The Role of the Intestinal Microbiota in Inflammatory Bowel Disease

Inflammatory bowel disease: IBD) arises from complex interactions of genetic, environmental, and microbial factors. The intestinal microbiota is crucial for IBD induction and complex shifts in microbiota composition occur in IBD, but disease has not been consistently associated with presence or absence of a specific microbe. It is thus controversial whether fulfilling Koch\u27s postulates for individual bacterial species is relevant to IBD and whether disease-associated alterations in microbial colonization are predictive of underlying etiology. Resolving these controversies has been challenging due to paucity of animal models with rapid disease onset, experimental reliance on gnotobiotic animals, and difficulty specifically isolating many commensal intestinal bacteria. We fulfilled Koch\u27s postulates in a host genotype-specific fashion, using non-gnotobiotic methods to show that common commensal Bacteroides species induced disease in a genetic mouse model of IBD whereas an Enterobacteriaceae species that was significantly enriched during spontaneous disease was not itself sufficient for disease induction. We studied mice with a human-relevant IBD-susceptibility mutation which spontaneously develop intestinal inflammation resembling human ulcerative colitis. Antibiotics blocked colitis induction and mice remained disease-free after treatment cessation but developed disease if subsequently colonized with intestinal contents from untreated donors or with intestinal contents grown in mixed culture on media selective for Gram-negative obligate anaerobes. We therefore isolated common commensal Bacteroides species, introduced them into antibiotic-pre-treated mice, and confirmed colonization by specific, quantitative re-isolation in culture. Isolates colonized susceptible and non-susceptible mice equivalently but induced disease exclusively in susceptible animals, suggesting susceptibility was due to differences in host response rather than altered colonization susceptibility. In contrast to commensal Bacteroides, Enterobacteriaceae were \u3e100-fold enriched in the microbiota during spontaneous disease in our mice, supporting observations in other animal models and in human patients. However an Enterobacteriaceae isolate from a spontaneously colitic mouse was not sufficient to induce disease in antibiotic-pre-treated animals despite robust colonization. We thus identified distinct subsets of commensals with and without IBD-inducing potential and showed that these subsets would not have been predicted based on disease-associated shifts in the microbiota. Our findings establish experimental criteria and a conceptual framework for understanding the intestinal microbiota\u27s involvement in IBD

Discharge Readiness After Liver Transplant Is Not One Size Fits All

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162709/2/lt25864_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162709/1/lt25864.pd

Neuromedin U partially mediates leptin-induced hypothalamo-pituitary adrenal (HPA) stimulation and has a physiological role in the regulation of the HPA axis in the rat.

Intracerebroventricular (ICV) administration of the hypothalamic neuropeptide neuromedin U (NMU) or the adipostat hormone leptin increases plasma ACTH and corticosterone. The relationship between leptin and NMU in the regulation of the hypothalamo-pituitary adrenal (HPA) axis is currently unknown. In this study, leptin (1 nM) significantly increased the release of CRH from ex vivo hypothalamic explants by 207 ± 8.4% (P < 0.05 vs. basal), an effect blocked by the administration of anti-NMU IgG. The ICV administration of leptin (10 μg, 0.625 nmol) increased plasma ACTH and corticosterone 20 min after injection [plasma ACTH (picograms per milliliter): vehicle, 63 ± 20, leptin, 135 ± 36, P < 0.05; plasma corticosterone (nanograms per milliliter): vehicle, 285 ± 39, leptin, 452 ± 44, P < 0.01]. These effects were partially attenuated by the prior administration of anti-NMU IgG. Peripheral leptin also stimulated ACTH release, an effect attenuated by prior ICV administration of anti-NMU IgG. We examined the diurnal pattern of hypothalamic NMU mRNA expression and peptide content, plasma leptin, and plasma corticosterone. The diurnal changes in hypothalamic NMU mRNA expression were positively correlated with hypothalamic NMU peptide content, plasma corticosterone, and plasma leptin. The ICV administration of anti-NMU IgG significantly attenuated the dark phase rise in corticosterone [corticosterone (nanograms per milliliter): vehicle, 493 ± 38; NMU IgG, 342 ± 47 (P < 0.05)]. These studies suggest that NMU may play a role in the regulation of the HPA axis and partially mediate leptin-induced HPA stimulation. Copyright © 2006 by The Endocrine Society

Nasal Bone Fractures: Differences Amongst Sub-Specialty Consultants

BACKGROUND: Nasal fractures constitute the largest proportion of facial trauma each year, however, there is no consensus management. In this study, we investingated the role of the consultant and the functional and aesthetic outcomes of procedures performed to address nasal bone fractures. METHODS: A retrospective chart review of patients who sustained nasal bone fractures was conducted from 8/1/14 through 1/23/18. Categorical variables were analyzed using chi-squared testing and Fisher\u27s exact test, where appropriate, while continuous variables were compared using Mann-Whitney U testing. RESULTS: During the study period, 136 patients met inclusion criteria for full analysis. The mean age of this cohort was 47.6 ± 20.2 years with the majority identifying as African-American (53.7%) and male (67.2%). Otolaryngologists were significantly more likely to assess pre-operative nasal obstruction (100%) compared to plastic surgeons (24.1%) ( CONCLUSIONS: Consultants across subspecialties differ in the management of nasal bone trauma. A more standardized approach is warranted by all individuals involved in the care of maxillofacial trauma patients

Sensitivity Projections for Dark Matter Searches with the Fermi Large Area Telescope

The nature of dark matter is a longstanding enigma of physics; it may consist of particles beyond the Standard Model that are still elusive to experiments. Among indirect search techniques, which look for stable products from the annihilation or decay of dark matter particles, or from axions coupling to high-energy photons, observations of the $\gamma$-ray sky have come to prominence over the last few years, because of the excellent sensitivity of the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope mission. The LAT energy range from 20 MeV to above 300 GeV is particularly well suited for searching for products of the interactions of dark matter particles. In this report we describe methods used to search for evidence of dark matter with the LAT, and review the status of searches performed with up to six years of LAT data. We also discuss the factors that determine the sensitivities of these searches, including the magnitudes of the signals and the relevant backgrounds, considering both statistical and systematic uncertainties. We project the expected sensitivities of each search method for 10 and 15 years of LAT data taking. In particular, we find that the sensitivity of searches targeting dwarf galaxies, which provide the best limits currently, will improve faster than the square root of observing time. Current LAT limits for dwarf galaxies using six years of data reach the thermal relic level for masses up to 120 GeV for the $b\bar{b}$ annihilation channel for reasonable dark matter density profiles. With projected discoveries of additional dwarfs, these limits could extend to about 250 GeV. With as much as 15 years of LAT data these searches would be sensitive to dark matter annihilations at the thermal relic cross section for masses to greater than 400 GeV (200 GeV) in the $b\bar{b}$ ($\tau^+ \tau^-$) annihilation channels.Comment: Updated with a few additional and corrected references; otherwise, text is identical to previous version. Submitted on behalf of the Fermi-LAT collaboration. Accepted for publication in Physics Reports, 59 pages, 34 figures; corresponding author: Eric Charles ([email protected]

Short gamma-ray bursts from dynamically-assembled compact binaries in globular clusters: pathways, rates, hydrodynamics and cosmological setting

We present a detailed assessment of the dynamical pathways leading to the coalescence of compact objects in Globular Clusters (GCs) and Short Gamma-Ray Burst (SGRB) production. We consider primordial binaries, dynamically formed binaries (through tidal two-body and three-body exchange interactions) and direct impacts of compact objects (WD/NS/BH). We show that if the primordial binary fraction is small, close encounters dominate the production rate of coalescing compact systems. We find that the two dominant channels are the interaction of field NSs with dynamically formed binaries, and two-body encounters. We then estimate the redshift distribution and host galaxy demographics of SGRB progenitors, and find that GCs can provide a significant contribution to the overall observed rate. We have carried out hydrodynamical modeling of evolution of close stellar encounters with WD/NS/BH, and show that there is no problem in accounting for the energy budget of a typical SGRB. The particulars of each encounter are variable and lead to interesting diversity: the encounter characteristics are dependent on the impact parameter, in contrast to the merger scenario; the nature of the compact star itself can produce very different outcomes; the presence of tidal tails in which material falls back onto the central object at later times is a robust feature of these calculations, with the mass involved being larger than for binary mergers. It is thus possible to account generically in this scenario for a prompt episode of energy release, as well as for activity many dynamical time scales later (abridged).Comment: Accepted for publication in ApJ (24 pages, 19 figures

Modeling the temporal dynamics of cervicovaginal microbiota identifies targets that may promote reproductive health (vol 9, 163, 2021)

Following the publication of the original article [1], the authors noticed a misspelling on the name of one of the co-authors. “Musie S. Ghebermichael” should read “Musie S. Ghebremichael” The original article has been updated

Modeling the temporal dynamics of cervicovaginal microbiota identifies targets that may promote reproductive health

BACKGROUND: Cervicovaginal bacterial communities composed of diverse anaerobes with low Lactobacillus abundance are associated with poor reproductive outcomes such as preterm birth, infertility, cervicitis, and risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV). Women in sub-Saharan Africa have a higher prevalence of these high-risk bacterial communities when compared to Western populations. However, the transition of cervicovaginal communities between high- and low-risk community states over time is not well described in African populations. RESULTS: We profiled the bacterial composition of 316 cervicovaginal swabs collected at 3-month intervals from 88 healthy young Black South African women with a median follow-up of 9 months per participant and developed a Markov-based model of transition dynamics that accurately predicted bacterial composition within a broader cross-sectional cohort. We found that Lactobacillus iners-dominant, but not Lactobacillus crispatus-dominant, communities have a high probability of transitioning to high-risk states. Simulating clinical interventions by manipulating the underlying transition probabilities, our model predicts that the population prevalence of low-risk microbial communities could most effectively be increased by manipulating the movement between L. iners- and L. crispatus-dominant communities. CONCLUSIONS: The Markov model we present here indicates that L. iners-dominant communities have a high probability of transitioning to higher-risk states. We additionally identify transitions to target to increase the prevalence of L. crispatus-dominant communities. These findings may help guide future intervention strategies targeted at reducing bacteria-associated adverse reproductive outcomes among women living in sub-Saharan Africa. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40168-021-01096-9