Toward Whole-Brain Minimally-Invasive Vascular Imaging

Imaging the brain vasculature can be critical for cerebral perfusion monitoring in the context of neurocritical care. Although ultrasensitive Doppler (UD) can provide good sensitivity to cerebral blood volume (CBV) in a large field of view, it remains difficult to perform through the skull. In this work, we investigate how a minimally invasive burr hole, performed for intracranial pressure (ICP) monitoring, could be used to map the entire brain vascular tree. We explored the use of a small motorized phased array probe with a non-implantable preclinical prototype in pigs. The scan duration (18 min) and coverage (62 $\pm$ 12 % of the brain) obtained allowed global CBV variations detection (relative in brain Dopplerdecrease =-3[-4-+16]% \& Dopplerincrease. = +1[-3-+15]%, n = 6 \& 5) and stroke detection (relative in core Dopplerstroke. =-25%, n = 1). This technology could one day be miniaturized to be implanted for brain perfusion monitoring in neurocritical care

The Drosophila MAPK p38c Regulates Oxidative Stress and Lipid Homeostasis in the Intestine

The p38 mitogen-activated protein (MAP) kinase signaling cassette has been implicated in stress and immunity in evolutionarily diverse species. In response to a wide variety of physical, chemical and biological stresses p38 kinases phosphorylate various substrates, transcription factors of the ATF family and other protein kinases, regulating cellular adaptation to stress. The Drosophila genome encodes three p38 kinases named p38a, p38b and p38c. In this study, we have analyzed the role of p38c in the Drosophila intestine. The p38c gene is expressed in the midgut and upregulated upon intestinal infection. We showed that p38c mutant flies are more resistant to infection with the lethal pathogen Pseudomonas entomophila but are more susceptible to the non-pathogenic bacterium Erwinia carotovora 15. This phenotype was linked to a lower production of Reactive Oxygen Species (ROS) in the gut of p38c mutants, whereby the transcription of the ROS-producing enzyme Duox is reduced in p38c mutant flies. Our genetic analysis shows that p38c functions in a pathway with Mekk1 and Mkk3 to induce the phosphorylation of Atf-2, a transcription factor that controls Duox expression. Interestingly, p38c deficient flies accumulate lipids in the intestine while expressing higher levels of antimicrobial peptide and metabolic genes. The role of p38c in lipid metabolism is mediated by the Atf3 transcription factor. This observation suggests that p38c and Atf3 function in a common pathway in the intestine to regulate lipid metabolism and immune homeostasis. Collectively, our study demonstrates that p38c plays a central role in the intestine of Drosophila. It also reveals that many roles initially attributed to p38a are in fact mediated by p38c

Discriminative imaging of maternal and fetal blood flow within the placenta using ultrafast ultrasound

Remerciements à INRA UCEA et CR2iInternational audienceBeing able to map accurately placental blood flow in clinics could have major implications in the diagnosis and follow-up of pregnancy complications such as intrauterine growth restriction (IUGR). Moreover, the impact of such an imaging modality for a better diagnosis of placental dysfunction would require to solve the unsolved problem of discriminating the strongly intricated maternal and fetal vascular networks. However, no current imaging modality allows both to achieve sufficient sensitivity and selectivity to tell these entangled flows apart. Although ultrasound imaging would be the clinical modality of choice for such a problem, conventional Doppler echography both lacks of sensibility to detect and map the placenta microvascularization and a concept to discriminate both entangled flows. In this work, we propose to use an ultrafast Doppler imaging approach both to map with an enhanced sensitivity the small vessels of the placenta (~100 μm) and to assess the variation of the Doppler frequency simultaneously in all pixels of the image within a cardiac cycle. This approach is evaluated in vivo in the placenta of pregnant rabbits: By studying the local flow pulsatility pixel per pixel, it becomes possible to separate maternal and fetal blood in 2D from their pulsatile behavior. Significance Statement: The in vivo ability to image and discriminate maternal and fetal blood flow within the placenta is an unsolved problem which could improve the diagnosis of pregnancy complications such as intrauterine growth restriction or preeclampsia. To date, no imaging modality has both sufficient sensitivity and selectivity to discriminate these intimately entangled flows. We demonstrate that Ultrafast Doppler ultrasound method with a frame rate 100x faster than conventional imaging solves this issue. It permits the mapping of small vessels of the placenta (~100 μm) in 2D with an enhanced sensitivity. By assessing pixel-per-pixel pulsatility within single cardiac cycles, it achieves maternal and fetal blood flow discrimination

Liver fibrosis staging using supersonic shear imaging : a clinical study on 142 patients

International audienceI. Background, Motivation and ObjectiveFibrosis staging can be assessed by a rough estimation of the liver stiffness averaged along an ultrasonic A-line. Providing a complete 2D map of liver stiffness would thus be of great clinical interest for the diagnosis of hepatic fibrosis and help prevent upcoming cirrhosis. However, such measurement requires both a quantitative value of shear elasticity and a great precision to discriminate between different fibrosis levels. Beyond the scope of non-invasive fibrosis quantification, it is also envisioned that quantitative elasticity imaging of liver will have potential interest for liver cancer diagnosis. In this work, the Supersonic Shear Imaging technique (SSI) is proposed to map the in vivo viscoelastic parameters of liver on patients with hepatitis C and derive a mean elasticity of liver tissues. The results are compared to biological tests (Fib4, Apri, Forns) and Fibroscan® measurements. II. Statement of Contribution / MethodsThe SSI technique is based on the radiation force induced by a conventional ultrasonic probe to generate a planar shear wave deep into tissues. The shear wave propagation throughout the medium is caught in real time thanks to an ultrafast ultrasound scanner (up to 5000 frames/s). Using modified sequences and post-processing, this technique is implemented on curved arrays in order to get a larger field of view of liver tissues. A study on 150 HCV patients with different fibrosis stages F has been conducted in order to investigate the accuracy of the technique (F ϵ [0;4]). Quantitative maps of liver elasticity are produced for each volunteer with a linear and a curved array. III. ResultsB-mode images of 120x75 mm² and corresponding elasticity maps are obtained using a 2.5 MHz curved ultrasonic probe with a good reproducibility and accuracy. The shear wave phase velocity dispersion is also calculated. This study shows a good correlation between the values obtained by SSI and the fibrosis levels diagnosed by biological tests (p-index 0.9 for F>3 and Y> 0.8 for F>2). Results are also compared (r2 > 0.92) to the Fibroscan® elasticity measurement by fitting the velocity dispersion curves obtained by SSI at 50 Hz.IV. Discussion and ConclusionsThis real-time elasticity mapping using an ultrasonic curved probe offers better signal to noise ratio than linear arrays and a larger area in the patient's liver (13.3±2.8 cm² estimation area). This gives more confidence on the accuracy of the diagnosis of the fibrosis stage. Furthermore, the elasticity parameters obtained with SSI give access to the shear wave group velocity and the phase velocity. As a consequence, the SSI assessment of liver stiffness could potentially give more information on the viscoelasticity properties of the liver

A single modular serine protease integrates signals from pattern-recognition receptors upstream of the Drosophila Toll pathway

The Drosophila Toll receptor does not interact directly with microbial determinants, but is instead activated by a cleaved form of the cytokine-like molecule Spätzle. During the immune response, Spätzle is processed by complex cascades of serine proteases, which are activated by secreted pattern-recognition receptors. Here, we demonstrate the essential role of ModSP, a modular serine protease, in the activation of the Toll pathway by gram-positive bacteria and fungi. Our analysis shows that ModSP integrates signals originating from the circulating recognition molecules GNBP3 and PGRP-SA and connects them to the Grass-SPE-Spätzle extracellular pathway upstream of the Toll receptor. It also reveals the conserved role of modular serine proteases in the activation of insect immune reactions

Reliability of diagnostic coding in intensive care patients

International audienceABSTRACT: INTRODUCTION: Administrative coding of medical diagnoses in intensive care unit (ICU) patients is mandatory in order to create databases for use in epidemiological and economic studies. We assessed the reliability of coding between different ICU physicians. METHOD: One hundred medical records selected randomly from 29,393 cases collected between 1998 and 2004 in the French multicenter Outcomerea ICU database were studied. Each record was sent to two senior physicians from independent ICUs who recoded the diagnoses using the International Statistical Classification of Diseases and Related Health Problems: Tenth Revision (ICD-10) after being trained according to guidelines developed by two French national intensive care medicine societies: the French Society of Intensive Care Medicine (SRLF) and the French Society of Anesthesiology and Intensive Care Medicine (SFAR). These codes were then compared with the original codes, which had been selected by the physician treating the patient. A specific comparison was done for the diagnoses of septicemia and shock (codes derived from A41 and R57, respectively). RESULTS: The ICU physicians coded an average of 4.6 +/- 3.0 (range 1 to 32) diagnoses per patient, with little agreement between the three coders. The primary diagnosis was matched by both external coders in 34% (95% confidence interval (CI) 25% to 43%) of cases, by only one in 35% (95% CI 26% to 44%) of cases, and by neither in 31% (95% CI 22% to 40%) of cases. Only 18% (95% CI 16% to 20%) of all codes were selected by all three coders. Similar results were obtained for the diagnoses of septicemia and/or shock. CONCLUSION: In a multicenter database designed primarily for epidemiological and cohort studies in ICU patients, the coding of medical diagnoses varied between different observers. This could limit the interpretation and validity of research and epidemiological programs using diagnoses as inclusion criteria

Leptomeningeal collaterals regulate reperfusion in ischemic stroke

Recanalization is the mainstay of ischemic stroke treatment. However, even with timely clot removal, many stroke patients recover poorly. Leptomeningeal collaterals (LMCs) are pial anastomotic vessels with yet unknown functions. Utilizing a thrombin-based mouse model of stroke and the gold standard fibrinolytic treatment rt-PA, we here show that LMCs play a critical role in preserving vascular function in ischemic territories. We applied laser speckle contrast imaging, ultrafast ultrasound, and two-photon microscopy, to show that after thrombolysis, LMCs allow for gradual reperfusion resulting in small infarcts. On the contrary, in mice with poor LMCs, distal segments of recanalized arteries collapse and deleterious hyperemia causes hemorrhage and mortality. Accordingly, in stroke patients with poor collaterals undergoing thrombectomy, rapid reperfusion resulted in hemorrhagic transformation and unfavorable recovery. Thus, we identify LMCs as key components regulating reperfusion after stroke. Future therapeutic interventions should aim to enhance collateral function, allowing for gradual reperfusion of ischemic tissues after stroke

Inhibitor of apoptosis 2 and TAK1-binding protein are components of the Drosophila Imd pathway

The Imd signaling cascade, similar to the mammalian TNF-receptor pathway, controls antimicrobial peptide expression in Drosophila. We performed a large-scale RNAi screen to identify novel components of the Imd pathway in Drosophila S2 cells. In all, 6713 dsRNAs from an S2 cell-derived cDNA library were analyzed for their effect on Attacin promoter activity in response to Escherichia coli. We identified seven gene products required for the Attacin response in vitro, including two novel Imd pathway components: inhibitor of apoptosis 2 (Iap2) and transforming growth factor-activated kinase 1 (TAK1)-binding protein (TAB). Iap2 is required for antimicrobial peptide response also by the fat body in vivo. Both these factors function downstream of Imd. Neither TAB nor Iap2 is required for Relish cleavage, but may be involved in Relish nuclear localization in vitro, suggesting a novel mode of regulation of the Imd pathway. Our results show that an RNAi-based approach is suitable to identify genes in conserved signaling cascades