Andrew D. Kane

Efficient Multi-Scale 3D CNN with Fully Connected CRF for Accurate Brain Lesion Segmentation

HIGHLIGHTSAn efficient 11‐layers deep, multi‐scale, 3D CNN architecture.A novel training strategy that significantly boosts performance.The first employment of a 3D fully connected CRF for post‐processing.State‐of‐the‐art performance on three challenging lesion segmentation tasks.New insights into the automatically learned intermediate representations. ABSTRACT We propose a dual pathway, 11‐layers deep, three‐dimensional Convolutional Neural Network for the challenging task of brain lesion segmentation. The devised architecture is the result of an in‐depth analysis of the limitations of current networks proposed for similar applications. To overcome the computational burden of processing 3D medical scans, we have devised an efficient and effective dense training scheme which joins the processing of adjacent image patches into one pass through the network while automatically adapting to the inherent class imbalance present in the data. Further, we analyze the development of deeper, thus more discriminative 3D CNNs. In order to incorporate both local and larger contextual information, we employ a dual pathway architecture that processes the input images at multiple scales simultaneously. For post‐processing of the networks soft segmentation, we use a 3D fully connected Conditional Random Field which effectively removes false positives. Our pipeline is extensively evaluated on three challenging tasks of lesion segmentation in multi‐channel MRI patient data with traumatic brain injuries, brain tumours, and ischemic stroke. We improve on the state‐of‐the‐art for all three applications, with top ranking performance on the public benchmarks BRATS 2015 and ISLES 2015. Our method is computationally efficient, which allows its adoption in a variety of research and clinical settings. The source code of our implementation is made publicly available.

Developmental Programming of Cardiovascular Dysfunction by Prenatal Hypoxia and Oxidative Stress

Fetal hypoxia is a common complication of pregnancy. It has been shown to programme cardiac and endothelial dysfunction in the offspring in adult life. However, the mechanisms via which this occurs remain elusive, precluding the identification of potential therapy. Using an integrative approach at the isolated organ, cellular and molecular levels, we tested the hypothesis that oxidative stress in the fetal heart and vasculature underlies the molecular basis via which prenatal hypoxia programmes cardiovascular dysfunction in later life. In a longitudinal study, the effects of maternal treatment of hypoxic (13% O2) pregnancy with an antioxidant on the cardiovascular system of the offspring at the end of gestation and at adulthood were studied. On day 6 of pregnancy, rats (n = 20 per group) were exposed to normoxia or hypoxia ± vitamin C. At gestational day 20, tissues were collected from 1 male fetus per litter per group (n = 10). The remaining 10 litters per group were allowed to deliver. At 4 months, tissues from 1 male adult offspring per litter per group were either perfusion fixed, frozen, or dissected for isolated organ preparations. In the fetus, hypoxic pregnancy promoted aortic thickening with enhanced nitrotyrosine staining and an increase in cardiac HSP70 expression. By adulthood, offspring of hypoxic pregnancy had markedly impaired NO-dependent relaxation in femoral resistance arteries, and increased myocardial contractility with sympathetic dominance. Maternal vitamin C prevented these effects in fetal and adult offspring of hypoxic pregnancy. The data offer insight to mechanism and thereby possible targets for intervention against developmental origins of cardiac and peripheral vascular dysfunction in offspring of risky pregnancy.

Partial contributions of developmental hypoxia and undernutrition to prenatal alterations in somatic growth and cardiovascular structure and function

OBJECTIVE The objective of the study was to compare and contrast the effects of developmental hypoxia vs undernutrition on fetal growth, cardiovascular morphology, and function. STUDY DESIGN On day 15 of gestation, Wistar dams were divided into control, hypoxic (10% O(2)), or undernourished (35% reduction in food intake) pregnancy. On day 20, fetal thoraces were fixed, and the fetal heart and aorta underwent quantitative histological analysis. In a separate group, fetal aortic vascular reactivity was determined via wire myography. RESULTS Both hypoxic and undernourished pregnancy was associated with asymmetric fetal growth restriction. Pregnancy complicated by hypoxia promoted fetal aortic thickening without changes in cardiac volumes when expressed as a percentage of total heart volume. In contrast, maternal undernutrition affected fetal cardiac morphology without changes in aortic structure. Fetal aortic vascular reactivity was also differentially affected by hypoxia or undernutrition. CONCLUSION Developmental hypoxia or undernutrition in late gestation has differential effects on fetal cardiovascular morphology and function.

Unsupervised Domain Adaptation in Brain Lesion Segmentation with Adversarial Networks

Significant advances have been made towards building accurate automatic segmentation systems for a variety of biomedical applications using machine learning. However, the performance of these systems often degrades when they are applied on new data that differ from the training data, for example, due to variations in imaging protocols. Manually annotating new data for each test domain is not a feasible solution. In this work we investigate unsupervised domain adaptation using adversarial neural networks to train a segmentation method which is more robust to differences in the input data, and which does not require any annotations on the test domain. Specifically, we derive domain-invariant features by learning to counter an adversarial network, which attempts to classify the domain of the input data by observing the activations of the segmentation network. Furthermore, we propose a multi-connected domain discriminator for improved adversarial training. Our system is evaluated using two MR databases of subjects with traumatic brain injuries, acquired using different scanners and imaging protocols. Using our unsupervised approach, we obtain segmentation accuracies which are close to the upper bound of supervised domain adaptation.

Statin treatment depresses the fetal defence to acute hypoxia via increasing nitric oxide bioavailability

Non‐technical summary  The fetal cardiovascular defence to episodes of reduced oxygenation, or acute hypoxia, includes redistribution of the cardiac output away from peripheral and towards essential circulations, such as those perfusing the brain – the so called brain‐sparing effect. The peripheral vasoconstriction is triggered by a chemoreflex and maintained by constrictor hormones. Nitric oxide (NO) synthesis during hypoxia opposes these mechanisms, but the balance of all effects favours constriction. Statins are drugs commonly used to lower cholesterol. Since women are delaying pregnancy until later in life, there is increasing clinical interest in treating pregnant women with statins. However, statins have other effects, including increasing NO levels, and their effects on the physiology of the fetus are completely unknown. Here, we show that fetal exposure to statins depresses the fetal peripheral constrictor response to acute hypoxia via increasing NO bioavailability. Use of statins in pregnancy should be viewed with caution.

Redox modulation of the fetal cardiovascular defence to hypoxaemia

Episodes of hypoxia in utero present a potentially serious challenge to the fetus, but are counteracted by defence responses including marked redistribution of blood flow from peripheral circulations to the brain. Here, we report the novel observation that the oxidant tone is an important modulator of this cardiovascular defence. Using pregnant Welsh Mountain sheep surgically prepared for long‐term recording, we investigated in vivo the effects on the fetal cardiovascular defence to acute hypoxaemia of fetal treatment with the antioxidant vitamin C. The mechanisms via which vitamin C may affect the vascular oxidant tone were investigated by monitoring fetal plasma concentrations of nitrates and nitrites, by determining changes in the activity of superoxide dismutase (SOD) in fetal plasma, and by investigating the effect of vitamin C treatment on the fetal cardiovascular defence to hypoxaemia following nitric oxide (NO) synthase blockade. Fetal treatment with vitamin C markedly depressed the normal femoral constrictor response to acute hypoxaemia in the fetus (5.2 ± 1.0 vs. 1.1 ± 0.3 mmHg (ml min−1)−1, mean ±s.e.m.; P < 0.05) an effect which was completely restored following NO synthase blockade (6.2 ± 1.3 mmHg (ml min−1)−1). Compared to saline infusion, fetal treatment with vitamin C during acute hypoxaemia also significantly increased fetal plasma SOD activity from normoxic baseline (−8.9 ± 6.5 vs. 15.0 ± 6.6% inhibition, P < 0.05) and decreased the plasma concentration ratio of nitrate:nitrite from normoxic baseline (ΔNO3−:NO2−; 0.15 ± 0.30 vs. −0.29 ± 0.11, P < 0.05). The data provide in vivo evidence of redox modulation of redistribution of blood flow in the fetus, part of the fetal brain sparing during acute hypoxaemic stress.

Fetal in vivo continuous cardiovascular function during chronic hypoxia.

The in vivo fetal cardiovascular defence to chronic hypoxia has remained by and large an enigma because no technology has been available to induce significant and prolonged fetal hypoxia whilst recording longitudinal changes in fetal regional blood flow as the hypoxic pregnancy is developing. We introduce a new technique able to maintain chronically instrumented maternal and fetal sheep preparations under isobaric chronic hypoxia for most of gestation, beyond levels that can be achieved by high altitude and of relevance in magnitude to the human intrauterine growth‐restricted fetus. This technology permits wireless recording in free‐moving animals of longitudinal maternal and fetal cardiovascular function, including beat‐to‐beat alterations in pressure and blood flow signals in regional circulations. The relevance and utility of the technique is presented by testing the hypotheses that the fetal circulatory brain sparing response persists during chronic fetal hypoxia and that an increase in reactive oxygen species in the fetal circulation is an involved mechanism.

Heart Disease Link to Fetal Hypoxia and Oxidative Stress

The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia.

A role for xanthine oxidase in the control of fetal cardiovascular function in late gestation sheep

Key points  •  There is growing physiological and clinical interest in the role of the enzyme xanthine oxidase in the regulation of fetal cardiovascular function. •  The xanthine oxidase inhibitor allopurinol is undergoing human clinical trials in complicated pregnancy to protect the fetal brain from injury by decreasing excessive generation of reactive oxygen species (ROS) and increasing nitric oxide (NO) availability. However, the effects on fetal cardiovascular physiology of xanthine oxidase inhibition are largely unknown. •  We have previously reported that the balance between ROS and NO plays an important physiological role in the control of fetal cardiovascular function. Therefore, it seems likely that allopurinol might perturb this balance and alter fetal cardiovascular homeostasis. •  Here, we report that maternal allopurinol treatment in late gestation ovine pregnancy has significant in vivo effects on umbilical blood flow and the cardiovascular system of the mother and fetus by altering NO and β1‐adrenergic mechanisms. •  The evidence suggests that xanthine oxidase has an important role in basal cardiovascular function in the fetus during late gestation. Therefore, further research is warranted before safe clinical application of maternal allopurinol during pregnancy in humans.

Xanthine oxidase and the fetal cardiovascular defence to hypoxia in late gestation ovine pregnancy

Periods of impaired oxygenation or acute hypoxia in the fetus can be common during labour and how the fetus withstands these challenges is of interest. During hypoxia, the fetus shunts blood flow away from peripheral and towards essential vascular beds: the so called brain‐sparing effect. Part of the peripheral vasoconstriction is driven by reactive oxygen species (ROS) that inactivate nitric oxide (NO), thereby limiting its vasodilator action. Here, we investigate the source of ROS generation contributing to fetal peripheral vasoconstriction during hypoxia, and show that xanthine oxidase (XO) is fundamentally involved. Fetal exposure to the XO inhibitor allopurinol markedly diminished the peripheral vasoconstriction during hypoxia via NO‐dependent mechanisms. The data increase our understanding of the physiological control of fetal cardiovascular function during stress. The findings are also of significant clinical relevance as allopurinol is being administered to pregnant women in clinical obstetric trials.