Evaluation and comparison of current fetal ultrasound image segmentation methods for biometric measurements: a grand challenge.

This paper presents the evaluation results of the methods submitted to Challenge US: Biometric Measurements from Fetal Ultrasound Images, a segmentation challenge held at the IEEE International Symposium on Biomedical Imaging 2012. The challenge was set to compare and evaluate current fetal ultrasound image segmentation methods. It consisted of automatically segmenting fetal anatomical structures to measure standard obstetric biometric parameters, from 2D fetal ultrasound images taken on fetuses at different gestational ages (21 weeks, 28 weeks, and 33 weeks) and with varying image quality to reflect data encountered in real clinical environments. Four independent sub-challenges were proposed, according to the objects of interest measured in clinical practice: abdomen, head, femur, and whole fetus. Five teams participated in the head sub-challenge and two teams in the femur sub-challenge, including one team who tackled both. Nobody attempted the abdomen and whole fetus sub-challenges. The challenge goals were two-fold and the participants were asked to submit the segmentation results as well as the measurements derived from the segmented objects. Extensive quantitative (region-based, distance-based, and Bland-Altman measurements) and qualitative evaluation was performed to compare the results from a representative selection of current methods submitted to the challenge. Several experts (three for the head sub-challenge and two for the femur sub-challenge), with different degrees of expertise, manually delineated the objects of interest to define the ground truth used within the evaluation framework. For the head sub-challenge, several groups produced results that could be potentially used in clinical settings, with comparable performance to manual delineations. The femur sub-challenge had inferior performance to the head sub-challenge due to the fact that it is a harder segmentation problem and that the techniques presented relied more on the femur's appearance.

Spirometric alterations in workers in the chromium electroplating industry.

The spirometric values (VC, FeV1, FEF25-75%) were studied in 44 workers of 17 chromium electroplating plants. Urinary chromium was also measured. The dynamic values of spirometry are lower amongst the workers who have higher urinary chromium. The part that can be attributed to tobacco smoking is much lower than that of chromium. The workers dealing with chromium electroplating in poor conditions seem to be subjects at risk in developing obstructive respiratory syndrome. The hazard seems to be especially high in plants dealing with hard chromium plating.

Thymus-independent generation of NK1+ T cells in vitro from fetal liver precursors.

NK1.1+TCR alpha beta+ (NK1+) T cells are an unusual subset of mouse TCR alpha beta+ cells found primarily in adult thymus and liver. In contrast to conventional TCR alpha beta+ cells, NK1+ T cells have a TCR repertoire that is highly skewed to V alpha14 and to Vbeta8, -7, and -2. The developmental origin and ligand specificity of NK1+ T cells are controversial. We show here that NK1+ T cells with a typically biased V alpha and V beta repertoire develop in cytokine-supplemented suspension cultures of fetal liver established from either normal or athymic mice. Furthermore, NK1+ T cell development in fetal liver cultures is abrogated in beta2m-deficient mice (which lack MHC class I and other related molecules) and can be partially inhibited by the presence of anti-CD1 mAbs. Moreover, mixing experiments indicate that recombination-deficient SCID fetal liver cells can reconstitute NK1+ T cell development in beta2m-deficient fetal liver cultures. Collectively, our data demonstrate that NK1+ T cells can develop extrathymically from fetal liver precursors and that a beta2m-associated ligand (putatively CD1) present on nonlymphoid cells is essential for their positive selection and/or expansion.

Epigenetic alterations and constitutive Wnt signaling are early events in the progression from Barrett's esophagus to esophageal adenocarcinoma

SUMMARY Barrett's esophagus (BE) is an acquired condition in which the normal squamous epithelium in the distal esophagus is replaced by a metaplastic columnar epithelium, as a complication of chronic gastroesophageal reflux. The clinical significance of this disease is its associated predisposition to esophageal adenocarcinoma (EAC). EAC is a highly lethal disease. Better understanding of the pathogenesis of columnar metaplasia and its progression to cancer might allow the identification of biomarkers that can be used for early diagnosis, which will improve the patient survival. In this study, an improved protocol for methylation-sensitive single-strand conformation analysis, which is used to analyze promoter methylation, is proposed and a methylation-sensitive dot blot assay is described, which allows a rapid, easy, and sensitive detection of promoter methylation. Both methods were applied to study the methylation pattern of the APC promoter in histologically normal appearing gastric mucosa. The APC promoter showed monoallelic methylation, and because the methylated allele differed between the different gastric cell types, this corresponded to allelic exclusion. The APC methylation pattern was frequently altered in noimal gastric mucosa associated with neoplastic lesions, indicating that changes in the pattern of promoter methylation might precede the development of neoplasia, without accompanying histological manifestations. An epigenetic profile of 10 genes important in EAC was obtained in this study; 5 promoter genes (APC, TIMP3, TERT, CDKN2A and SFRP1) were found to be hypermethylated in the tumors. Furthermore, the promoter of APC, TIMP3 and TERT was frequently methylated in BE samples from EAC patients, but rarely in BE samples that did not progress to EAC. These three biomarkers might therefore be considered as potential predictive markers for increased EAC risk. Analysis of Wnt pathway alterations indicated that WNT2 ligand is overexpressed as early as the low-grade dysplastic stage and downregulation by promoter methylation of the SFRP1 gene occurrs already in the metaplastic lesions. Moreover, loss of APC expression is not the only factor involved in the activation of the Wnt pathway. These results indicate that a variety of biologic, mostly epigenetic events occurs very early in the carcinogenesis of BE. This new information might lead to improved early diagnosis of EAC and thus open the way to a possible application of these biomarkers in the prediction of increased EAC risk progression. RESUME L'oesophage de Barrett est une lésion métaplasique définie par le remplacement de la muqueuse malpighienne du bas oesophage par une muqueuse cylindrique glandulaire, suite à une agression chronique par du reflux gastro-esophagien. La plus importante signification clinique de cette maladie est sa prédisposition au développement d'un adénocarcinome. Le pronostic de l'adénocarcinome sur oesophage de Barrett est sombre. Seule une meilleure compréhension de la pathogenèse de l'épithélium métaplasique et de sa progression néoplasique permettrait l'identification de biomarqueurs pouvant être utilisés pour un diagnostic précoce ; la survie du patient serait ainsi augmentée. Dans cette étude, un protocole amélioré pour l'analyse de la méthylation par conformation simple brin est proposé. De plus, une technique d'analyse par dot blot permettant une détection rapide, facile et sensible de la méthylation d'un promoteur est décrite. Les deux méthodes ont été appliquées à l'étude de la méthylation du promoteur du gène APC dans des muqueuses gastriques histologiquement normales. Le promoteur APC a montré une méthylation monoallélique et, parce que les allèles méthylés différaient entre les différents types de cellules gastriques, celle-ci correspondait à une méthylation allélique exclusive. La méthylation d'APC a été trouvée fréquemment altérée dans la muqueuse gastrique normale associée à des lésions néoplasiques. Ceci indique que des changements dans la méthylation d'un promoteur peuvent précéder le développement d'une tumeur, et cela sans modification histologique. Un profil épigénétique des adénocarcinomes sur oesophage de Barrett a été obtenu dans cette étude. Cinq promoteurs (APC, TIMP3, TERT, CDKN2A et SFRP1) ont été trouvés hyperméthylés dans les tumeurs. Les promoteurs d'APC, TIMP3 et TERT étaient fréquemment méthylés dans l'épithélium métaplasique proche d'un adénocarcinome et rarement dans l'épithélium sans évolution néoplasique. Ces trois biomarkers pourraient par conséquent être considérés comme marqueur prédicatif d'un risque accru de développer une tumeur. L'analyse des altérations de la voie Wnt a montré que WNT2 est surexprimé déjà dans des dysplasies de bas-grade et que la dérégulation de SFRP1 par méthylation de son promoteur intervenait dans les lésions métaplasiques. Une perte d'expression d'APC n'est pas le seul facteur impliqué dans l'activation de cette voie. Ces résultats montrent qu'une grande diversité d'événements biologiques, principalement épigénétiques, surviennent très tôt lors de la carcinogenèse de l'oesophage de Barrett. Ces nouveaux éléments pourraient améliorer le diagnostic précoce et rendre possible l'application de ces biomarqueurs dans la prédiction d'un risque accru de développer un adénocarcinome sur un oesophage de Barrett.

Right ventricular dysfunction in children and adolescents conceived by assisted reproductive technologies.

Assisted reproductive technologies (ART) predispose the offspring to vascular dysfunction, arterial hypertension, and hypoxic pulmonary hypertension. Recently, cardiac remodeling and dysfunction during fetal and early postnatal life have been reported in offspring of ART, but it is not known whether these cardiac alterations persist later in life and whether confounding factors contribute to this problem. We, therefore, assessed cardiac function and pulmonary artery pressure by echocardiography in 54 healthy children conceived by ART (mean age 11.5 ± 2.4 yr) and 54 age-matched (12.2 ± 2.3 yr) and sex-matched control children. Because ART is often associated with low birth weight and prematurity, two potential confounders associated with cardiac dysfunction, only singletons born with normal birth weight at term were studied. Moreover, because cardiac remodeling in infants conceived by ART was observed in utero, a situation associated with increased right heart load, we also assessed cardiac function during high-altitude exposure, a condition associated with hypoxic pulmonary hypertension-induced right ventricular overload. We found that, while at low altitude cardiac morphometry and function was not different between children conceived by ART and control children, under the stressful conditions of high-altitude-induced pressure overload and hypoxia, larger right ventricular end-diastolic area and diastolic dysfunction (evidenced by lower E-wave tissue Doppler velocity and A-wave tissue Doppler velocity of the lateral tricuspid annulus) were detectable in children and adolescents conceived by ART. In conclusion, right ventricular dysfunction persists in children and adolescents conceived by ART. These cardiac alterations appear to be related to ART per se rather than to low birth weight or prematurity.

An efficient total variation algorithm for super-resolution in fetal brain MRI with adaptive regularization.

Although fetal anatomy can be adequately viewed in new multi-slice MR images, many critical limitations remain for quantitative data analysis. To this end, several research groups have recently developed advanced image processing methods, often denoted by super-resolution (SR) techniques, to reconstruct from a set of clinical low-resolution (LR) images, a high-resolution (HR) motion-free volume. It is usually modeled as an inverse problem where the regularization term plays a central role in the reconstruction quality. Literature has been quite attracted by Total Variation energies because of their ability in edge preserving but only standard explicit steepest gradient techniques have been applied for optimization. In a preliminary work, it has been shown that novel fast convex optimization techniques could be successfully applied to design an efficient Total Variation optimization algorithm for the super-resolution problem. In this work, two major contributions are presented. Firstly, we will briefly review the Bayesian and Variational dual formulations of current state-of-the-art methods dedicated to fetal MRI reconstruction. Secondly, we present an extensive quantitative evaluation of our SR algorithm previously introduced on both simulated fetal and real clinical data (with both normal and pathological subjects). Specifically, we study the robustness of regularization terms in front of residual registration errors and we also present a novel strategy for automatically select the weight of the regularization as regards the data fidelity term. Our results show that our TV implementation is highly robust in front of motion artifacts and that it offers the best trade-off between speed and accuracy for fetal MRI recovery as in comparison with state-of-the art methods.

Multicontrast connectometry: A new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cerebellar pathology occurs in late multiple sclerosis (MS) but little is known about cerebellar changes during early disease stages. In this study, we propose a new multicontrast "connectometry" approach to assess the structural and functional integrity of cerebellar networks and connectivity in early MS. METHODS: We used diffusion spectrum and resting-state functional MRI (rs-fMRI) to establish the structural and functional cerebellar connectomes in 28 early relapsing-remitting MS patients and 16 healthy controls (HC). We performed multicontrast "connectometry" by quantifying multiple MRI parameters along the structural tracts (generalized fractional anisotropy-GFA, T1/T2 relaxation times and magnetization transfer ratio) and functional connectivity measures. Subsequently, we assessed multivariate differences in local connections and network properties between MS and HC subjects; finally, we correlated detected alterations with lesion load, disease duration, and clinical scores. RESULTS: In MS patients, a subset of structural connections showed quantitative MRI changes suggesting loss of axonal microstructure and integrity (increased T1 and decreased GFA, P < 0.05). These alterations highly correlated with motor, memory and attention in patients, but were independent of cerebellar lesion load and disease duration. Neither network organization nor rs-fMRI abnormalities were observed at this early stage. CONCLUSION: Multicontrast cerebellar connectometry revealed subtle cerebellar alterations in MS patients, which were independent of conventional disease markers and highly correlated with patient function. Future work should assess the prognostic value of the observed damage. Hum Brain Mapp 36:1609-1619, 2015. © 2014 Wiley Periodicals, Inc.

Caloric restriction induces energy-sparing alterations in skeletal muscle contraction, fiber composition and local thyroid hormone metabolism that persist during catch-up fat upon refeeding.

Weight regain after caloric restriction results in accelerated fat storage in adipose tissue. This catch-up fat phenomenon is postulated to result partly from suppressed skeletal muscle thermogenesis, but the underlying mechanisms are elusive. We investigated whether the reduced rate of skeletal muscle contraction-relaxation cycle that occurs after caloric restriction persists during weight recovery and could contribute to catch-up fat. Using a rat model of semistarvation-refeeding, in which fat recovery is driven by suppressed thermogenesis, we show that contraction and relaxation of leg muscles are slower after both semistarvation and refeeding. These effects are associated with (i) higher expression of muscle deiodinase type 3 (DIO3), which inactivates tri-iodothyronine (T3), and lower expression of T3-activating enzyme, deiodinase type 2 (DIO2), (ii) slower net formation of T3 from its T4 precursor in muscles, and (iii) accumulation of slow fibers at the expense of fast fibers. These semistarvation-induced changes persisted during recovery and correlated with impaired expression of transcription factors involved in slow-twitch muscle development. We conclude that diminished muscle thermogenesis following caloric restriction results from reduced muscle T3 levels, alteration in muscle-specific transcription factors, and fast-to-slow fiber shift causing slower contractility. These energy-sparing effects persist during weight recovery and contribute to catch-up fat.

BRAF Alterations as Therapeutic Targets in Non-Small-Cell Lung Cancer.

BACKGROUND: Several subsets of non-small-cell lung cancer (NSCLC) are defined by molecular alterations acting as tumor drivers, some of them being currently therapeutically actionable. The rat sarcoma (RAS)-rapidly accelerated fibrosarcoma (RAF)-mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway constitutes an attractive potential target, as v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations occur in 2-4% of NSCLC adenocarcinoma. METHODS: Here, we review the latest clinical data on BRAF serine/threonine kinase inhibitors in NSCLC. RESULTS: Treatment of V600E BRAF-mutated NSCLC with BRAF inhibitor monotherapy demonstrated encouraging antitumor activity. Combination of BRAF and MEK inhibitors using dabrafenib and trametinib is under evaluation. Preliminary data suggest superior efficacy compared with BRAF inhibitor monotherapy. CONCLUSION: Targeting BRAF alterations represents a promising new therapeutic approach for a restricted subset of oncogene-addicted NSCLC. Prospect ive trials refining this strategy are ongoing. A next step will probably aim at combining BRAF inhibitors and immunotherapy or alternatively improve a multilevel mitogen-activated protein kinase (MAPK) pathway blockade by combining with ERK inhibitors.

Fetal laser therapy: applications in the management of fetal pathologies.

Fetoscopic coagulation of placental anastomoses is the treatment of choice for severe twin-to-twin transfusion syndrome. In the present day, fetal laser therapy is also used to treat amniotic bands, chorioangiomas, sacrococcygeal teratomas, lower urinary tract obstructions and chest masses, all of which will be reviewed in this article. Amniotic band syndrome can cause limb amputation by impairing downstream blood flow. Large chorioangiomas (>4 cm), sacrococcygeal teratomas or fetal hyperechoic lung lesions can lead to fetal compromise and hydrops by vascular steal phenomenon or compression. Renal damage, bladder dysfunction and lastly death because of pulmonary hypolasia may be the result of megacystis caused by a posterior urethral valve. The prognosis of these pathologies can be dismal, and therapy options are limited, which has brought fetal laser therapy to the forefront. Management options discussed here are laser release of amniotic bands, laser coagulation of the placental or fetal tumor feeding vessels and laser therapy by fetal cystoscopy. This review, largely based on case reports, does not intend to provide a level of evidence supporting laser therapy over other treatment options. Centralized evaluation by specialists using strict selection criteria and long-term follow-up of these rare cases are now needed to prove the value of endoscopic or ultrasound-guided laser therapy.

Fetal programming and epigenetic mechanisms in arterial hypertension.

PURPOSE OF REVIEW: To provide an overview of available evidence of the potential role of epigenetics in the pathogenesis of hypertension and vascular dysfunction. RECENT FINDINGS: Arterial hypertension is a highly heritable condition. Surprisingly, however, genetic variants only explain a tiny fraction of the phenotypic variation and the term 'missing heritability' has been coined to describe this phenomenon. Recent evidence suggests that phenotypic alteration that is unrelated to changes in DNA sequence (thereby escaping detection by classic genetic methodology) offers a potential explanation. Here, we present some basic information on epigenetics and review recent work consistent with the hypothesis of epigenetically induced arterial hypertension. SUMMARY: New technologies that enable the rigorous assessment of epigenetic changes and their phenotypic consequences may provide the basis for explaining the missing heritability of arterial hypertension and offer new possibilities for treatment and/or prevention.