Fecal Lactoferrin and Other Stool Markers during Normal Pregnancy and in Inflammatory Bowel Diseases: A Prospective Study and Review of the Literature

Introduction: Management of inflammatory bowel diseases (IBDs) - both Crohn's disease (CD) and ulcerative colitis (UC) - during pregnancy can be challenging since most monitoring tools available in nonpregnant patients are contraindicated.Objectives: The aim of the study was to test whether fecal inflammatory markers - specifically fecal lactoferrin - physiologically change during normal pregnancy as a prerequisite to use them to monitor IBD activity during pregnancy.Methods: Fecal lactoferrin was tested in healthy pregnant and nonpregnant women from the same geographic area and age range (18-40 years) - all negative for clinical gastrointestinal tract inflammation. A retrospective review of fecal lactoferrin levels contrasted with the Simple Endoscopic Score for CD, and the Disease Activity Index for UC was also performed in women with active IBDs within the same age range and geographical area.Results: In 30 nonpregnant subjects, fecal lactoferrin levels were 0.87 \ub1 1.08 mug/g. In 49 pregnant subjects, levels were 0.59 \ub1 0.83, 0.87 \ub1 1.13, and 0.85 \ub1 1.06 mug/g during the first, second, and third trimester, respectively (p = 0.64), with average levels for the 3 trimesters of 0.81 \ub1 1.04 mug/g (p = 0.61 compared to nonpregnant subjects). Sequential fecal lactoferrin levels (n = 26) did not differ from one trimester to the other in the individual subjects (p = 0.80). In 45 female IBD patients (27 with CD and 18 with UC), fecal lactoferrin levels were correlated with disease activity as defined by the endoscopic scores: 218, 688, and 1,175 mug/g for CD and 931, 2,088, and 2,509 mug/g for UC, respectively, for mild, moderate, and severe activity.Conclusions: Fecal lactoferrin levels during normal pregnancy are superimposable to those of nonpregnant women and significantly below levels in women of the same childbearing age with active IBDs. Additional published data - reviewed in this atricle - and our own indicate that fecal lactoferrin and other markers can be potentially used to monitor disease activity in pregnant IBD patients

15th Annual Legal Issues for Financial Institutions Conference

Program and materials from the 15th Annual Legal Issues for Financial Institutions Conference held by UK/CLE on March 10-11, 1995

Genetic architecture of laterality defects revealed by whole exome sequencing

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

Validation of MIPAS ClONO2 measurements

Altitude profiles of ClONO2 retrieved with the IMK (Institut fur Meteorologie und Klimaforschung) science-oriented data processor from MIPAS/Envisat (Michelson Interferometer for Passive Atmospheric Sounding on Envisat) mid-infrared limb emission measurements between July 2002 and March 2004 have been validated by comparison with balloon-borne (Mark IV, FIRS2, MIPAS-B), airborne (MIPAS-STR), ground-based (Spitsbergen, Thule, Kiruna, Harestua, Jungfraujoch, Izana, Wollongong, Lauder), and spaceborne (ACE-FTS) observations. With few exceptions we found very good agreement between these instruments and MIPAS with no evidence for any bias in most cases and altitude regions. For balloon-borne measurements typical absolute mean differences are below 0.05 ppbv over the whole altitude range from 10 to 39 km. In case of ACE-FTS observations mean differences are below 0.03 ppbv for observations below 26 km. Above this altitude the comparison with ACE-FTS is affected by the photochemically induced diurnal variation of ClONO2. Correction for this by use of a chemical transport model led to an overcompensation of the photochemical effect by up to 0.1 ppbv at altitudes of 30-35 km in case of MIPAS-ACE-FTS comparisons while for the balloon-borne observations no such inconsistency has been detected. The comparison of MIPAS derived total column amounts with ground-based observations revealed no significant bias in the MIPAS data. Mean differences between MIPAS and FTIR column abundances are 0.11 +/- 0.12 x 10(14) cm(-2) (1.0 +/- 1.1%) and -0.09 +/- 0.19 x 10(14) cm(-2) (-0.8 +/- 1.7%), depending on the coincidence criterion applied. chi(2) tests have been performed to assess the combined precision estimates of MIPAS and the related instruments. When no exact coincidences were available as in case of MIPAS-FTIR or MIPAS-ACE-FTS comparisons it has been necessary to take into consideration a coincidence error term to account for chi(2) deviations. From the resulting chi(2) profiles there is no evidence for a systematic over/underestimation of the MIPAS random error analysis.Peer reviewe

A visual and curatorial approach to clinical variant prioritization and disease gene discovery in genome-wide diagnostics

Background: Genome-wide data are increasingly important in the clinical evaluation of human disease. However, the large number of variants observed in individual patients challenges the efficiency and accuracy of diagnostic review. Recent work has shown that systematic integration of clinical phenotype data with genotype information can improve diagnostic workflows and prioritization of filtered rare variants. We have developed visually interactive, analytically transparent analysis software that leverages existing disease catalogs, such as the Online Mendelian Inheritance in Man database (OMIM) and the Human Phenotype Ontology (HPO), to integrate patient phenotype and variant data into ranked diagnostic alternatives. Methods: Our tool, “OMIM Explorer” (http://www.omimexplorer.com), extends the biomedical application of semantic similarity methods beyond those reported in previous studies. The tool also provides a simple interface for translating free-text clinical notes into HPO terms, enabling clinical providers and geneticists to contribute phenotypes to the diagnostic process. The visual approach uses semantic similarity with multidimensional scaling to collapse high-dimensional phenotype and genotype data from an individual into a graphical format that contextualizes the patient within a low-dimensional disease map. The map proposes a differential diagnosis and algorithmically suggests potential alternatives for phenotype queries—in essence, generating a computationally assisted differential diagnosis informed by the individual’s personal genome. Visual interactivity allows the user to filter and update variant rankings by interacting with intermediate results. The tool also implements an adaptive approach for disease gene discovery based on patient phenotypes. Results: We retrospectively analyzed pilot cohort data from the Baylor Miraca Genetics Laboratory, demonstrating performance of the tool and workflow in the re-analysis of clinical exomes. Our tool assigned to clinically reported variants a median rank of 2, placing causal variants in the top 1 % of filtered candidates across the 47 cohort cases with reported molecular diagnoses of exome variants in OMIM Morbidmap genes. Our tool outperformed Phen-Gen, eXtasy, PhenIX, PHIVE, and hiPHIVE in the prioritization of these clinically reported variants. Conclusions: Our integrative paradigm can improve efficiency and, potentially, the quality of genomic medicine by more effectively utilizing available phenotype information, catalog data, and genomic knowledge

Proteasomal Degradation of TRIM5α during Retrovirus Restriction

The host protein TRIM5α inhibits retroviral infection at an early post-penetration stage by targeting the incoming viral capsid. While the detailed mechanism of restriction remains unclear, recent studies have implicated the activity of cellular proteasomes in the restriction of retroviral reverse transcription imposed by TRIM5α. Here, we show that TRIM5α is rapidly degraded upon encounter of a restriction-susceptible retroviral core. Inoculation of TRIM5α-expressing human 293T cells with a saturating level of HIV-1 particles resulted in accelerated degradation of the HIV-1-restrictive rhesus macaque TRIM5α protein but not the nonrestrictive human TRIM5α protein. Exposure of cells to HIV-1 also destabilized the owl monkey restriction factor TRIMCyp; this was prevented by addition of the inhibitor cyclosporin A and was not observed with an HIV-1 virus containing a mutation in the capsid protein that relieves restriction by TRIMCyp IVHIV. Likewise, human TRIM5α was rapidly degraded upon encounter of the restriction-sensitive N-tropic murine leukemia virus (N-MLV) but not the unrestricted B-MLV. Pretreatment of cells with proteasome inhibitors prevented the HIV-1-induced loss of both rhesus macaque TRIM5α and TRIMCyp proteins. We also detected degradation of endogenous TRIM5α in rhesus macaque cells following HIV-1 infection. We conclude that engagement of a restriction-sensitive retrovirus core results in TRIM5α degradation by a proteasome-dependent mechanism

Systematic Neighborhood Observations at High Spatial Resolution: Methodology and Assessment of Potential Benefits

There is a growing body of public health research documenting how characteristics of neighborhoods are associated with differences in the health status of residents. However, little is known about how the spatial resolution of neighborhood observational data or community audits affects the identification of neighborhood differences in health. We developed a systematic neighborhood observation instrument for collecting data at very high spatial resolution (we observe each parcel independently) and used it to collect data in a low-income minority neighborhood in Dallas, TX. In addition, we collected data on the health status of individuals residing in this neighborhood. We then assessed the inter-rater reliability of the instrument and compared the costs and benefits of using data at this high spatial resolution. Our instrument provides a reliable and cost-effect method for collecting neighborhood observational data at high spatial resolution, which then allows researchers to explore the impact of varying geographic aggregations. Furthermore, these data facilitate a demonstration of the predictive accuracy of self-reported health status. We find that ordered logit models of health status using observational data at different spatial resolution produce different results. This implies a need to analyze the variation in correlative relationships at different geographic resolutions when there is no solid theoretical rational for choosing a particular resolution. We argue that neighborhood data at high spatial resolution greatly facilitates the evaluation of alternative geographic specifications in studies of neighborhood and health