Vancomycin-resistant Enterococcus faecium sequence type 796 - rapid international dissemination of a new epidemic clone

Background: Vancomycin-resistant Enterococcus faecium (VRE) is a leading cause of hospital-acquired infections. New, presumably better-adapted strains of VRE appear unpredictably; it is uncertain how they spread despite improved infection control. We aimed to investigate the relatedness of a novel sequence type (ST) of vanB E. faecium - ST796 - very near its time of origin from hospitals in three Australian states and New Zealand. Methods: Following near-simultaneous outbreaks of ST796 in multiple institutions, we gathered then tested colonization and bloodstream infection isolates' antimicrobial resistance (AMR) phenotypes, and phylogenomic relationships using whole genome sequencing (WGS). Patient meta-data was explored to trace the spread of ST796. Results: A novel clone of vanB E. faecium (ST796) was first detected at one Australian hospital in late 2011, then in two New Zealand hospitals linked by inter-hospital transfers from separate Melbourne hospitals. ST796 also appeared in hospitals in South Australia and New South Wales and was responsible for at least one major colonization outbreak in a Neonatal Intensive Care Unit without identifiable links between centers. No exceptional AMR was detected in the isolates. While WGS analysis showed very limited diversity at the core genome, consistent with recent emergence of the clone, clustering by institution was observed. Conclusions: Evolution of new E. faecium clones, followed by recognized or unrecognized movement of colonized individuals then rapid intra-institutional cross-transmission best explain the multi-center, multistate and international outbreak we observed

Sensitivity of imaging for multifocal-multicentric breast carcinoma

<p>Abstract</p> <p>Background</p> <p>This retrospective study aims to determine: 1) the sensitivity of preoperative mammography (Mx) and ultrasound (US), and re-reviewed Mx to detect multifocal multicentric breast carcinoma (MMBC), defined by pathology on surgical specimens, and 2) to analyze the characteristics of both detected and undetected foci on Mx and US.</p> <p>Methods</p> <p>Three experienced breast radiologists re-reviewed, independently, digital mammography of 97 women with MMBC pathologically diagnosed on surgical specimens. The radiologists were informed of all neoplastic foci, and blinded to the original mammograms and US reports. With regards to Mx, they considered the breast density, number of foci, the Mx characteristics of the lesions and their BI-RADS classification. For US, they considered size of the lesions, BI-RADS classification and US pattern and lesion characteristics. According to the histological size, the lesions were classified as: index cancer, 2nd lesion, 3rd lesion, and 4th lesion. Any pathologically identified malignant foci not previously described in the original imaging reports, were defined as undetected or missed lesions. Sensitivity was calculated for Mx, US and re-reviewed Mx for detecting the presence of the index cancer as well as additional satellite lesions.</p> <p>Results</p> <p>Pathological examination revealed 13 multifocal and 84 multicentric cancers with a total of 303 malignant foci (282 invasive and 21 non invasive). Original Mx and US reports had an overall sensitivity of 45.5% and 52.9%, respectively. Mx detected 83/97 index cancers with a sensitivity of 85.6%. The number of lesions <it>un</it>detected by original Mx was 165/303. The Mx pattern of breasts with undetected lesions were: fatty in 3 (1.8%); scattered fibroglandular density in 40 (24.3%), heterogeneously dense in 91 (55.1%) and dense in 31 (18.8%) cases. In breasts with an almost entirely fatty pattern, Mx sensitivity was 100%, while in fibroglandular or dense pattern it was reduced to 45.5%. Re-reviewed Mx detected only 3 additional lesions. The sensitivity of Mx was affected by the presence of dense breast tissue which obscured lesions or by an incorrect interpretation of suspicious findings.</p> <p>US detected 73/80 index cancers (sensitivity of 91.2%), US missed 117 malignant foci with a mean tumor diameter of 6.5 mm; the sensitivity was 52.9%</p> <p>Undetected lesions by US were those smallest in size and present in fatty breast or in the presence of microcalcifications without a visible mass.</p> <p>US sensitivity was affected by the presence of fatty tissue or by the extent of calcification.</p> <p>Conclusion</p> <p>Mx missed MMBC malignant foci more often in dense or fibroglandular breasts. US missed small lesions in mainly fatty breasts or when there were only microcalcifications. The combined sensitivity of both techniques to assess MMBC was 58%. We suggest larger studies on multimodality imaging.</p

Differential Expression of Melanopsin Isoforms Opn4L and Opn4S during Postnatal Development of the Mouse Retina

Photosensitive retinal ganglion cells (pRGCs) respond to light from birth and represent the earliest known light detection system to develop in the mouse retina. A number of morphologically and functionally distinct subtypes of pRGCs have been described in the adult retina, and have been linked to different physiological roles. We have previously identified two distinct isoforms of mouse melanopsin, Opn4L and Opn4S, which are generated by alternate splicing of the Opn4 locus. These isoforms are differentially expressed in pRGC subtypes of the adult mouse retina, with both Opn4L and Opn4S detected in M1 type pRGCs, and only Opn4L detected in M2 type pRGCs. Here we investigate the developmental expression of Opn4L and Opn4S and show a differential profile of expression during postnatal development. Opn4S mRNA is detected at relatively constant levels throughout postnatal development, with levels of Opn4S protein showing a marked increase between P0 and P3, and then increasing progressively over time until adult levels are reached by P10. By contrast, levels of Opn4L mRNA and protein are low at birth and show a marked increase at P14 and P30 compared to earlier time points. We suggest that these differing profiles of expression are associated with the functional maturation of M1 and M2 subtypes of pRGCs. Based upon our data, Opn4S expressing M1 type pRGCs mature first and are the dominant pRGC subtype in the neonate retina, whereas increased expression of Opn4L and the maturation of M2 type pRGCs occurs later, between P10 and P14, at a similar time to the maturation of rod and cone photoreceptors. We suggest that the distinct functions associated with these cell types will develop at different times during postnatal development

Predictive value of pathological and immunohistochemical parameters for axillary lymph node metastasis in breast carcinoma

<p>Abstract</p> <p>Background/Objective</p> <p>While several prognostic factors have been identified in breast carcinoma, the clinical outcome remains hard to predict for individual patients. Better predictive markers are needed to help guide difficult treatment decisions. Axillary lymph node metastasis (ALNM) is one of the most important prognostic determinants in breast carcinoma; however, the reasons why tumors vary in their capability to result in axillary metastasis remain unclear. Identifying breast carcinoma patients at risk for ALNM would improve treatment planning. This study aimed to identify the factors associated with ALNM in breast carcinoma, with particular emphasis on basal-like phenotype.</p> <p>Methods</p> <p>Breast carcinoma patients (n = 210) who underwent breast conserving surgery and axillary lymph node dissection (ALND) (level I and II) or modified radical mastectomy were included in this study. Pathological and immunohistochemical data including individual receptor/gene status was collected for analysis. The basal phenotype status was ascertained using the basal cytokeratin markers CK5, CK14, CK17 and EGFR.</p> <p>Results</p> <p>ALNM was found in 55% (n = 116) of the patients. On univariate analysis, multicentric disease, large tumor size (>2 cm), vascular and lymphatic invasion, epithelial hyperplasia, necrosis, in situ carcinoma and perineural invasion were associated with higher risk for ALNM, whereas CK5, CK14, EGFR positivity and basal-like tumor type were associated with lower risk. On multivariate analysis, CK5 positivity (OR 0.003, 95%CI 0.000-0.23, p = 0.009) and lymphatic/vascular invasion (OR 17.94, 95%CI 4.78-67.30, p < 0.001) were found to be independent predictors.</p> <p>Conclusions</p> <p>Although the value of complete ALND has been questioned in invasive breast cancer patients, treatment decisions for breast carcinoma have been influenced by many parameters, including lymph node status. Since histopathologic characteristics and expression of biological markers varies among the same histologic subtypes of breast carcinoma, specific clinical and histopathologic features of the primary tumor and ALN status like sentinel node might be used to tailor the loco-regional and systemic treatment in different clinical settings.</p

Medicine in the Popular Press: The Influence of the Media on Perceptions of Disease

In an age of increasing globalization and discussion of the possibility of global pandemics, increasing rates of reporting of these events may influence public perception of risk. The present studies investigate the impact of high levels of media reporting on the perceptions of disease. Undergraduate psychology and medical students were asked to rate the severity, future prevalence and disease status of both frequently reported diseases (e.g. avian flu) and infrequently reported diseases (e.g. yellow fever). Participants considered diseases that occur frequently in the media to be more serious, and have higher disease status than those that infrequently occur in the media, even when the low media frequency conditions were considered objectively ‘worse’ by a separate group of participants. Estimates of severity also positively correlated with popular print media frequency in both student populations. However, we also see that the concurrent presentation of objective information about the diseases can mitigate this effect. It is clear from these data that the media can bias our perceptions of disease

A Threshold Equation for Action Potential Initiation

In central neurons, the threshold for spike initiation can depend on the stimulus and varies between cells and between recording sites in a given cell, but it is unclear what mechanisms underlie this variability. Properties of ionic channels are likely to play a role in threshold modulation. We examined in models the influence of Na channel activation, inactivation, slow voltage-gated channels and synaptic conductances on spike threshold. We propose a threshold equation which quantifies the contribution of all these mechanisms. It provides an instantaneous time-varying value of the threshold, which applies to neurons with fluctuating inputs. We deduce a differential equation for the threshold, similar to the equations of gating variables in the Hodgkin-Huxley formalism, which describes how the spike threshold varies with the membrane potential, depending on channel properties. We find that spike threshold depends logarithmically on Na channel density, and that Na channel inactivation and K channels can dynamically modulate it in an adaptive way: the threshold increases with membrane potential and after every action potential. Our equation was validated with simulations of a previously published multicompartemental model of spike initiation. Finally, we observed that threshold variability in models depends crucially on the shape of the Na activation function near spike initiation (about −55 mV), while its parameters are adjusted near half-activation voltage (about −30 mV), which might explain why many models exhibit little threshold variability, contrary to experimental observations. We conclude that ionic channels can account for large variations in spike threshold

Semen CD4+ T cells and macrophages are productively infected at all stages of SIV infection in macaques.

International audienceThe mucosal events of HIV transmission have been extensively studied, but the role of infected cells present in the genital and rectal secretions, and in the semen, in particular, remains a matter of debate. As a prerequisite to a thorough in vivo investigation of the early transmission events through infected cells, we characterized in detail by multi-parameter flow cytometry the changes in macaque seminal leukocytes during SIVmac251 infection, focusing on T cells, macrophages and dendritic cells. Using immunocytofluorescence targeting SIV proteins and real-time quantitative PCR targeting SIV DNA, we investigated the nature of the infected cells on sorted semen leukocytes from macaques at different stages of infection. Finally, we cocultured semen CD4(+) T cells and macrophages with a cell line permissive to SIV infection to assess their infectivity in vitro. We found that primary infection induced strong local inflammation, which was associated with an increase in the number of leukocytes in semen, both factors having the potential to favor cell-associated virus transmission. Semen CD4(+) T cells and macrophages were productively infected at all stages of infection and were infectious in vitro. Lymphocytes had a mucosal phenotype and expressed activation (CD69 & HLA-DR) and migration (CCR5, CXCR4, LFA-1) markers. CD69 expression was increased in semen T cells by SIV infection, at all stages of infection. Macrophages predominated at all stages and expressed CD4, CCR5, MAC-1 and LFA-1. Altogether, we demonstrated that semen contains the two major SIV-target cells (CD4+ T cells and macrophages). Both cell types can be productively infected at all stages of SIV infection and are endowed with markers that may facilitate transmission of infection during sexual exposure

Estimating Mass Properties of Dinosaurs Using Laser Imaging and 3D Computer Modelling

Body mass reconstructions of extinct vertebrates are most robust when complete to near-complete skeletons allow the reconstruction of either physical or digital models. Digital models are most efficient in terms of time and cost, and provide the facility to infinitely modify model properties non-destructively, such that sensitivity analyses can be conducted to quantify the effect of the many unknown parameters involved in reconstructions of extinct animals. In this study we use laser scanning (LiDAR) and computer modelling methods to create a range of 3D mass models of five specimens of non-avian dinosaur; two near-complete specimens of Tyrannosaurus rex, the most complete specimens of Acrocanthosaurus atokensis and Strutiomimum sedens, and a near-complete skeleton of a sub-adult Edmontosaurus annectens. LiDAR scanning allows a full mounted skeleton to be imaged resulting in a detailed 3D model in which each bone retains its spatial position and articulation. This provides a high resolution skeletal framework around which the body cavity and internal organs such as lungs and air sacs can be reconstructed. This has allowed calculation of body segment masses, centres of mass and moments or inertia for each animal. However, any soft tissue reconstruction of an extinct taxon inevitably represents a best estimate model with an unknown level of accuracy. We have therefore conducted an extensive sensitivity analysis in which the volumes of body segments and respiratory organs were varied in an attempt to constrain the likely maximum plausible range of mass parameters for each animal. Our results provide wide ranges in actual mass and inertial values, emphasizing the high level of uncertainty inevitable in such reconstructions. However, our sensitivity analysis consistently places the centre of mass well below and in front of hip joint in each animal, regardless of the chosen combination of body and respiratory structure volumes. These results emphasize that future biomechanical assessments of extinct taxa should be preceded by a detailed investigation of the plausible range of mass properties, in which sensitivity analyses are used to identify a suite of possible values to be tested as inputs in analytical models

Morphogenesis of the T4 tail and tail fibers

Remarkable progress has been made during the past ten years in elucidating the structure of the bacteriophage T4 tail by a combination of three-dimensional image reconstruction from electron micrographs and X-ray crystallography of the components. Partial and complete structures of nine out of twenty tail structural proteins have been determined by X-ray crystallography and have been fitted into the 3D-reconstituted structure of the "extended" tail. The 3D structure of the "contracted" tail was also determined and interpreted in terms of component proteins. Given the pseudo-atomic tail structures both before and after contraction, it is now possible to understand the gross conformational change of the baseplate in terms of the change in the relative positions of the subunit proteins. These studies have explained how the conformational change of the baseplate and contraction of the tail are related to the tail's host cell recognition and membrane penetration function. On the other hand, the baseplate assembly process has been recently reexamined in detail in a precise system involving recombinant proteins (unlike the earlier studies with phage mutants). These experiments showed that the sequential association of the subunits of the baseplate wedge is based on the induced-fit upon association of each subunit. It was also found that, upon association of gp53 (gene product 53), the penultimate subunit of the wedge, six of the wedge intermediates spontaneously associate to form a baseplate-like structure in the absence of the central hub. Structure determination of the rest of the subunits and intermediate complexes and the assembly of the hub still require further study

A review of the phytochemical support for the shifting defence hypothesis

Several theories have been developed to explain why invasive species are very successful and develop into pest species in their new area. The shifting defence hypothesis (SDH) argues that invasive plant species quickly evolve towards new defence levels in the invaded area because they lack their specialist herbivores but are still under attack by local (new) generalist herbivores. The SDH predicts that plants should increase their cheap, toxic defence compounds and lower their expensive digestibility reducing compounds. As a net result resources are saved that can be allocated to growth and reproduction giving these plants a competitive edge over the local plant species. We conducted a literature study to test whether toxic defence compounds in general are increased in the invaded area and if digestibility reducing compounds are lowered. We specifically studied the levels of pyrrolizidine alkaloids, a toxin which is known for its beneficial and detrimental impact against specialists and generalists, respectively. Digestibility reducers did not show a clear trend which might be due to the small number of studies and traits measured. The meta analysis showed that toxic compounds in general and pyrrolizidine alkaloid levels specifically, increased significantly in the invaded area, supporting the predictions of the SDH that a fast evolution takes place in the allocation towards defence