Phagocytosis of Legionella pneumophila is mediated by human monocyte complement receptors.

We have examined receptors mediating phagocytosis of the intracellular bacterial pathogen, Legionella pneumophila. Three mAbs against the type 3 complement receptor (CR3), which recognizes C3bi, inhibit adherence of L. pneumophila to monocytes by 64 +/- 8% to 74 +/- 11%. An mAb against the type 1 complement receptor (CR1), which recognizes C3b, inhibits adherence by 68 +/- 1%. mAbs against other monocyte surface antigens do not significantly influence adherence. Monocytes plated on substrates of L. pneumophila membranes modulate their CR1 and CR3 receptors but not Fc receptors; such monocytes bind 70% fewer C3b-coated erythrocytes and 53% fewer C3bi-coated erythrocytes than control monocytes. Adherence of L. pneumophila to monocytes in nonimmune sera is dependent on heat-labile serum opsonins; adherence is markedly reduced in heat-inactivated serum (84% reduction) or buffer alone (97% reduction) compared with fresh serum. mAbs against CR1 and CR3 receptors also inhibit L. pneumophila intracellular multiplication and protect monocyte monolayers from destruction by this bacterium. This study demonstrates that human monocyte complement receptors, CR1 and CR3, mediate phagocytosis of L. pneumophila. These receptors may play a general role in mediating phagocytosis of intracellular pathogens

Induction immunosuppression in adults undergoing liver transplantation: a network meta-analysis

BACKGROUND: Liver transplantation is considered the definitive treatment for people with liver failure. As part of post-liver transplantation management, immunosuppression (suppressing the host immunity) is given to prevent graft rejections. Immunosuppressive drugs can be classified into those that are used for a short period during the beginning phase of immunosuppression (induction immunosuppression) and those that are used over the entire lifetime of the individual (maintenance immunosuppression), because it is widely believed that graft rejections are more common during the first few months after liver transplantation. Some drugs such as glucocorticosteroids may be used for both induction and maintenance immunosuppression because of their multiple modalities of action. There is considerable uncertainty as to whether induction immunosuppression is necessary and if so, the relative efficacy of different immunosuppressive agents. OBJECTIVES: To assess the comparative benefits and harms of different induction immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different induction immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until July 2019 to identify randomised clinical trials in adults undergoing liver transplantation. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or status) in adults undergoing liver transplantation. We excluded randomised clinical trials in which participants had multivisceral transplantation and those who already had graft rejections. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, and hazard ratio (HR) with 95% credible intervals (CrIs) based on an available case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS: We included a total of 25 trials (3271 participants; 8 treatments) in the review. Twenty-three trials (3017 participants) were included in one or more outcomes in the review. The trials that provided the information included people undergoing primary liver transplantation for various indications and excluded those with HIV and those with renal impairment. The follow-up in the trials ranged from three to 76 months, with a median follow-up of 12 months among trials. All except one trial were at high risk of bias, and the overall certainty of evidence was very low. Overall, approximately 7.4% of people who received the standard regimen of glucocorticosteroid induction died and 12.2% developed graft failure. All-cause mortality and graft failure was lower with basiliximab compared with glucocorticosteroid induction: all-cause mortality (HR 0.53, 95% CrI 0.31 to 0.93; network estimate, based on 2 direct comparison trials (131 participants; low-certainty evidence)); and graft failure (HR 0.44, 95% CrI 0.28 to 0.70; direct estimate, based on 1 trial (47 participants; low-certainty evidence)). There was no evidence of differences in all-cause mortality and graft failure between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). There was also no evidence of differences in serious adverse events (proportion), serious adverse events (number), renal failure, any adverse events (proportion), any adverse events (number), liver retransplantation, graft rejections (any), or graft rejections (requiring treatment) between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the studies reported health-related quality of life. FUNDING: the source of funding for 14 trials was drug companies who would benefit from the results of the study; two trials were funded by neutral organisations who have no vested interests in the results of the study; and the source of funding for the remaining nine trials was unclear. AUTHORS' CONCLUSIONS: Based on low-certainty evidence, basiliximab induction may decrease mortality and graft failure compared to glucocorticosteroids induction in people undergoing liver transplantation. However, there is considerable uncertainty about this finding because this information is based on small trials at high risk of bias. The evidence is uncertain about the effects of different induction immunosuppressants on other clinical outcomes, including graft rejections. Future randomised clinical trials should be adequately powered, employ blinding, avoid post-randomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, graft failure, and health-related quality of life

Impaired neonatal macrophage phagocytosis is not explained by overproduction of prostaglandin E2

<p>Abstract</p> <p>Background</p> <p>Neonates and young infants manifest increased susceptibility to bacterial, viral and fungal lung infections. Previous work has identified a role for eicosanoids in mediating host defense functions of macrophages. This study examines the relationship between alveolar macrophage (AM) host defense and production of lipid mediators during the neonatal period compared to adult AMs.</p> <p>Methods</p> <p>AMs were harvested from young (day 7 and day 14) and adult (~10 week) rats. The functionality of these cells was assessed by examining their ability to phagocytose opsonized targets, produce cytokines, eicosanoids and intracellular cAMP measured by enzyme immunoassays, and gene expression of proteins, enzymes and receptors essential for eicosanoid generation and phagocytosis measured by real time RT-PCR.</p> <p>Results</p> <p>AMs from young animals (day 7 and 14) were defective in their ability to phagocytose opsonized targets and produce tumor necrosis factor (TNF)- α. In addition, young AMs produce more prostaglandin (PG) E₂, a suppressor of host defense, and less leukotriene (LT) B₄, a promoter of host defense. Young AMs express higher levels of enzymes responsible for the production of PGE₂and LTB₄; however, there was no change in the expression of E prostanoid (EP) receptors or LT receptors. Despite the similar EP profiles, young AMs are more responsive to PGE₂as evidenced by their increased production of the important second messenger, cyclic AMP. In addition, young AMs express higher levels of PDE3B and lower levels of PDE4C compared to adult AMs. However, even though the young AMs produced a skewed eicosanoid profile, neither the inhibition of PGE₂by aspirin nor the addition of exogenous LTB₄rescued the defective opsonized phagocytosis. Examination of a receptor responsible for mediating opsonized phagocytosis showed a significant decrease in the gene expression levels of the Fcgamma receptor in young (day 7) AMs compared to adult AMs.</p> <p>Conclusion</p> <p>These results suggest that elevated production of PGE₂and decreased production of LTB₄do not contribute to impaired opsonized macrophage phagocytosis and highlight an important difference between young and adult AMs.</p

Measurement of the branching fraction and CP content for the decay B(0) -> D(*+)D(*-)

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APS.We report a measurement of the branching fraction of the decay B0→D*+D*- and of the CP-odd component of its final state using the BABAR detector. With data corresponding to an integrated luminosity of 20.4  fb-1 collected at the Υ(4S) resonance during 1999–2000, we have reconstructed 38 candidate signal events in the mode B0→D*+D*- with an estimated background of 6.2±0.5 events. From these events, we determine the branching fraction to be B(B0→D*+D*-)=[8.3±1.6(stat)±1.2(syst)]×10-4. The measured CP-odd fraction of the final state is 0.22±0.18(stat)±0.03(syst).This work is supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the A.P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Measurement of D-s(+) and D-s(*+) production in B meson decays and from continuum e(+)e(-) annihilation at √s=10.6 GeV

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APSNew measurements of Ds+ and Ds*+ meson production rates from B decays and from qq̅ continuum events near the Υ(4S) resonance are presented. Using 20.8 fb-1 of data on the Υ(4S) resonance and 2.6 fb-1 off-resonance, we find the inclusive branching fractions B(B⃗Ds+X)=(10.93±0.19±0.58±2.73)% and B(B⃗Ds*+X)=(7.9±0.8±0.7±2.0)%, where the first error is statistical, the second is systematic, and the third is due to the Ds+→φπ+ branching fraction uncertainty. The production cross sections σ(e+e-→Ds+X)×B(Ds+→φπ+)=7.55±0.20±0.34pb and σ(e+e-→Ds*±X)×B(Ds+→φπ+)=5.8±0.7±0.5pb are measured at center-of-mass energies about 40 MeV below the Υ(4S) mass. The branching fractions ΣB(B⃗Ds(*)+D(*))=(5.07±0.14±0.30±1.27)% and ΣB(B⃗Ds*+D(*))=(4.1±0.2±0.4±1.0)% are determined from the Ds(*)+ momentum spectra. The mass difference m(Ds+)-m(D+)=98.4±0.1±0.3MeV/c2 is also measured.This work was supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the Swiss NSF, A. P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications

Patient- and system-related barriers for the earlier diagnosis of colorectal cancer

<p>Abstract</p> <p>Background</p> <p>A cohort of colorectal cancer (CRC) patients represents an opportunity to study missed opportunities for earlier diagnosis. Primary objective: To study the epidemiology of diagnostic delays and failures to offer/complete CRC screening. Secondary objective: To identify system- and patient-related factors that may contribute to diagnostic delays or failures to offer/complete CRC screening.</p> <p>Methods</p> <p>Setting: Rural Veterans Administration (VA) Healthcare system. Participants: CRC cases diagnosed within the VA between 1/1/2000 and 3/1/2007. Data sources: progress notes, orders, and pathology, laboratory, and imaging results obtained between 1/1/1995 and 12/31/2007. Completed CRC screening was defined as a fecal occult blood test or flexible sigmoidoscopy (both within five years), or colonoscopy (within 10 years); delayed diagnosis was defined as a gap of more than six months between an abnormal test result and evidence of clinician response. A summary abstract of the antecedent clinical care for each patient was created by a certified gastroenterologist (GI), who jointly reviewed and coded the abstracts with a general internist (TW).</p> <p>Results</p> <p>The study population consisted of 150 CRC cases that met the inclusion criteria. The mean age was 69.04 (range 35-91); 99 (66%) were diagnosed due to symptoms; 61 cases (46%) had delays associated with system factors; of them, 57 (38% of the total) had delayed responses to abnormal findings. Fifteen of the cases (10%) had prompt symptom evaluations but received no CRC screening; no patient factors were identified as potentially contributing to the failure to screen/offer to screen. In total, 97 (65%) of the cases had missed opportunities for early diagnosis and 57 (38%) had patient factors that likely contributed to the diagnostic delay or apparent failure to screen/offer to screen.</p> <p>Conclusion</p> <p>Missed opportunities for earlier CRC diagnosis were frequent. Additional studies of clinical data management, focusing on following up abnormal findings, and offering/completing CRC screening, are needed.</p

A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy

Candidate antibacterials are usually identified on the basis of their in vitro activity. However, the apparent inhibitory activity of new leads can be misleading because most culture media do not reproduce an environment relevant to infection in vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism can affect antimicrobial activity. Novel pyrimidine–imidazoles (PIs) were identified in a whole-cell screen against Mycobacterium tuberculosis. Lead optimization generated in vitro potent derivatives with desirable pharmacokinetic properties, yet without in vivo efficacy. Mechanism of action studies linked the PI activity to glycerol metabolism, which is not relevant for M. tuberculosis during infection. PIs induced self-poisoning of M. tuberculosis by promoting the accumulation of glycerol phosphate and rapid ATP depletion. This study underlines the importance of understanding central bacterial metabolism in vivo and of developing predictive in vitro culture conditions as a prerequisite for the rational discovery of new antibiotics

Group B Streptococcal β-Hemolysin/Cytolysin Directly Impairs Cardiomyocyte Viability and Function

BACKGROUND: Group B Streptococcus (GBS) is a leading cause of neonatal sepsis where myocardial dysfunction is an important contributor to poor outcome. Here we study the effects of the GBS pore-forming beta-hemolysin/cytolysin (Bh/c) exotoxin on cardiomyocyte viability, contractility, and calcium transients. METHODOLOGY/PRINCIPAL FINDINGS: HL-1 cardiomyocytes exposed to intact wild-type (WT) or isogenic Deltabeta h/c mutant GBS, or to cell-free extracts from either strain, were assessed for viability by trypan blue exclusion and for apoptosis by TUNEL staining. Functionality of exposed cardiomyocytes was analyzed by visual quantitation of the rate and extent of contractility. Mitochondrial membrane polarization was measured in TMRE-loaded cells exposed to GBS beta h/c. Effects of GBS beta h/c on calcium transients were studied in fura-2AM-loaded primary rat ventricular cardiomyocytes. Exposure of HL-1 cardiomyocytes to either WT GBS or beta h/c extracts significantly reduced both rate and extent of contractility and later induced necrotic and apoptotic cell death. No effects on cardiomyocyte viability or function were observed after treatment with Deltabeta h/c mutant bacteria or extracts. The beta h/c toxin was associated with complete and rapid loss of detectable calcium transients in primary neonatal rat ventricular cardiomyocytes and induced a loss of mitochondrial membrane polarization. These effects on viability and function were abrogated by the beta h/c inhibitor, dipalmitoyl phosphatidylcholine (DPPC). CONCLUSIONS/SIGNIFICANCE: Our data show a rapid loss of cardiomyocyte viability and function induced by GBS beta h/c, and these deleterious effects are inhibited by DPPC, a normal constituent of human pulmonary surfactant.. These findings have clinical implications for the cardiac dysfunction observed in neonatal GBS infections

Xenohormone transactivities are inversely associated to serum POPs in Inuit

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