growth factor, important to vessel development. In vitro, low levels of IGF-I prevent vascular endothelial growth factor-induced activation of protein kinase B (Akt), a kinase critical for endothelial cell survival. Our results from studies in premature infants suggest that if the IGF-I level is sufficient after birth, normal vessel development occurs and retinopathy of prematurity does not develop. When IGF-I is persistently low, vessels cease to grow, maturing avascular retina becomes hypoxic and vascular endothelial growth factor accumulates in the vitreous. As IGF-I increases to a critical level, retinal neovascularization is triggered. These data indicate that serum IGF-I levels in premature infants can predict which infants will develop retinopathy of prematurity and further suggests that early restoration of IGF-I in premature infants to normal levels could prevent this disease.

The Mouse Retina as an Angiogenesis Model

The mouse retina has been used extensively over the past decades to study both physiologic and pathologic angiogenesis. Over time, various mouse retina models have evolved into well-characterized and robust tools for in vivo angiogenesis research. This article is a review of the angiogenic development of the mouse retina and a discussion of some of the most widely used vascular disease models. From the multitude of studies performed in the mouse retina, a selection of representative works is discussed in more detail regarding their role in advancing the understanding of both the ocular and general mechanisms of angiogenesis.

Advanced-stage cervical carcinomas are defined by a recurrent pattern of chromosomal aberrations revealing high genetic instability and a consistent gain of chromosome arm 3q

We have analyzed 30 cases of advanced‐stage cervical squamous cell carcinoma (stages IIb–IV) by comparative genomic hybridization (CGH). The most consistent chromosomal gain in the aneuploid tumors was mapped to chromosome arm 3q in 77% of the cases. Acquisition of genetic material also occurred frequently on 1q (47%), 5p (30%), 6p (27%), and 20 (23%). Recurrent losses were mapped on 2q (33%), 3p (50%), 4 (33%), 8p (23%), and 13q (27%). High‐level copy number increases were mapped to chromosome 8, chromosome arms 3q, 5p, 8q, 12p, 14q, 17q, 19q, 20p, and 20q, and chromosomal bands 3q26‐27, 9p23‐24, 11q22‐23, and 12p13. In the majority of the cases, the presence of high‐risk human papilloma virus genomes was detected. High proliferative activity was accompanied by crude aneuploidy. Increased p21/WAF‐1 activity, but low or undetectable expression of TP53 were representative for the immunophenotype. This study confirms the importance of a gain of chromosome arm 3q in cervical carcinogenesis and identifies additional, recurrent chromosomal aberrations that are required for progression from stage I tumors to advanced‐stage carcinomas. Genes Chromosom. Cancer 19:233–240, 1997. Published 1997 Wiley‐Liss, Inc.

Incidence of and risk factors for neonatal morbidity after active perinatal care : extremely preterm infants study in Sweden (EXPRESS)

Aims:  The aim of this study was to determine the incidence of neonatal morbidity in extremely preterm infants and to identify associated risk factors.

Early Weight Gain Predicts Retinopathy in Preterm Infants: New, Simple, Efficient Approach to Screening

BACKGROUND. The risk for sight-threatening retinopathy of prematurity is predicted by using gestational age and/or weight at birth. All infants below a threshold undergo serial ophthalmologic examinations for identification of those who would benefit from treatment (∼10%). We hypothesized that factoring in postnatal weight gain could identify children at risk for sight-threatening retinopathy of prematurity more specifically and earlier. METHODS. Weekly weights from birth to postmenstrual week 36 were retrospectively entered into a surveillance system that gave an alarm when the rate of weight gain decreased to a certain level. For all children (N = 354) screened and/or treated for retinopathy of prematurity at Sahlgrenska University Hospital in 2004–2007, weekly weights were recorded. One child was excluded because of known nonphysiologic weight gain (hydrocephalus). RESULTS. For 127 (36%) of 353 children, no alarm was given; for 40%, alarm at low risk was given after postmenstrual week 32. None of those children developed retinopathy of prematurity requiring treatment. Of the remaining 24% of children who received alarm at high or low risk before 32 postmenstrual weeks, 41% developed proliferative retinopathy of prematurity and 29% were treated because of sight-threatening disease. The median time from alarm to treatment was 9 weeks. CONCLUSIONS. The weight, insulin-like growth factor, neonatal retinopathy of prematurity algorithm detected early 100% of infants who developed retinopathy of prematurity requiring treatment and correctly predicted the majority who did not require treatment. With this simple postnatal evaluation, costly stressful eye examinations can be markedly reduced (∼75% of infants). In addition, early identification of children at risk may lead to the initiation of interventions and possibly prevent sight-threatening retinopathy of prematurity.

IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth.

Vessel loss precipitates many diseases. In particular, vessel loss resulting in hypoxia induces retinal neovascularization in diabetic retinopathy and in retinopathy of prematurity (ROP), major causes of blindness. Here we define insulin-like growth factor binding protein-3 (IGFBP3) as a new modulator of vascular survival and regrowth in oxygen-induced retinopathy. In IGFBP3-deficient mice, there was a dose-dependent increase in oxygen-induced retinal vessel loss. Subsequent to oxygen-induced retinal vessel loss, Igfbp3−/− mice had a 31% decrease in retinal vessel regrowth versus controls after returning to room air. No difference in serum insulin-like growth factor 1 (IGF1) levels was observed among groups. Wild-type mice treated with exogenous IGFBP3 had a significant increase in vessel regrowth. This correlated with a 30% increase in endothelial progenitor cells in the retina at postnatal day 15, indicating that IGFBP3 could be serving as a progenitor cell chemoattractant. In a prospective clinical study, we measured IGFBP3 (and IGF1) plasma levels weekly and examined retinas in all premature infants born at gestational ages <32 weeks at high risk for ROP. The mean level of IGFBP3 at 30–35 weeks postmenstrual age (PMA) for infants with proliferative ROP (ROP stages 3>, n = 13) was 802 μg/liter, and for infants with no ROP (ROP stage 0, n = 38) the mean level was 974 μg/liter (P < 0.03). These results suggest that IGFBP3, acting independently of IGF1, helps to prevent oxygen-induced vessel loss and to promote vascular regrowth after vascular destruction in vivo in a dose-dependent manner, resulting in less retinal neovascularization.

Validation of a New Retinopathy of Prematurity Screening Method Monitoring Longitudinal Postnatal Weight and Insulinlike Growth Factor I

OBJECTIVE To validate in a prospective study the surveillance algorithm WINROP for detecting infants at risk for proliferative retinopathy of prematurity (ROP). METHODS Fifty preterm infants with a mean gestational age of 26 weeks were included. In the first step of WINROP, weekly measures of body weight and serum insulinlike growth factor I (IGF-I) level from birth until postmenstrual age 36 weeks are entered and compared with expected development. If any of the variables show a negative deviation to a certain degree, an alarm is given. In the second step, gestational age, birth weight, and IGF binding protein 3 level are entered. RESULTS The WINROP algorithm identified all children (100% sensitivity) who were diagnosed with proliferative ROP 1.1 to 21.6 weeks later. No infants with no alarm or with alarm at low risk developed proliferative ROP. Alarm at high risk before postmenstrual age 32 weeks was given for 22 of 50 infants (44%); 9 of these infants developed proliferative ROP (54% specificity), of whom 8 were treated. CONCLUSION The WINROP algorithm may be a useful tool for modification of ROP screening.

Postnatal Head Growth Deficit Among Premature Infants Parallels Retinopathy of Prematurity and Insulin-like Growth Factor-1 Deficit

BACKGROUND. We hypothesized that in premature infants, retinal vascular growth retardation between birth and postmenstrual age of ∼30 to 32 weeks that initiates retinopathy of prematurity is paralleled by brain growth retardation. METHODS. In a prospective longitudinal study, we measured postnatal head growth, retinopathy of prematurity stage, protein and energy intake, severity of illness and serum insulin-like growth factor-1 levels in 58 preterm infants (mean gestational age at birth: 27.6 weeks) from birth until postmenstrual age of ∼40 weeks. RESULTS. Premature infant head growth decelerates dramatically after birth until postmenstrual age of ∼30 weeks. Head growth retardation coincides with retinal vascular growth suppression. Accelerated growth follows between post menstrual ages of ∼30 to 32 weeks and ∼40 weeks. The degree of head growth retardation up to postmenstrual age of 31 weeks corresponds to the degree of retinopathy of prematurity and to the degree of suppression of serum levels of insulin-like growth factor-1. At postmenstrual age of 31 weeks, if a child’s head circumference SD is below −2.5, then the probability of also developing at least stage 3 retinopathy of prematurity increases fivefold compared with head circumference above −2.5 SD (32% vs 6%) suggesting parallel processes in brain and retina. Serum insulin-like growth factor-1 levels correlate positively with head circumference SD score and with the degree of retinopathy of prematurity. CONCLUSIONS. The correlation between head and retinal growth is consistent with insulin growth factor-1 being one of the postnatal growth factors involved in this multifactorial process and also suggests that factors that contribute to retinopathy of prematurity during this critical period may also affect neurological dysfunction. Additional studies are required to establish this connection.

Low Gestational Age Associated with Abnormal Retinal Vascularization and Increased Blood Pressure in Adult Women

The objective was to investigate any possible relationship between functional and structural vascular changes in women with low gestational age and/or low birth weight by analyzing the retinal vascular pattern in women with thoroughly documented blood pressure. Retinal vessel morphology was evaluated by digital image analysis of ocular fundus photographs in 47 subjects, aged 23–30 y. The women were allocated into three groups: 1) those born preterm and appropriate for gestational age (AGA), with a median gestational age at birth of 30 wk and a median birth weight of 1250 g (n = 14); 2) those born small for gestational age (SGA) but full term (median 40 wk), with a median birth weight of 2130 g (n = 17), and 3) those born full term, AGA, and with a median birth weight of 3640 g (n = 16). Women born preterm had significantly higher length index for arterioles compared with the other two groups (median 1.11 and 1.08, respectively, p = 0.005). In addition, the preterm-born women had significantly fewer number of vascular branching points compared with the controls (median 27 and 30, respectively, p = 0.03). The abnormal retinal vascularization observed in ex-preterm women together with an increased casual blood pressure observed in these subjects suggests that being born preterm does have effects on the vascular system that persist into adult life. In addition, it demonstrates that preterm birth seems to affect the vascular system both functionally and structurally, which, in adulthood, could result in a lower threshold for the development of vascular disease.