Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells

Contains fulltext : 171426.pdf (publisher's version ) (Open Access)Cells in homeostasis metabolize glucose mainly through the tricarboxylic acid cycle and oxidative phosphorylation, while activated cells switch their basal metabolism to aerobic glycolysis. In this study, we examined whether metabolic reprogramming toward aerobic glycolysis is important for the host response to Mycobacterium tuberculosis (Mtb). Through transcriptional and metabolite analysis we show that Mtb induces a switch in host cellular metabolism toward aerobic glycolysis in human peripheral blood mononuclear cells (PBMCs). The metabolic switch is TLR2 dependent but NOD2 independent, and is mediated in part through activation of the AKT-mTOR (mammalian target of rapamycin) pathway. We show that pharmacological inhibition of the AKT/mTOR pathway inhibits cellular responses to Mtb both in vitro in human PBMCs, and in vivo in a model of murine tuberculosis. Our findings reveal a novel regulatory layer of host responses to Mtb that will aid understanding of host susceptibility to Mtb, and which may be exploited for host-directed therapy

Physiopathology of coxiella burnetii infection and host immunologic response

Coxiella burnetii is an interesting example of obligate intracellular bacteria that has uniquely evolved to thrive in the harshest conditions. The bacterium can infect a wide range of host species and also exhibit a wide spectrum of clinical manifestations. C. burnetii infection can cause abortions in small ruminants, reproductive problems in cattle, and acute or chronic disease in humans. The high infectivity and zoonotic potential of C. burnetii was recently witnessed in the unprecedented Q fever outbreak in the Netherlands (2007-2010). A complete understanding of how C. burnetii can cause disease requires an appreciation of the host immune responses. This may in turn help to improve diagnostics tests, develop effective vaccines and pharmacological agents against infection, and reduce health-care burden by controlling the disease.</p

Genetic variation in TLR10 is not associated with chronic Q fever, despite the inhibitory effect of TLR10 on Coxiella burnetii-induced cytokines in vitro

Coxiella burnetii, the causative agent of Q fever, is recognized by TLR2. TLR10 can act as an inhibitory receptor on TLR2-derived immune responses. Therefore, we investigated the role of TLR10 on C. burnetii-induced cytokine production and assessed whether genetic polymorphisms in TLR10 influences the development of chronic Q fever. HEK293 cells, transfected with TLR2, TLR10 or TLR2/TLR10, and human peripheral blood mononuclear cells (PBMCs) in the presence of anti-TLR10, were stimulated with C. burnetii. In both assays, the absence of TLR10 resulted in increased cytokine responses after C. burnetii stimulation. In addition, the effect of single nucleotide polymorphisms (SNPs) in TLR10 was examined in healthy volunteers whose PBMCs were stimulated with C. burnetii Nine Mile or the Dutch outbreak isolate C. burnetii 3262. Individuals bearing SNPs in TLR10 displayed increased cytokine production upon C. burnetii 3262 stimulation. Furthermore, 139 chronic Q fever patients and 220 controls were genotyped for TLR10 N241H, I775V and I369L. None of these polymorphisms were associated with increased susceptibility to chronic Q fever. In conclusion, TLR10 has an inhibitory effect on in vitro cytokine production by C. burnetii, but the presence of TLR10 polymorphisms does not lead to an increased risk of developing chronic Q fever.</p

Talking matters: Abused women's views on disclosure of partner abuse to the family doctor and its role in handling the abuse situation

Objective: We aimed to explore what women valued most in disclosing partner abuse to their doctor and whether disclosure played a role in handling their abuse situation. Methods: A qualitative method was used to understand abused women's views and experiences with disclosure to their family doctor. Thirty-six women were interviewed within 4 weeks after disclosure to their family doctor. Results: Most women went to see the doctor for some medical complaint, and only three women planned to disclose the abuse. Twenty-five women valued most their doctor's communicative approach with empathy or empowering and nine women valued most the instrumental approach. Eight women of the latter group wanted this combined with a communicative approach. After disclosure to the family doctor, a group of women (n = 20) perceived a real change in their possibilities to handle their situation. They appeared to be in a position we named: 'in transition', a state in which they started or continued a process of change. Another group of women (n = 13) appeared to be in a 'locked-up' position, a state without any prospect on change, feeling out of control and fearing the abuser. Three women reacted reserved towards change. Conclusion: A communicative approach, providing empathy and empowerment, is important to women in disclosing partner abuse. More than half of the women perceived possibilities for a change. Practice implications: Talking about abuse is an important step in a woman's process of change. Doctors should acknowledge the advantage of their position as a professional confidant and ask women about abuse. (c) 2007 Elsevier Ireland Ltd. All rights reserved

New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline

Abstract Background There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product profiles (TPPs) for medicines to prevent spontaneous preterm birth and manage preterm labor. The objectives of this study were to 1) analyse the research and development pipeline of medicines for preterm birth and 2) compare these medicines to target product profiles for spontaneous preterm birth to identify the most promising candidates. Methods Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched to identify candidate medicines (including drugs, dietary supplements and biologics) and populate the Accelerating Innovations for Mothers (AIM) database. This database was screened for all candidates that have been investigated for preterm birth. Candidates in clinical development were ranked against criteria from TPPs, and classified as high, medium or low potential. Preclinical candidates were categorised by product type, archetype and medicine subclass. Results The AIM database identified 178 candidates. Of the 71 candidates in clinical development, ten were deemed high potential (Prevention: Omega-3 fatty acid, aspirin, vaginal progesterone, oral progesterone, L-arginine, and selenium; Treatment: nicorandil, isosorbide dinitrate, nicardipine and celecoxib) and seven were medium potential (Prevention: pravastatin and lactoferrin; Treatment: glyceryl trinitrate, retosiban, relcovaptan, human chorionic gonadotropin and Bryophyllum pinnatum extract). 107 candidates were in preclinical development. Conclusions This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals

Coxiella burnetii isolates originating from infected cattle induce a more pronounced proinflammatory cytokine response compared to isolates from infected goats and sheep

Coxiella burnetii is the causative agent of Q fever. Although the prevalence of C. burnetii in cattle is much higher than in goats and sheep, infected cattle are rarely associated with human outbreaks. We investigated whether the immune response of humans differs after contact with C. burnetii isolates from different host origins or with different multilocus variable number of tandem repeat analysis (MLVA) genotypes. Cytokine responses were measured in human peripheral blood mononuclear cells (PBMCs) stimulated with 16 C. burnetii isolates with known MLVA genotype from goats, sheep, cattle, acute and chronic Q fever patients. Coxiella burnetii isolates originating from cattle induce significantly more IL-1β, TNF-α and IL-22 than the isolates from goats, sheep or chronic Q fever patients. Comparing the cytokine induction of the isolates based on their MVLA genotype did not reveal differences in response between the MLVA genotypes. The proinflammatory cytokine response induced in human PBMCs by C. burnetii isolates from cattle may explain the low incidence of human Q fever outbreaks caused by cattle. The cytokine profile of PBMCs stimulated with C. burnetii isolates from chronic Q fever patients resembles isolates from goats. Furthermore, cytokine responses seem to be depending on host origin than on MLVA genotype

Prophylactic antibiotics for uterine evacuation procedures to treat miscarriage

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: The objective of this review is to evaluate the effectiveness of routine antibiotic prophylaxis to women undergoing uterine evacuation procedures to treat miscarriage.

Stakeholders’ distribution by WHO global regions.

The proportion of stakeholders who participated in the (A) interviews (n = 23) and (B) survey (n = 46), in each of the WHO global regions. AFR = African region (yellow), AMR = Region of the Americas (blue), SEAR = South-East Asian region (light green), EUR = European region (red), EMR = Eastern Mediterranean region (dark green), WPR = Western Pacific region (black).</p