Multiple roles of mouse Numb in tuning developmental cell fates.

BACKGROUND: Notch signaling regulates multiple differentiation processes and cell fate decisions during both invertebrate and vertebrate development. Numb encodes an intracellular protein that was shown in Drosophila to antagonize Notch signaling at binary cell fate decisions of certain cell lineages. Although overexpression experiments suggested that Numb might also antagonize some Notch activity in vertebrates, the developmental processes in which Numb is involved remained elusive. RESULTS: We generated mice with a homozygous inactivation of Numb. These mice died before embryonic day E11.5, probably because of defects in angiogenic remodeling and placental dysfunction. Mutant embryos had an open anterior neural tube and impaired neuronal differentiation within the developing cranial central nervous system (CNS). In the developing spinal cord, the number of differentiated motoneurons was reduced. Within the peripheral nervous system (PNS), ganglia of cranial sensory neurons were formed. Trunk neural crest cells migrated and differentiated into sympathetic neurons. In contrast, a selective differentiation anomaly was observed in dorsal root ganglia, where neural crest--derived progenitor cells had migrated normally to form ganglionic structures, but failed to differentiate into sensory neurons. CONCLUSIONS: Mouse Numb is involved in multiple developmental processes and required for cell fate tuning in a variety of lineages. In the nervous system, Numb is required for the generation of a large subset of neuronal lineages. The restricted requirement of Numb during neural development in the mouse suggests that in some neuronal lineages, Notch signaling may be regulated independently of Numb.

Stimulated-echo acquisition mode (STEAM) MRI for black-blood delayed hyperenhanced myocardial imaging.

PURPOSE: To develop a breathhold method for black-blood viability imaging of the heart that may facilitate identifying the endocardial border. MATERIALS AND METHODS: Three stimulated-echo acquisition mode (STEAM) images were obtained almost simultaneously during the same acquisition using three different demodulation values. Two of the three images were used to construct a black-blood image of the heart. The third image was a T(1)-weighted viability image that enabled detection of hyperintense infarcted myocardium after contrast agent administration. The three STEAM images were combined into one composite black-blood viability image of the heart. The composite STEAM images were compared to conventional inversion-recovery (IR) delayed hyperenhanced (DHE) images in nine human subjects studied on a 3T MRI scanner. RESULTS: STEAM images showed black-blood characteristics and a significant improvement in the blood-infarct signal-difference to noise ratio (SDNR) when compared to the IR-DHE images (34 +/- 4.1 vs. 10 +/- 2.9, mean +/- standard deviation (SD), P < 0.002). There was sufficient myocardium-infarct SDNR in the STEAM images to accurately delineate infarcted regions. The extracted infarcts demonstrated good agreement with the IR-DHE images. CONCLUSION: The STEAM black-blood property allows for better delineation of the blood-infarct border, which would enhance the fast and accurate measurement of infarct size.

Correction of through-plane deformation artifacts in stimulated echo acquisition mode cardiac imaging.

Attempts to use a stimulated echo acquisition mode (STEAM) in cardiac imaging are impeded by imaging artifacts that result in signal attenuation and nulling of the cardiac tissue. In this work, we present a method to reduce this artifact by acquiring two sets of stimulated echo images with two different demodulations. The resulting two images are combined to recover the signal loss and weighted to compensate for possible deformation-dependent intensity variation. Numerical simulations were used to validate the theory. Also, the proposed correction method was applied to in vivo imaging of normal volunteers (n = 6) and animal models with induced infarction (n = 3). The results show the ability of the method to recover the lost myocardial signal and generate artifact-free black-blood cardiac images.

Dissolution-reprecipitation of zircon at low-temperature, high-pressure conditions (Lanzo Massif, Italy)

An eclogite facies meta-plagiogranite from the Lanzo massif (western Alps, Italy) contains crystals of zircon intimately associated with allanite. Zircon displays different microtextures ranging from pristine, euhedral, and magmatic to fractured, porous varieties with mosaic zoning, and pervasive recrystallization into euhedral microcrystals. Fractures and voids in the recrystallized zircon microcrystals are mainly filled by high-pressure Na-rich pyroxene. Electron backscattered diffraction analysis revealed a similar crystallographic orientation for primary magmatic zircon crystals and microcrystals, with less than 2 degrees misorientation among neighboring microdomains. The textural change is coupled with chemical and isotopic modifications: recrystallized zircon domains contain significantly less Th and light- to mid-REE, but are richer in Sr than magmatic zircon crystals. Magmatic zircon preserves the protolith U-Pb age of 163.5 +/- 1.7 Ma, whereas zircon microcrystals have a mean age of 55 +/- 1 Ma. The coexisting allanite also contains inclusions of Na-rich pyroxene and has chemical features (elevated Sr and Ni contents and lack of Eu anomaly) indicating formation at high pressure. Despite being associated texturally with zircon, allanite yields a younger Th-Pb age of 46.5 +/- 3.0 Ma, suggesting that the Lanzo unit remained at relatively high pressure conditions for similar to 8 m.y. Zircon recrystallization proceeded with volume reduction and loss of material to an alkaline metamorphic fluid that acted as the agent for a coupled dissolution-reprecipitation process. Recrystallization occurred with minimum transport, in a low-strain environment, and was not significantly enhanced by metamictization. The source of the fluid for zircon recrystallization is most probably related to prograde devolatilization reactions in the surrounding serpentinite.

Method for performing cerebral perfusion-weighted MRI in neonates

Cerebral perfusion-weighted imaging (PWI) in neonates is known to be technically difficult and there are very few published studies on its use in preterm infants. In this paper, we describe one convenient method to perform PWI in neonates, a method only recently used in newborns. A device was used to manually inject gadolinium contrast material intravenously in an easy, quick and reproducible way. We studied 28 newborn infants, with various gestational ages and weights, including both normal infants and those suffering from different brain pathologies. A signal intensity-time curve was obtained for each infant, allowing us to build perfusion maps. This technique offered a fast and easy method to manually inject a bolus gadolinium contrast material, which is essential in performing PWI in neonates. Cerebral PWI is technically feasible and reproducible in neonates of various gestational age and with various pathologies.

Le point sur l'ergométrie en 2012 dans le diagnostic de la maladie coronarienne.

Background In patients presenting with acute cardiac symptoms, abnormal ECG and raised troponin, myocarditis may be suspected after normal angiography. Aims To analyse cardiac magnetic resonance (CMR) findings in patients with a provisional diagnosis of acute coronary syndrome (ACS) in whom acute myocarditis was subsequently considered more likely. Methods and results 79 patients referred for CMR following an admission with presumed ACS and raised serum troponin in whom no culprit lesion was detected were studied. 13% had unrecognised myocardial infarction and 6% takotsubo cardiomyopathy. The remainder (81%) were diagnosed with myocarditis. Mean age was 45615 years and 70% were male. Left ventricular ejection fraction (EF) was 58610%; myocardial oedema was detected in 58%. A myocarditic pattern of late gadolinium enhancement (LGE) was detected in 92%. Abnormalities were detected more frequently in scans performed within 2 weeks of symptom onset: oedema in 81% vs 11% (p<0.0005), and LGE in 100% vs 76% (p<0.005). In 20 patients with both an acute (<2 weeks) and convalescent scan (>3 weeks), oedema decreased from 84% to 39% (p<0.01) and LGE from 5.6 to 3.0 segments (p¼0.005). Three patients presented with sustained ventricular tachycardia, another died suddenly 4 days after admission and one resuscitated 7 weeks following presentation. All 5 patients had preserved EF. Conclusions Our study emphasises the importance of access to CMR for heart attack centres. If myocarditis is suspected, CMR scanning should be performed within 14 days. Myocarditis should not be regarded as benign, even when EF is preserved.

Preoperative assessment of neurovesical function in children with anorectal malformation: association with vertebral and spinal malformations.

PURPOSE: We preoperatively assessed neurovesical function and spinal cord function in children with anorectal malformations. In cases of neurovesical dysfunction we looked for an association with vertebral malformation or myelodysplasia. MATERIALS AND METHODS: We prospectively evaluated 80 children with anorectal malformations via preoperative urodynamics and magnetic resonance imaging of the spine. Bladder compliance and volume, detrusor activity and vesicosphincteric synergy during voiding allowed urodynamic evaluation. Results were reported according to Wingspread and Krickenbeck classifications of anorectal malformations. RESULTS: Urodynamic findings were pathological in 14 children (18%). Pathological evaluations did not seem related to type of fistula or level of anorectal malformation. Vertebral anomalies were seen in 34 patients (43%) and myelodysplasia in 16 (20%). Neither vertebral anomaly nor myelodysplasia seemed associated with type of fistula or severity of anorectal malformation. Of 14 children with pathological urodynamics no vertebral anomaly or myelodysplasia was found in 7. Of 66 children with normal urodynamics 40 presented with vertebral or spinal malformation. CONCLUSIONS: Lower urinary tract dysfunction is common in patients with anorectal malformations. Normal spine or spinal cord does not exclude neurovesical dysfunction. Myelodysplasia or vertebral anomaly does not determine lower urinary tract dysfunction. Thus, we recommend preoperative urodynamic assessment of the bladder and magnetic resonance imaging of the spine in children with anorectal malformations.

Holt Oram syndrome: a registry-based study in Europe.

BACKGROUND: Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterised by upper limb anomalies and congenital heart defects. We present epidemiological and clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries. METHODS: The study was based on data collected during 1990-2011 by 34 registries. The registries are population-based and use multiple sources of information to collect data on all types of birth using standardized definitions, methodology and coding. Diagnostic criteria for inclusion in the study were the presence of radial ray abnormalities and congenital heart disease (CHD), or the presence of either radial ray anomaly or CHD, with family history of HOS. RESULTS: A total of 73 cases of HOS were identified, including 11 (15.1%) TOPFA and 62 (84.9%) LB. Out of 73 HOS cases, 30.8% (20/65) were suspected prenatally, 55.4% (36/65) at birth, 10.7% (7/65) in the first week of life, and 3.1% (2/65) in the first year of life. The prenatal detection rate was 39.2% (20/51), with no significant change over the study period. In 55% (11/20) of prenatally detected cases, parents decided to terminate pregnancy. Thumb anomalies were reported in all cases. Agenesis/hypoplasia of radius was present in 49.2% (30/61), ulnar aplasia/hypoplasia in 24.6% (15/61) and humerus hypoplasia/phocomelia in 42.6% (26/61) of patients. Congenital heart defects (CHD) were recorded in 78.7% (48/61) of patients. Isolated septal defects were present in 54.2 (26/48), while 25% (12/48) of patients had complex/severe CHD. The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births. CONCLUSIONS: HOS is a rare genetic condition showing regional variation in its prevalence. It is often missed prenatally, in spite of the existence of major structural anomalies. When discovered, parents in 45% (9/20) of cases opt for the continuation of pregnancy. Although a quarter of patients have severe CHD, the overall first week survival is very good, which is important information for counselling purposes.

Risk of a Down syndrome live birth in women 45 years of age and older.

OBJECTIVES: To determine the risk of a Down syndrome (DS) live birth for women 45 years of age and over. METHODS: A meta-analysis of data from five published articles, 13 EUROCAT congenital anomaly population registers and two unpublished sources. RESULTS: Information was available on the number of DS live births occurring amongst 13,745 live births to women 45 years of age and over. Information was also available on DS pregnancies diagnosed prenatally that were subsequently terminated. These pregnancies were adjusted for expected fetal loss to estimate the number of live births that would have occurred in the absence of prenatal diagnoses, when a total of 471 DS live births were estimated to have occurred. The risk of a DS birth did not increase for women 45 years of age and over. The average risk was 34 per 1000 births (95% CI: 31-37). CONCLUSION: The risk of a DS live birth for women 45 years of age and over is considerably lower than has often been previously assumed. The most likely explanation is that women of this age are more likely to miscarry DS pregnancies than younger mothers.

CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome.

Cyclin-dependent kinases (CDKs) regulate a variety of fundamental cellular processes. CDK10 stands out as one of the last orphan CDKs for which no activating cyclin has been identified and no kinase activity revealed. Previous work has shown that CDK10 silencing increases ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2)-driven activation of the MAPK pathway, which confers tamoxifen resistance to breast cancer cells. The precise mechanisms by which CDK10 modulates ETS2 activity, and more generally the functions of CDK10, remain elusive. Here we demonstrate that CDK10 is a cyclin-dependent kinase by identifying cyclin M as an activating cyclin. Cyclin M, an orphan cyclin, is the product of FAM58A, whose mutations cause STAR syndrome, a human developmental anomaly whose features include toe syndactyly, telecanthus, and anogenital and renal malformations. We show that STAR syndrome-associated cyclin M mutants are unable to interact with CDK10. Cyclin M silencing phenocopies CDK10 silencing in increasing c-Raf and in conferring tamoxifen resistance to breast cancer cells. CDK10/cyclin M phosphorylates ETS2 in vitro, and in cells it positively controls ETS2 degradation by the proteasome. ETS2 protein levels are increased in cells derived from a STAR patient, and this increase is attributable to decreased cyclin M levels. Altogether, our results reveal an additional regulatory mechanism for ETS2, which plays key roles in cancer and development. They also shed light on the molecular mechanisms underlying STAR syndrome.

Detection and Characterization of Preferential Flow Paths in the Downstream Area of a Hazardous Landfill

We have used surface-based electrical resistivity tomography to detect and characterize preferential hydraulic pathways in the immediate downstream area of an abandoned, hazardous landfill. The landfill occupies the void left by a former gravel pit and its base is close to the groundwater table and lacking an engineered barrier. As such, this site is remarkably typical of many small- to medium-sized waste deposits throughout the densely populated and heavily industrialized foreland on both sides of the Alpine arc. Outflows of pollutants lastingly contaminated local drinking water supplies and necessitated a partial remediation in the form of a synthetic cover barrier, which is meant to prevent meteoric water from percolating through the waste before reaching the groundwater table. Any future additional isolation of the landfill in the form of lateral barriers thus requires adequate knowledge of potential preferential hydraulic pathways for outflowing contaminants. Our results, inferred from a suite of tomographically inverted surfaced-based electrical resistivity profiles oriented roughly perpendicular to the local hydraulic gradient, indicate that potential contaminant outflows would predominantly occur along an unexploited lateral extension of the original gravel deposit. This finds its expression as a distinct and laterally continuous high-resistivity anomaly in the resistivity tomograms. This interpretation is ground-truthed through a litholog from a nearby well. Since the probed glacio-fluvial deposits are largely devoid of mineralogical clay, the geometry of hydraulic and electrical pathways across the pore space of a given lithological unit can be assumed to be identical, which allows for an order-of-magnitude estimation of the overall permeability structure. These estimates indicate that the permeability of the imaged extension of the gravel body is at least two to three orders-of-magnitude higher than that of its finer-grained embedding matrix. This corroborates the preeminent role of the high-resistivity anomaly as a potential preferential flow path.

Identification of different heart tissues from MRI C-SENC images using an unsupervised multi-stage fuzzy clustering technique.

PURPOSE: To objectively characterize different heart tissues from functional and viability images provided by composite-strain-encoding (C-SENC) MRI. MATERIALS AND METHODS: C-SENC is a new MRI technique for simultaneously acquiring cardiac functional and viability images. In this work, an unsupervised multi-stage fuzzy clustering method is proposed to identify different heart tissues in the C-SENC images. The method is based on sequential application of the fuzzy c-means (FCM) and iterative self-organizing data (ISODATA) clustering algorithms. The proposed method is tested on simulated heart images and on images from nine patients with and without myocardial infarction (MI). The resulting clustered images are compared with MRI delayed-enhancement (DE) viability images for determining MI. Also, Bland-Altman analysis is conducted between the two methods. RESULTS: Normal myocardium, infarcted myocardium, and blood are correctly identified using the proposed method. The clustered images correctly identified 90 +/- 4% of the pixels defined as infarct in the DE images. In addition, 89 +/- 5% of the pixels defined as infarct in the clustered images were also defined as infarct in DE images. The Bland-Altman results show no bias between the two methods in identifying MI. CONCLUSION: The proposed technique allows for objectively identifying divergent heart tissues, which would be potentially important for clinical decision-making in patients with MI.

MR features of gastrointestinal stromal tumors.

We report on two patients presenting with gastrointestinal stromal tumors (GIST). The important tumor size and the marked tissular hypersignal seen on T2-weighted magnetic resonance images (MRI) should be considered as magnetic resonance (MR) features strongly indicating diagnosis of GIST.

Relaxivity of Gd-based contrast agents on X nuclei with long intrinsic relaxation times in aqueous solutions.

The relaxivity of commercially available gadolinium (Gd)-based contrast agents was studied for X-nuclei resonances with long intrinsic relaxation times ranging from 6 s to several hundred seconds. Omniscan in pure 13C formic acid had a relaxivity of 2.9 mM(-1) s(-1), whereas its relaxivity on glutamate C1 and C5 in aqueous solution was approximately 0.5 mM(-1) s(-1). Both relaxivities allow the preparation of solutions with a predetermined short T1 and suggest that in vitro substantial sensitivity gains in their measurement can be achieved. 6Li has a long intrinsic relaxation time, on the order of several minutes, which was strongly affected by the contrast agents. Relaxivity ranged from approximately 0.1 mM(-1) s(-1) for Omniscan to 0.3 for Magnevist, whereas the relaxivity of Gd-DOTP was at 11 mM(-1) s(-1), which is two orders of magnitude higher. Overall, these experiments suggest that the presence of 0.1- to 10-microM contrast agents should be detectable, provided sufficient sensitivity is available, such as that afforded by hyperpolarization, recently introduced to in vivo imaging.

Néphropathie au produit de contraste [Contrast-induced nephropathy].

Iodine and gadolinium-based contrast induced nephropathy is the third leading cause of hospital-acquired acute kidney injury. It is essentially observed in patients with defined risk factors and is associated with increased morbidity and mortality. The prevention of contrast induced nephropathy consists in volume expansion through intravenous sodium chloride 0.9% or sodium bicarbonate 1.4%. Comparative randomized controlled trials appear to show a benefit in favor of sodium bicarbonate over saline fluids. According to last evidence, N-acetylcysteine does not provide additional benefit over intravenous fluids.