Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical ...symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines.
HFC-23 (also known as CHF3, fluoroform or trifluoromethane) is a potent greenhouse gas (GHG), with a global warming potential (GWP) of 14 800 for a 100-year time horizon. It is an unavoidable ...by-product of HCFC-22 (CHClF2, chlorodifluoromethane) production. HCFC-22, an ozone depleting substance (ODS), is used extensively in commercial refrigeration and air conditioning, in the extruded polystyrene (XPS) foam industries (dispersive applications) and also as a feedstock in fluoropolymer manufacture (a non-dispersive use). Aside from small markets in specialty uses, HFC-23 has historically been considered a waste gas that was, and often still is, simply vented to the atmosphere. Efforts have been made in the past two decades to reduce HFC-23 emissions, including destruction (incineration) in facilities in developing countries under the United Nations Framework Convention on Climate Change's (UNFCCC) Clean Development Mechanism (CDM), and by process optimization and/or voluntary incineration by most producers in developed countries. We present observations of lower-tropospheric mole fractions of HFC-23 measured by "Medusa" GC/MSD instruments from ambient air sampled in situ at the Advanced Global Atmospheric Gases Experiment (AGAGE) network of five remote sites (2007–2009) and in Cape Grim air archive (CGAA) samples (1978–2009) from Tasmania, Australia. These observations are used with the AGAGE 2-D atmospheric 12-box model and an inverse method to produce model mole fractions and a "top-down" HFC-23 emission history. The model 2009 annual mean global lower-tropospheric background abundance is 22.6 (±0.2) pmol mol−1. The derived HFC-23 emissions show a "plateau" during 1997–2003, followed by a rapid ~50% increase to a peak of 15.0 (+1.3/−1.2) Gg/yr in 2006. Following this peak, emissions of HFC-23 declined rapidly to 8.6 (+0.9/−1.0) Gg/yr in 2009, the lowest annual emission of the past 15 years. We derive a 1990–2008 "bottom-up" HFC-23 emission history using data from the United Nations Environment Programme and the UNFCCC. Comparison with the top-down HFC-23 emission history shows agreement within the stated uncertainties. In the 1990s, HFC-23 emissions from developed countries dominated all other sources, then began to decline and eventually became fairly constant during 2003–2008. By this point, with developed countries' emissions essentially at a plateau, the major factor controlling the annual dynamics of global HFC-23 emissions became the historical rise of developing countries' HCFC-22 dispersive use production, which peaked in 2007. Thereafter in 2007–2009, incineration through CDM projects became a larger factor, reducing global HFC-23 emissions despite rapidly rising HCFC-22 feedstock production in developing countries.
HCFC-22 (CHClF2, chlorodifluoromethane) is an ozone-depleting substance (ODS) as well as a significant greenhouse gas (GHG). HCFC-22 has been used widely as a refrigerant fluid in cooling and ...air-conditioning equipment since the 1960s, and it has also served as a traditional substitute for some chlorofluorocarbons (CFCs) controlled under the Montreal Protocol. A low frequency record on tropospheric HCFC-22 since the late 1970s is available from measurements of the Southern Hemisphere Cape Grim Air Archive (CGAA) and a few Northern Hemisphere air samples (mostly from Trinidad Head) using the Advanced Global Atmospheric Gases Experiment (AGAGE) instrumentation and calibrations. Since the 1990s high-frequency, high-precision, in situ HCFC-22 measurements have been collected at these AGAGE stations. Since 1992, the Global Monitoring Division of the National Oceanic and Atmospheric Administration/Earth System Research Laboratory (NOAA/ESRL) has also collected flasks on a weekly basis from remote sites across the globe and analyzed them for a suite of halocarbons including HCFC-22. Additionally, since 2006 flasks have been collected approximately daily at a number of tower sites across the US and analyzed for halocarbons and other gases at NOAA. All results show an increase in the atmospheric mole fractions of HCFC-22, and recent data show a growth rate of approximately 4% per year, resulting in an increase in the background atmospheric mole fraction by a factor of 1.7 from 1995 to 2009. Using data on HCFC-22 consumption submitted to the United Nations Environment Programme (UNEP), as well as existing bottom-up emission estimates, we first create globally-gridded a priori HCFC-22 emissions over the 15 yr since 1995. We then use the three-dimensional chemical transport model, Model for Ozone and Related Chemical Tracers version 4 (MOZART v4), and a Bayesian inverse method to estimate global as well as regional annual emissions. Our inversion indicates that the global HCFC-22 emissions have an increasing trend between 1995 and 2009. We further find a surge in HCFC-22 emissions between 2005 and 2009 from developing countries in Asia – the largest emitting region including China and India. Globally, substantial emissions continue despite production and consumption being phased out in developed countries currently.
Since the successful introduction of checkpoint inhibitors targeting the adaptive immune system, monoclonal antibodies inhibiting CD47-SIRPα interaction have shown promise in enhancing anti-tumor ...treatment efficacy. Apart from SIRPα, neutrophils express a broad repertoire of inhibitory receptors, including several members of the sialic acid-binding receptor (SIGLEC) family. Here, we demonstrate that interaction between tumor cell-expressed sialic acids and SIGLEC-5/14 on neutrophils inhibits antibody-dependent cellular cytotoxicity (ADCC). We observed that conjugate formation and trogocytosis, both essential processes for neutrophil ADCC, were limited by the sialic acid-SIGLEC-5/14 interaction. During neutrophil-tumor cell conjugate formation, we found that inhibition of the interaction between tumor-expressed sialic acids and SIGLEC-5/14 on neutrophils increased the CD11b/CD18 high affinity conformation. By dynamic acoustic force measurement, the binding between tumor cells and neutrophils was assessed. The interaction between SIGLEC-5/14 and the sialic acids was shown to inhibit the CD11b/CD18-regulated binding between neutrophils and antibody-opsonized tumor cells. Moreover, the interaction between sialic acids and SIGLEC-5/14-consequently hindered trogocytosis and tumor cell killing. In summary, our results provide evidence that the sialic acid-SIGLEC-5/14 interaction is an additional target for innate checkpoint blockade in the tumor microenvironment.
Membrane cholesterol modulates a variety of cell signaling pathways and functions. While cholesterol depletion by high-density lipoproteins (HDLs) has potent anti-inflammatory effects in various cell ...types, its effects on inflammatory responses in macrophages remain elusive. Here we show overt pro-inflammatory effects of HDL-mediated passive cholesterol depletion and lipid raft disruption in murine and human primary macrophages in vitro. These pro-inflammatory effects were confirmed in vivo in peritoneal macrophages from apoA-I transgenic mice, which have elevated HDL levels. In line with these findings, the innate immune responses required for clearance of P. aeruginosa bacterial infection in lung were compromised in mice with low HDL levels. Expression analysis, ChIP-PCR, and combinatorial pharmacological and genetic intervention studies unveiled that both native and reconstituted HDL enhance Toll-like-receptor-induced signaling by activating a PKC-NF-κB/STAT1-IRF1 axis, leading to increased inflammatory cytokine expression. HDL’s pro-inflammatory activity supports proper functioning of macrophage immune responses.
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•HDLs exert pro-inflammatory effects on mouse (in vitro and in vivo) and human macrophages•Passive rather than active cholesterol depletion by HDL enhances TLR responses•HDL modulates cytokine production by activating PKC-NF-κB/STAT1 signaling•Mice with low HDL levels show delayed and defective innate immune responses
Van der Vorst et al. reveal overt pro-inflammatory effects of HDL, mediated by passive cholesterol depletion and activation of a PKC-NF-κB/STAT1-IRF axis, on murine and human macrophages. HDL pro-inflammatory activity helps macrophages maintain efficient innate immune responses to Gram-negative P. aeruginosa infection.
Abstract Objective This study was performed to determine whether satellite LVSI in women with early stage cervical carcinoma is an independent prognostic factor for recurrence and survival. Methods A ...total of 210 eligible patients with FIGO stages IA2 and IB1 cervical carcinoma, who underwent radical hysterectomy or radical trachelectomy with pelvic lymphadenectomy between January 2000 and December 2012, were included. Variables studied included age, histology type, differentiation grade, tumor size (TS), depth of invasion (DI), lymph node metastasis (LNM), conjoined lymphovascular space invasion (LVSI) and satellite LVSI. Univariate and multivariate analyses were performed to define variables that best predict recurrence and survival. Results Univariate analysis showed that differentiation grade, depth of invasion, tumor size, lymph node metastasis, and both conjoined LVSI and satellite LVSI were significantly associated with recurrence and survival. Using multivariate analysis, differentiation grade (HR 3.63, 95%-CI 1.51–8.72), conjoined LVSI (HR 5.95, 95%-CI 1.57–22.53) and satellite LVSI (HR 7.45, 95%-CI 3.03–18.27) were independent prognostic factors for recurrence; LNM (HR 5.55, 95%-CI 1.52–20.26) and satellite LVSI (HR 8.94, 95%-CI 2.43–32.95) were prognostic factors for overall survival. For patients with low-risk cervical cancer without LNM only satellite LVSI correlated significantly with disease-free and overall survival. Conclusion Differentiation grade, DI, TS, LNM, and conjoined LVSI as well as satellite LVSI were prognostic factors for DFS and OS. Satellite LVSI is the most important factor predicting DFS and OS in early stage cervical cancer, especially when lymph nodes are negative.
An expedient, high-yielding synthesis of two types of triazole-linked glycopeptides is described. These novel and stable glycopeptide mimics were prepared via Cu(I)-catalyzed 3 + 2 cycloaddition of ...either azide-functionalized glycosides and acetylenic amino acids or acetylenic glycosides and azide-containing amino acids.
Diet plays a pivotal role in the onset and progression of Crohn's disease (CD). Nutritional interventions revealed effects on intestinal inflammation and gut microbial composition. However, data from ...well-designed and controlled dietary trials are lacking. Therefore, evidence-based dietary recommendations are still unavailable to patients and physicians. Here, we aim to investigate the effects of an evidence-based anti-inflammatory diet, and an ileocolonic-targeted capsule containing vitamin B
, B
and C (ColoVit) on patients with CD and their healthy household members.
In this multicentre, randomised, placebo-controlled, partially blinded nutritional intervention trial, we aim to recruit 255 CD patients with Harvey-Bradshaw Index <8 and a faecal calprotectin (FCal) cut-off of ≥100 µg/g at baseline. Participants will be randomised into two experimental intervention groups and one placebo group. In the experimental groups, participants will either adhere to the Groningen anti-inflammatory diet (GrAID) or ingest an ileocolonic-delivered oral vitamin B
/B
/C capsule (ColoVit). The study consists of a 12-week controlled interventional phase, which proceeds to a 9-month observational follow-up phase in which patients allocated to the GrAID group will be requested to continue the intervention on their own accord. Household members of participating patients will be asked to participate in the trial as healthy subjects and are allocated to the same group as their peer. The primary study outcome for patients is the change in FCal level from baseline. The primary outcome for household members is the change in gut microbial composition, which is set as secondary outcome for patients.
The protocol has been approved by the Institutional Review Board of the Stichting Beoordeling Ethiek Biomedisch Onderzoek in Assen, the Netherlands. Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed journals and conference presentations.
NCT04913467.
Holocene oceanographic conditions in Disko Bay, West Greenland, were reconstructed from high‐resolution diatom records derived from two marine sediment cores. A modern data set composed of 35 dated ...surface sediment samples collected along the West Greenland coast accompanied by remote sensing data was used to develop a diatom transfer function to reconstruct April sea ice concentration (SIC) supported by July sea surface temperature (SST) in the area. Our quantitative reconstruction shows that oceanographic changes recorded throughout the last ~11,000 years reflect seasonal interplay between spring (April SIC) and summer (July SST) conditions. Our records show clear correlation with climate patterns identified from ice core data from GISP2 and Agassiz‐Renland for the early to middle Holocene. The early Holocene deglaciation of western Greenland Ice Sheet was characterized in Disko Bay by initial strong centennial‐scale fluctuations in April SIC with amplitude of over 40%, followed by high April SIC and July SST. These conditions correspond to a general warming of the climate in the Northern Hemisphere. A decrease in April SIC and July SST was recorded during the Holocene Thermal Optimum reflecting more stable spring‐summer conditions in Disko Bay. During the late Holocene, high April SIC characterized the Medieval Climate Anomaly, while high July SST prevailed during the Little Ice Age, supporting previously identified antiphase relationship between surface waters in West Greenland and climate in NW Europe. This antiphase pattern might reflect seasonal variations in regional oceanographic conditions and large‐scale fluctuations within the North Atlantic Oscillation and Atlantic Meridional Overturning Circulation.
Key Points
The West Greenland surface sediments were quality‐checked regarding “modern” age using radionuclide measurements
Sea ice and sea surface temperature (SST) transfer functions were developed from the modern diatom data set
April Sea Ice Concentration and July SST were reconstructed in Disko Bay for the past circa 11000 years
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