Candida species distribution and antifungal susceptibility testing according to European Committee on Antimicrobial Susceptibility Testing and new vs. old Clinical and Laboratory Standards Institute clinical breakpoints: a 6-year prospective candidaemia survey from the fungal infection network of Switzerland.

We analyzed the species distribution of Candida blood isolates (CBIs), prospectively collected between 2004 and 2009 within FUNGINOS, and compared their antifungal susceptibility according to clinical breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in 2013, and the Clinical and Laboratory Standards Institute (CLSI) in 2008 (old CLSI breakpoints) and 2012 (new CLSI breakpoints). CBIs were tested for susceptiblity to fluconazole, voriconazole and caspofungin by microtitre broth dilution (Sensititre(®) YeastOne? test panel). Of 1090 CBIs, 675 (61.9%) were C. albicans, 191 (17.5%) C. glabrata, 64 (5.9%) C. tropicalis, 59 (5.4%) C. parapsilosis, 33 (3%) C. dubliniensis, 22 (2%) C. krusei and 46 (4.2%) rare Candida species. Independently of the breakpoints applied, C. albicans was almost uniformly (>98%) susceptible to all three antifungal agents. In contrast, the proportions of fluconazole- and voriconazole-susceptible C. tropicalis and F-susceptible C. parapsilosis were lower according to EUCAST/new CLSI breakpoints than to the old CLSI breakpoints. For caspofungin, non-susceptibility occurred mainly in C. krusei (63.3%) and C. glabrata (9.4%). Nine isolates (five C. tropicalis, three C. albicans and one C. parapsilosis) were cross-resistant to azoles according to EUCAST breakpoints, compared with three isolates (two C. albicans and one C. tropicalis) according to new and two (2 C. albicans) according to old CLSI breakpoints. Four species (C. albicans, C. glabrata, C. tropicalis and C. parapsilosis) represented >90% of all CBIs. In vitro resistance to fluconazole, voriconazole and caspofungin was rare among C. albicans, but an increase of non-susceptibile isolates was observed among C. tropicalis/C. parapsilosis for the azoles and C. glabrata/C. krusei for caspofungin according to EUCAST and new CLSI breakpoints compared with old CLSI breakpoints.

Resting-brain functional connectivity predicted by analytic measures of network communication.

The complex relationship between structural and functional connectivity, as measured by noninvasive imaging of the human brain, poses many unresolved challenges and open questions. Here, we apply analytic measures of network communication to the structural connectivity of the human brain and explore the capacity of these measures to predict resting-state functional connectivity across three independently acquired datasets. We focus on the layout of shortest paths across the network and on two communication measures-search information and path transitivity-which account for how these paths are embedded in the rest of the network. Search information is an existing measure of information needed to access or trace shortest paths; we introduce path transitivity to measure the density of local detours along the shortest path. We find that both search information and path transitivity predict the strength of functional connectivity among both connected and unconnected node pairs. They do so at levels that match or significantly exceed path length measures, Euclidean distance, as well as computational models of neural dynamics. This capacity suggests that dynamic couplings due to interactions among neural elements in brain networks are substantially influenced by the broader network context adjacent to the shortest communication pathways.

Spatial weights : constructing weight-compatible exchange matrices from proximity matrices

Exchange matrices represent spatial weights as symmetric probability distributions on pairs of regions, whose margins yield regional weights, generally well-specified and known in most contexts. This contribution proposes a mechanism for constructing exchange matrices, derived from quite general symmetric proximity matrices, in such a way that the margin of the exchange matrix coincides with the regional weights. Exchange matrices generate in turn diffusive squared Euclidean dissimilarities, measuring spatial remoteness between pairs of regions. Unweighted and weighted spatial frameworks are reviewed and compared, regarding in particular their impact on permutation and normal tests of spatial autocorrelation. Applications include tests of spatial autocorrelation with diagonal weights, factorial visualization of the network of regions, multivariate generalizations of Moran's I, as well as "landscape clustering", aimed at creating regional aggregates both spatially contiguous and endowed with similar features.

Citrus fruit and cancer risk in a network of case-control studies.

BACKGROUND: Citrus fruit has shown a favorable effect against various cancers. To better understand their role in cancer risk, we analyzed data from a series of case-control studies conducted in Italy and Switzerland. PATIENTS AND METHODS: The studies included 955 patients with oral and pharyngeal cancer, 395 with esophageal, 999 with stomach, 3,634 with large bowel, 527 with laryngeal, 2,900 with breast, 454 with endometrial, 1,031 with ovarian, 1,294 with prostate, and 767 with renal cell cancer. All cancers were incident and histologically confirmed. Controls were admitted to the same network of hospitals for acute, nonneoplastic conditions. Odds ratios (OR) were estimated by multiple logistic regression models, including terms for major identified confounding factors for each cancer site, and energy intake. RESULTS: The ORs for the highest versus lowest category of citrus fruit consumption were 0.47 (95% confidence interval, CI, 0.36-0.61) for oral and pharyngeal, 0.42 (95% CI, 0.25-0.70) for esophageal, 0.69 (95% CI, 0.52-0.92) for stomach, 0.82 (95% CI, 0.72-0.93) for colorectal, and 0.55 (95% CI, 0.37-0.83) for laryngeal cancer. No consistent association was found with breast, endometrial, ovarian, prostate, and renal cell cancer. CONCLUSIONS: Our findings indicate that citrus fruit has a protective role against cancers of the digestive and upper respiratory tract.

Endocytic and secretory traffic in Arabidopsis merge in the trans-Golgi network/early endosome, an independent and highly dynamic organelle.

Plants constantly adjust their repertoire of plasma membrane proteins that mediates transduction of environmental and developmental signals as well as transport of ions, nutrients, and hormones. The importance of regulated secretory and endocytic trafficking is becoming increasingly clear; however, our knowledge of the compartments and molecular machinery involved is still fragmentary. We used immunogold electron microscopy and confocal laser scanning microscopy to trace the route of cargo molecules, including the BRASSINOSTEROID INSENSITIVE1 receptor and the REQUIRES HIGH BORON1 boron exporter, throughout the plant endomembrane system. Our results provide evidence that both endocytic and secretory cargo pass through the trans-Golgi network/early endosome (TGN/EE) and demonstrate that cargo in late endosomes/multivesicular bodies is destined for vacuolar degradation. Moreover, using spinning disc microscopy, we show that TGN/EEs move independently and are only transiently associated with an individual Golgi stack.

Outcome and prognostic factors in olfactory neuroblastoma: a rare cancer network study.

Purpose: To assess the outcome in patients with olfactory neuroblastoma (ONB). Methods and Materials: Seventy-seven patients treated for nonmetastatic ONB between 1971 and 2004 were included. According to Kadish classification, there were 11 patients with Stage A, 29 with Stage B, and 37 with Stage C. T-classification included 9 patients with T1, 26 with T2, 16 with T3, 15 with T4a, and 11 with T4b tumors. Sixty-eight patients presented with N0 (88%) disease. Results: Most of the patients (n = 56, 73 %) benefited from surgery (S), and total excision was possible in 44 patients (R0 in 32, R1 in 13, R2 in 11). All but five patients benefited from RT, and chemotherapy was given in 21(27%). Median follow-up period was 72 months (range, 6-315). The 5-year overall survival (OS), disease-free survival (DES), locoregional control, and local control were 64%, 57%, 62%, and 70%, respectively. In univariate analyses, favorable factors were Kadish A or B disease, T1 T3 tumors, no nodal involvement, curative surgery, R0/R1 resection, and RT-dose 54 Gy or higher. Multivariate analysis revealed that the best independent factors predicting the outcome were T1 T3, N0, R0/R1 resection, and total RT dose (54 Gy or higher). Conclusion: In this multicenter retrospective study, patients with ONB treated with R0 or R1 surgical resection followed by at least 54-Gy postoperative RT had the best outcome. Novel strategies including concomitant chemotherapy and/or higher dose RT should be prospectively investigated in this rare disease for which local failure remains a problem.

Angiofil-mediated visualization of the vascular system by microcomputed tomography: a feasibility study.

Visualization of the vascular systems of organs or of small animals is important for an assessment of basic physiological conditions, especially in studies that involve genetically manipulated mice. For a detailed morphological analysis of the vascular tree, it is necessary to demonstrate the system in its entirety. In this study, we present a new lipophilic contrast agent, Angiofil, for performing postmortem microangiography by using microcomputed tomography. The new contrast agent was tested in 10 wild-type mice. Imaging of the vascular system revealed vessels down to the caliber of capillaries, and the digital three-dimensional data obtained from the scans allowed for virtual cutting, amplification, and scaling without destroying the sample. By use of computer software, parameters such as vessel length and caliber could be quantified and remapped by color coding onto the surface of the vascular system. The liquid Angiofil is easy to handle and highly radio-opaque. Because of its lipophilic abilities, it is retained intravascularly, hence it facilitates virtual vessel segmentation, and yields an enduring signal which is advantageous during repetitive investigations, or if samples need to be transported from the site of preparation to the place of actual analysis, respectively. These characteristics make Angiofil a promising novel contrast agent; when combined with microcomputed tomography, it has the potential to turn into a powerful method for rapid vascular phenotyping.

Early stage primary bone lymphoma - a retrospective, multicenter rare cancer network (rcn) study

Purpose: Primary bone lymphoma (PBL) accounts for less than 1% of all malignant lymphomas, and 4-5% of all extra-nodal lymphomas. In this study, the disease profile, outcome, and prognostic factors were assessed in patients with stage I and II PBL.Patients and Methods: Thirteen Rare Cancer Network (RCN) institutions enrolled 116 consecutive patients with PBL treated between 1987 and 2008 in this study. Inclusion criteria were age > 16 years, stage I and II, minimum 6 months follow-up and a biopsy-proven confirmation of non-Hodgkin's lymphoma (NHL). Eighty-seven patients underwent chemoradiotherapy (CXRT), 15 radiotherapy (RT) without (13) or with (2) surgery, 14 chemotherapy (CXT) without (9) or with (5) surgery. Median RT dose was 40 Gy (range: 4-60). The median number of CXT cycles was 6 (range: 2-8). Median follow-up was 41 months (range: 6-242).Results: The overall response rate at the end of treatment was 91% (CR 74%, PR 17%). Local recurrence or progression was observed in 12 (10%) patients, and systemic recurrence in 17 (15%). Causes of death included disease progression in 21, unrelated in 5, CXT-related toxicity in 1, and second primary cancer in 2 patients. The 5-yr overall survival (OS), lymphoma-specific survival (LSS), and local control (LC) were 76%, 78% and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for OS were age <50 years (P=0.008), international prognostic index (IPI) score ≤1 (P=0.009), high grade histology (P=0.04), CXRT (P=0.05), CXT (P=0,0004), complete response (CR) (P<0.0001), number of CXT cycles ( ≥6 ) (P=0.01), and RT dose > 40 Gy (P=0.005). All above-mentioned parameters were also significant for LSS except for age and number of chemotherapy cycles. For LC, only CR and stage I were favorable factors. In multivariate analysis, IPI score, RT dose, complete response, and chemotherapy were independently influencing the outcome (OS and LSS). Complete response at the end of treatment was the only predicting factor for LC. Six patients developed grade 3 or more toxicities, according to Common Terminology Criteria for Adverse Events (CTCAE) V3.0.Conclusion: This large multicenter study confirms the relatively good prognosis of early stage PBL treated with combined CXRT. Local control was excellent, while systemic failures were rare. An adequate dose of RT (40 Gy or more) and complete CXT regime (≥ 6 cycles) were associated with better outcome.

Visualization of RNA polymerase II ternary transcription complexes formed in vitro on a Xenopus laevis vitellogenin gene.

Stable ternary transcription complexes assembled in vitro, using a HeLa whole-cell extract, have been isolated and visualized by electron microscopy. The formation of these stable complexes on the DNA fragment used as template, the 5' end region of the Xenopus laevis vitellogenin gene B2, depends on factors present in the whole-cell extract, RNA polymerase II and at least two nucleotides. Interestingly, bending in the DNA fragment was frequently observed at the binding site of RNA polymerase II. Dinucleotides that can prime initiation within a short sequence of approximately 10 contiguous nucleotides centered around the initiation site used in vivo, also favour the formation of stable complexes. In addition, pre-initiation complexes were isolated and it was shown that factors in the extract involved in their formation are more abundant than the RNA polymerase II molecules available for binding. The possible implication of this observation relative to the in vivo situation is discussed.

Diffusion Spectrum Imaging after stroke shows structural changes in the contra-lateral motor network correlating with functional recovery

There is growing interest in understanding the role of the non-injured contra-lateral hemisphere in stroke recovery. In the experimental field, histological evidence has been reported that structural changes occur in the contra-lateral connectivity and circuits during stroke recovery. In humans, some recent imaging studies indicated that contra-lateral sub-cortical pathways and functional and structural cortical networks are remodeling, after stroke. Structural changes in the contra-lateral networks, however, have never been correlated to clinical recovery in patients. To determine the importance of the contra-lateral structural changes in post-stroke recovery, we selected a population of patients with motor deficits after stroke affecting the motor cortex and/or sub-cortical motor white matter. We explored i) the presence of Generalized Fractional Anisotropy (GFA) changes indicating structural alterations in the motor network of patientsâeuro? contra-lateral hemisphere as well as their longitudinal evolution ii) the correlation of GFA changes with patientsâeuro? clinical scores, stroke size and demographics data iii) and a predictive model.

Online teaching of inflammatory skin pathology by a French-speaking international university network

Introduction: Developments in technology, webbased teaching and whole slide imaging have broadened the teaching horizon in anatomic pathology. Creating online learning material including many types of media like radiologic images, videos, clinical and macroscopic photographs and whole slides imaging is now accessible to almost every university. Unfortunately, a major limiting factor to maintain and update the learning material is the amount of work, time and resources needed. In this perspective, a French national university network was initiated in 2011 to build mutualised online teaching pathology modules with clinical cases and tests. This network has been extended to an international level in 2012-2014 (Quebec, Switzerland and Ivory Coast). Method: One of the first steps of the international project was to build a learning module on inflammatory skin pathology intended for interns and residents of pathology and dermatology. A pathology resident from Quebec spent 6 weeks in France and Switzerland to develop the contents and build the module on an e-learning Moodle platform (http: //moodle.sorbonne-paris-cite.fr) under the supervision of two dermatopathologists (BV, MB). The learning module contains text, interactive clinical cases, tests with feedback, whole slides images (WSI), images and clinical photographs. For that module, the virtual slides are decentralized in 2 universities (Bordeaux and Paris 7). Each university is responsible of its own slide scanning, image storage and online display with virtual slide viewers. Results: The module on inflammatory skin pathology includes more than 50 web pages with French original content, tests and clinical cases, links to over 45 WSI and more than 50 micro and clinical photographs. The whole learning module is currently being revised by four dermatopathologists and two senior pathologists. It will be accessible to interns and residents in spring 2014. The experience and knowledge gained from that work will be transferred to the next international fellowship intern whose work will be aimed at creating lung and breast pathology learning modules. Conclusion: The challenges of sustaining a project of this scope are numerous. The technical aspect of whole-slide imaging and storage needs to be developed by each university or group. The content needs to be regularly updated, completed and its use and existence needs to be promoted by the different actors in pathology. Of the great benefits of that kind of project are the international partnerships and connections that have been established between numerous Frenchspeaking universities and pathologists with the common goals of promoting education in pathology and the use of technology including whole slide imaging. * The Moodle website is hosted by PRES Sorbonne Paris Cité, and financial supports for hardware have been obtained from UNF3S (http://www.unf3s.org/) and PRES Sorbonne Paris Cité. Financial support for international fellowships has been obtained from CFQCU (http://www.cfqcu.org/).

Extreme prematurity and intra uterine growth restriction effects in brain network topology at school age

Higher risk for long-term behavioral and emotional sequelae, with attentional problems (with or without hyperactivity) is now becoming one of the hallmarks of extreme premature (EP) birth and birth after pregancy conditions leading to poor intra uterine growth restriction (IUGR) [1,2]. However, little is know so far about the neurostructural basis of these complexe brain functional abnormalities that seem to have their origins in early critical periods of brain development. The development of cortical axonal pathways happens in a series of sequential events. The preterm phase (24-36 post conecptional weeks PCW) is known for being crucial for growth of the thalamocortical fiber bundles as well as for the development of long projectional, commisural and projectional fibers [3]. Is it logical to expect, thus, that being exposed to altered intrauterine environment (altered nutrition) or to extrauterine environment earlier that expected, lead to alterations in the structural organization and, consequently, alter the underlying white matter (WM) structure. Understanding rate and variability of normal brain development, and detect differences from typical development may offer insight into the neurodevelopmental anomalies that can be imaged at later stages. Due to its unique ability to non-invasively visualize and quantify in vivo white matter tracts in the brain, in this study we used diffusion MRI (dMRI) tractography to derive brain graphs [4,5,6]. This relatively simple way of modeling the brain enable us to use graph theory to study topological properties of brain graphs in order to study the effects of EP and IUGR on childrens brain connectivity at age 6 years old.

Digital holographic microscopy: a noninvasive contrast imaging technique allowing quantitative visualization of living cells with subwavelength axial accuracy.

We have developed a digital holographic microscope (DHM), in a transmission mode, especially dedicated to the quantitative visualization of phase objects such as living cells. The method is based on an original numerical algorithm presented in detail elsewhere [Cuche et al., Appl. Opt. 38, 6994 (1999)]. DHM images of living cells in culture are shown for what is to our knowledge the first time. They represent the distribution of the optical path length over the cell, which has been measured with subwavelength accuracy. These DHM images are compared with those obtained by use of the widely used phase contrast and Nomarski differential interference contrast techniques.