Chronic diarrhea associated with persistent norovirus excretion in patients with chronic lymphocytic leukemia: report of two cases

BACKGROUND: Chronic diarrhea in patients treated with immunosuppressive agents or suffering from immunosuppressive disease can represent a diagnostic and therapeutic challenge to the clinician. Norovirus infection, a major cause of acute epidemic diarrhea, has been described as a cause of chronic diarrhea in patients who are immunosuppressed, including transplant recipients and the very young. CASE PRESENTATIONS: We describe two patients, a 64 year-old man and a 59 year-old woman, both suffering from chronic lymphocytic leukemia and hypogammaglobulinemia, who developed chronic diarrhea resistant to therapy. In both cases, after months of symptoms, persistent norovirus infection--documented by repeatedly-positive high-sensitivity stool enzyme immunoassay--was found to be the cause. Both patients died with active diarrheal symptoms. CONCLUSIONS: We describe the first cases of advanced chronic lymphocytic leukemia to suffer from chronic symptomatic norovirus infection. Clinicians caring for such patients, particularly those with concomitant hypogammaglobulinema, who have chronic unexplained diarrhea, should consider norovirus infection in the differential diagnosis

Dengue Vaccines Regulatory Pathways: A Report on Two Meetings with Regulators of Developing Countries

Richard Mahoney and colleagues summarize two recent meetings convened by the Pediatric Dengue Vaccine Initiative and the Developing Countries' Vaccine Regulators Network on regulatory issues that need to be addressed before licensing dengue vaccines

Rotation of planet-harbouring stars

The rotation rate of a star has important implications for the detectability, characterisation and stability of any planets that may be orbiting it. This chapter gives a brief overview of stellar rotation before describing the methods used to measure the rotation periods of planet host stars, the factors affecting the evolution of a star's rotation rate, stellar age estimates based on rotation, and an overview of the observed trends in the rotation properties of stars with planets.Comment: 16 pages, 4 figures: Invited review to appear in 'Handbook of Exoplanets', Springer Reference Works, edited by Hans J. Deeg and Juan Antonio Belmont

Transit Photometry as an Exoplanet Discovery Method

Photometry with the transit method has arguably been the most successful exoplanet discovery method to date. A short overview about the rise of that method to its present status is given. The method's strength is the rich set of parameters that can be obtained from transiting planets, in particular in combination with radial velocity observations; the basic principles of these parameters are given. The method has however also drawbacks, which are the low probability that transits appear in randomly oriented planet systems, and the presence of astrophysical phenomena that may mimic transits and give rise to false detection positives. In the second part we outline the main factors that determine the design of transit surveys, such as the size of the survey sample, the temporal coverage, the detection precision, the sample brightness and the methods to extract transit events from observed light curves. Lastly, an overview over past, current and future transit surveys is given. For these surveys we indicate their basic instrument configuration and their planet catch, including the ranges of planet sizes and stellar magnitudes that were encountered. Current and future transit detection experiments concentrate primarily on bright or special targets, and we expect that the transit method remains a principal driver of exoplanet science, through new discoveries to be made and through the development of new generations of instruments.Comment: Review chapte

RAB-5 Controls the Cortical Organization and Dynamics of PAR Proteins to Maintain C. elegans Early Embryonic Polarity

In all organisms, cell polarity is fundamental for most aspects of cell physiology. In many species and cell types, it is controlled by the evolutionarily conserved PAR-3, PAR-6 and aPKC proteins, which are asymmetrically localized at the cell cortex where they define specific domains. While PAR proteins define the antero-posterior axis of the early C. elegans embryo, the mechanism controlling their asymmetric localization is not fully understood. Here we studied the role of endocytic regulators in embryonic polarization and asymmetric division. We found that depleting the early endosome regulator RAB-5 results in polarity-related phenotypes in the early embryo. Using Total Internal Reflection Fluorescence (TIRF) microscopy, we observed that PAR-6 is localized at the cell cortex in highly dynamic puncta and depleting RAB-5 decreased PAR-6 cortical dynamics during the polarity maintenance phase. Depletion of RAB-5 also increased PAR-6 association with clathrin heavy chain (CHC-1) and this increase depended on the presence of the GTPase dynamin, an upstream regulator of endocytosis. Interestingly, further analysis indicated that loss of RAB-5 leads to a disorganization of the actin cytoskeleton and that this occurs independently of dynamin activity. Our results indicate that RAB-5 promotes C. elegans embryonic polarity in both dynamin-dependent and -independent manners, by controlling PAR-6 localization and cortical dynamics through the regulation of its association with the cell cortex and the organization of the actin cytoskeleton

The search for transient astrophysical neutrino emission with IceCube-DeepCore

We present the results of a search for astrophysical sources of brief transient neutrino emission using IceCube and DeepCore data acquired between 2012 May 15 and 2013 April 30. While the search methods employed in this analysis are similar to those used in previous IceCube point source searches, the data set being examined consists of a sample of predominantly sub-TeV muon-neutrinos from the Northern Sky (-5 degrees < delta < 90 degrees) obtained through a novel event selection method. This search represents a first attempt by IceCube to identify astrophysical neutrino sources in this relatively unexplored energy range. The reconstructed direction and time of arrival of neutrino events are used to search for any significant self-correlation in the data set. The data revealed no significant source of transient neutrino emission. This result has been used to construct limits at timescales ranging from roughly 1 s to 10 days for generic soft-spectra transients. We also present limits on a specific model of neutrino emission from soft jets in core-collapse supernovae

Polymorphic Variation in TIRAP Is Not Associated with Susceptibility to Childhood TB but May Determine Susceptibility to TBM in Some Ethnic Groups

Host recognition of mycobacterial surface molecules occurs through toll like receptors (TLR) 2 and 6. The adaptor protein TIRAP mediates down stream signalling of TLR2 and 4, and polymorphisms in the TIRAP gene (TIRAP) have been associated with susceptibility and resistance to tuberculosis (TB) in adults. In order to investigate the role of polymorphic variation in TIRAP in childhood TB in South Africa, which has one of the highest TB incidence rates in the world, we screened the entire open reading frame of TIRAP for sequence variation in two cohorts of childhood TB from different ethnic groups (Xhosa and mixed ancestry). We identified 13 SNPs, including seven previously unreported, in the two cohorts, and found significant differences in frequency of the variants between the two ethnic groups. No differences in frequency between individual SNPs or combinations were found between TB cases and controls in either cohort. However the 558C→T SNP previously associated with TB meningitis (TBM) in a Vietnamese population was found to be associated with TBM in the mixed ancestry group. Polymorphisms in TIRAP do not appear to be involved in childhood TB susceptibility in South Africa, but may play a role in determining occurrence of TBM

Hydrodynamic Regulation of Monocyte Inflammatory Response to an Intracellular Pathogen

Systemic bacterial infections elicit inflammatory response that promotes acute or chronic complications such as sepsis, arthritis or atherosclerosis. Of interest, cells in circulation experience hydrodynamic shear forces, which have been shown to be a potent regulator of cellular function in the vasculature and play an important role in maintaining tissue homeostasis. In this study, we have examined the effect of shear forces due to blood flow in modulating the inflammatory response of cells to infection. Using an in vitro model, we analyzed the effects of physiological levels of shear stress on the inflammatory response of monocytes infected with chlamydia, an intracellular pathogen which causes bronchitis and is implicated in the development of atherosclerosis. We found that chlamydial infection alters the morphology of monocytes and trigger the release of pro-inflammatory cytokines TNF-α, IL-8, IL-1β and IL-6. We also found that the exposure of chlamydia-infected monocytes to short durations of arterial shear stress significantly enhances the secretion of cytokines in a time-dependent manner and the expression of surface adhesion molecule ICAM-1. As a functional consequence, infection and shear stress increased monocyte adhesion to endothelial cells under flow and in the activation and aggregation of platelets. Overall, our study demonstrates that shear stress enhances the inflammatory response of monocytes to infection, suggesting that mechanical forces may contribute to disease pathophysiology. These results provide a novel perspective on our understanding of systemic infection and inflammation

Different Patterns of Evolution in the Centromeric and Telomeric Regions of Group A and B Haplotypes of the Human Killer Cell Ig-Like Receptor Locus

The fast evolving human KIR gene family encodes variable lymphocyte receptors specific for polymorphic HLA class I determinants. Nucleotide sequences for 24 representative human KIR haplotypes were determined. With three previously defined haplotypes, this gave a set of 12 group A and 15 group B haplotypes for assessment of KIR variation. The seven gene-content haplotypes are all combinations of four centromeric and two telomeric motifs. 2DL5, 2DS5 and 2DS3 can be present in centromeric and telomeric locations. With one exception, haplotypes having identical gene content differed in their combinations of KIR alleles. Sequence diversity varied between haplotype groups and between centromeric and telomeric halves of the KIR locus. The most variable A haplotype genes are in the telomeric half, whereas the most variable genes characterizing B haplotypes are in the centromeric half. Of the highly polymorphic genes, only the 3DL3 framework gene exhibits a similar diversity when carried by A and B haplotypes. Phylogenetic analysis and divergence time estimates, point to the centromeric gene-content motifs that distinguish A and B haplotypes having emerged ∼6 million years ago, contemporaneously with the separation of human and chimpanzee ancestors. In contrast, the telomeric motifs that distinguish A and B haplotypes emerged more recently, ∼1.7 million years ago, before the emergence of Homo sapiens. Thus the centromeric and telomeric motifs that typify A and B haplotypes have likely been present throughout human evolution. The results suggest the common ancestor of A and B haplotypes combined a B-like centromeric region with an A-like telomeric region