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| 2. |
- Konsman, J.P., et al.
(författare)
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The vagus nerve mediates behavioural depression, but not fever, in response to peripheral immune signals, a functional anatomical analysis
- 2000
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Ingår i: European Journal of Neuroscience. - 0953-816X .- 1460-9568. ; 12:12, s. 4434-4446
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Tidskriftsartikel (refereegranskat)abstract
- Cytokines act on the brain to induce fever and behavioural depression after infection. Although several mechanisms of cytokine-to-brain communication have been proposed, their physiological significance is unclear. We propose that behavioural depression is mediated by the vagus nerve activating limbic structures, while fever would primarily be due to humoral mechanisms affecting the preoptic area, including interleukin-6 (IL-6) action on the organum vasculosum of the laminae terminalis (OVLT) and induction of prostaglandins. This study assessed the effects of subdiaphragmatic vagotomy in rats on fever, behavioural depression, as measured by the social interaction test, and Fos expression in the brain. These responses were compared with induction of the prostaglandin-producing enzyme cyclooxygenase-2 and the transcription factor Stat3 that translocates after binding of IL-6. Vagotomy blocked behavioural depression after intraperitoneal injection of recombinant rat IL-1ß (25 µg/kg) or lipopolysaccharide (250 µg/kg, LPS) and prevented Fos expression in limbic structures and ventromedial preoptic area, but not in the OVLT. Fever was not affected by vagotomy, but associated with translocation of Stat3 in the OVLT and cyclooxygenase-2 induction around blood vessels. These results indicate that the recently proposed vagal link between the immune system and the brain activates limbic structures to induce behavioural depression after abdominal inflammation. Although the vagus might play a role in fever in response to low doses of LPS by activating the ventromedial preoptic area, it is likely to be overridden during more severe infection by action of circulating IL-6 on the OVLT or prostaglandins induced along blood vessels of the preoptic area.
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| 4. |
- Baker, K., et al.
(författare)
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Performance of five pulse oximeters to detect hypoxaemia as an indicator of severe illness in children under five by frontline health workers in low resource settings- A prospective, multicentre, single-blinded, trial in Cambodia, Ethiopia, South Sudan, and Uganda
- 2021
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Ingår i: Eclinicalmedicine. - : Elsevier BV. - 2589-5370. ; 38
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low blood oxygen saturation (SpO2), or hypoxaemia, is an indicator of severe illness in children. Pulse oximetry is a globally accepted, non-invasive method to identify hypoxaemia, but rarely available outside higher-level facilities in resource-constrained countries. This study aims to evaluate the performance of different types of pulse oximeters amongst frontline health workers in Cambodia, Ethiopia, South Sudan, and Uganda. Methods: Five pulse oximeters (POx) which passed laboratory testing, out of an initial 32 potential pulse oximeters, were evaluated by frontline health workers for performance, defined as agreement between the SpO2 measurements of the test device and the reference standard. The study protocol is registered with the Australia New Zealand Clinical Trials Registry (Ref: ACTRrn12615000348550). Findings: Two finger-tip pulse oximeters (Contec and Devon), two handheld pulse oximeters (Lifebox and Utech), and one phone pulse oximeter (Masimo) passed the laboratory testing. They were evaluated for performance on 1,313 children under five years old by 207 frontline health workers between February and May 2015. Phone and handheld pulse oximeters had greater overall agreement with the reference standard (56%; 95% CI 0.52 - 0.60 to 68%; 95% CI 0.65 - 0.71) than the finger-tip POx (31%; 95% CI 0.26 to 0.36 and 47%; 95% CI 0.42 to 0.52). Fingertip POx performance was substantially lower in the 0-2 month olds; having just 17% and 25% agreement. The finger-tip devices more often underreported SpO2 readings (mean difference -7.9%; 95%CI -8.6,-7.2 and -3.9%; 95%CI -4.4,-3.4), and therefore over diagnosed hypoxaemia in the children assessed. Interpretation: While the Masimo phone pulse oximeter performed best, all handheld POx with age-specific probes performed well in the hands of frontline health workers, further highlighting their suitability as a screening tool of severe illness. The poor performance of the fingertip POx suggests they should not be used in children under five by frontline health workers. It is essential that POx are performance tested on children in routine settings (in vivo), not only in laboratories or controlled settings (in vitro), before being introduced at scale.
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| 5. |
- Baker, K., et al.
(författare)
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Performance of Four Respiratory Rate Counters to Support Community Health Workers to Detect the Symptoms of Pneumonia in Children in Low Resource Settings: A Prospective, Multicentre, Hospital-Based, Single-Blinded, Comparative Trial
- 2019
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Ingår i: EClinicalMedicine. - : Elsevier BV. - 2589-5370.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pneumonia is one of the leading causes of death in children under-five globally. The current diagnostic criteria for pneumonia are based on increased respiratory rate (RR) or chest in-drawing in children with cough and/or difficulty breathing. Accurately counting RR is difficult for community health workers (CHWs). Current RR counting devices are frequently inadequate or unavailable. This study analysed the performance of improved RR timers for detection of pneumonia symptoms in low-resource settings. Methods: Four RR timers were evaluated on 454 children, aged from 0 to 59 months with cough and/or difficulty breathing, over three months, by CHWs in hospital settings in Cambodia, Ethiopia, South Sudan and Uganda. The devices were the Mark Two ARI timer (MK2 ARI), counting beads with ARI timer, Rrate Android phone and the Respirometer feature phone applications. Performance was evaluated for agreement with an automated RR reference standard (Masimo Root patient monitoring and connectivity platform with ISA CO2 capnography). This study is registered with ANZCTR [ACTRN12615000348550]. Findings: While most CHWs managed to achieve a RR count with the four devices, the agreement was low for all; the mean difference of RR measurements from the reference standard for the four devices ranged from 0.5 (95% C.I. − 2.2 to 1.2) for the respirometer to 5.5 (95% C.I. 3.2 to 7.8) for Rrate. Performance was consistently lower for young infants (0 to < 2 months) than for older children (2 to ≤ 59 months). Agreement of RR classification into fast and normal breathing was moderate across all four devices, with Cohen's Kappa statistics ranging from 0.41 (SE 0.04) to 0.49 (SE 0.05). Interpretation: None of the four devices evaluated performed well based on agreement with the reference standard. The ARI timer currently recommended for use by CHWs should only be replaced by more expensive, equally performing, automated RR devices when aspects such as usability and duration of the device significantly improve the patient-provider experience. Funding: Bill & Melinda Gates Foundation [ OPP1054367]. © 2019
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| 7. |
- Beck, Carole, et al.
(författare)
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PARP3, a new therapeutic target to alter Rictor/mTORC2 signaling and tumor progression in BRCA1-associated cancers
- 2019
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Ingår i: Cell Death and Differentiation. - : Nature Publishing Group. - 1350-9047 .- 1476-5403. ; 26:9, s. 1615-1630
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Tidskriftsartikel (refereegranskat)abstract
- PARP3 has been shown to be a key driver of TGF beta-induced epithelial-to-mesenchymal transition (EMT) and sternness in breast cancer cells, emerging as an attractive therapeutic target. Nevertheless, the therapeutic value of PARP3 inhibition has not yet been assessed. Here we investigated the impact of the absence of PARP3 or its inhibition on the tumorigenicity of BRCA1-proficient versus BRCA1-deficient breast cancer cell lines, focusing on the triple-negative breast cancer subtype (TNBC). We show that PARP3 knockdown exacerbates centrosome amplification and genome instability and reduces survival of BRCA1-deficient TNBC cells. Furthermore, we engineered PARP3(-/- )BRCA1-deficient or BRCA1-proficient TNBC cell lines using the CRISPR/nCas9(D10A) gene editing technology and demonstrate that the absence of PARP3 selectively suppresses the growth, survival and in vivo tumorigenicity of BRCA1-deficient TNBC cells, mechanistically via effects associated with an altered Rictor/mTORC2 signaling complex resulting from enhanced ubiquitination of Rictor. Accordingly, PARP3 interacts with and ADP-ribosylates GSK3 beta, a positive regulator of Rictor ubiquitination and degradation. Importantly, these phenotypes were rescued by re-expression of a wild-type PARP3 but not by a catalytic mutant, demonstrating the importance of PARP3's catalytic activity. Accordingly, reduced survival and compromised Rictor/mTORC2 signaling were also observed using a cell-permeable PARP3-specific inhibitor. We conclude that PARP3 and BRCA1 are synthetic lethal and that targeting PARP3's catalytic activity is a promising therapeutic strategy for BRCA1-associated cancers via the Rictor/mTORC2 signaling pathway.
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| 9. |
- Konsman, J.P., et al.
(författare)
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How the immune and nervous systems interact during disease-associated anorexia
- 2001
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Ingår i: Nutrition (Burbank, Los Angeles County, Calif.). - 0899-9007 .- 1873-1244. ; 17:7-8, s. 664-668
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Anorexia is one of the most common symptoms associated with illness and constitutes an adaptive strategy in fighting acute infectious diseases. However, prolonged reduction in food intake and an increase in metabolic rate, as seen in the anorexia-cachexia syndrome, lead to depletion of body fat and protein reserves, thus worsening the organism's condition. Because the central nervous system controls many aspects of food intake, soluble factors known as cytokines that are secreted by immune cells might act on the brain to induce anorexia during disease. This review focuses on the communication pathways from the immune system to the brain that might mediate anorexia during disease. The vagus nerve is a rapid route of communication from the immune system to the brain, as subdiaphragmatic vagotomy attenuates the decrease in food-motivated behavior and c-Fos expression in the central nervous system in response to peripheral administration of the proinflammatory cytokine, interleukin-1ß, or bacterial lipopolysaccharide. At later time points after peripheral lipopolysaccharide administration, interleukin-1 itself acts in the brain to mediate anorexia and is found in the arcuate nucleus of the hypothalamus. The mechanisms by which interleukin-1ß gains access to the brain and the potential role of neuropeptide-Y-containing neurons in the arcuate hypothalamus in mediating anorexia during disease are discussed. Copyright © 2001 Elsevier Science Inc.
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| 10. |
- Lüscher, Bernhard, et al.
(författare)
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ADP-ribosyltransferases, an update on function and nomenclature
- 2022
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Ingår i: The FEBS Journal. - : John Wiley & Sons. - 1742-464X .- 1742-4658. ; 289:23, s. 7399-7410
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Tidskriftsartikel (refereegranskat)abstract
- ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes.
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