Involvement of Hypoxia-Inducible Factor-1 in the Inflammatory Responses of Human LAD2 Mast Cells and Basophils

We recently showed that hypoxia-inducible factor 1 (HIF-1) plays a crucial role in the pro-allergic functions of human basophils by transcriptional control of energy metabolism via glycolysis as well as directly triggering expression of the angiogenic cytokine vascular endothelium growth factor (VEGF). Here, we investigated HIF-1 involvement in controlling the synthesis of angiogenic and inflammatory cytokines from various human effector cells stimulated by IgE-dependent or innate immune triggers. Purified primary human basophils, LAD2 human mast cells and THP-1 human myeloid cells were used for investigations of FcεRI and Toll-like receptor (TLR) ligand-induced responses. In contrast to basophils, LAD2 mast cells expressed background levels of HIF-1α, which was largely independent of the effects of stem cell factor (SCF). Both mast cells and basophils expressed TLR2 and 4, albeit weakly compared to THP-1 cells. Cytokine production in mast cells following TLR ligand stimulation was markedly reduced by HIF-1α knockdown in LAD2 mast cells. In contrast, although HIF-1 is involved in IgE-mediated IL-4 secretion from basophils, it is not clearly induced by peptidoglycan (PGN). HIF-1α accumulation is critical for sustaining human allergic effector cell survival and function. This transcription complex facilitates generation of both pro-angiogenic and inflammatory cytokines in mast cells but has a differential role in basophil stimulation comparing IgE-dependent triggering with innate immune stimuli

CONCEPTT: Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial: A multi-center, multi-national, randomized controlled trial - Study protocol.

BACKGROUND: Women with type 1 diabetes strive for optimal glycemic control before and during pregnancy to avoid adverse obstetric and perinatal outcomes. For most women, optimal glycemic control is challenging to achieve and maintain. The aim of this study is to determine whether the use of real-time continuous glucose monitoring (RT-CGM) will improve glycemic control in women with type 1 diabetes who are pregnant or planning pregnancy. METHODS/DESIGN: A multi-center, open label, randomized, controlled trial of women with type 1 diabetes who are either planning pregnancy with an HbA1c of 7.0 % to ≤10.0 % (53 to ≤ 86 mmol/mol) or are in early pregnancy (<13 weeks 6 days) with an HbA1c of 6.5 % to ≤10.0 % (48 to ≤ 86 mmol/mol). Participants will be randomized to either RT-CGM alongside conventional intermittent home glucose monitoring (HGM), or HGM alone. Eligible women will wear a CGM which does not display the glucose result for 6 days during the run-in phase. To be eligible for randomization, a minimum of 4 HGM measurements per day and a minimum of 96 hours total with 24 hours overnight (11 pm-7 am) of CGM glucose values are required. Those meeting these criteria are randomized to RT- CGM or HGM. A total of 324 women will be recruited (110 planning pregnancy, 214 pregnant). This takes into account 15 and 20 % attrition rates for the planning pregnancy and pregnant cohorts and will detect a clinically relevant 0.5 % difference between groups at 90 % power with 5 % significance. Randomization will stratify for type of insulin treatment (pump or multiple daily injections) and baseline HbA1c. Analyses will be performed according to intention to treat. The primary outcome is the change in glycemic control as measured by HbA1c from baseline to 24 weeks or conception in women planning pregnancy, and from baseline to 34 weeks gestation during pregnancy. Secondary outcomes include maternal hypoglycemia, CGM time in, above and below target (3.5-7.8 mmol/l), glucose variability measures, maternal and neonatal outcomes. DISCUSSION: This will be the first international multicenter randomized controlled trial to evaluate the impact of RT- CGM before and during pregnancy in women with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01788527 Registration Date: December 19, 2012

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research

Cortical sensory suppression during arousal is due to the activity-dependent depression of thalamocortical synapses

The thalamus serves as a gate that regulates the flow of sensory inputs to the neocortex, and this gate is controlled by neuromodulators from the brainstem reticular formation that are released during arousal. Here we show in rats that sensory-evoked responses were suppressed in the neocortex by activating the brainstem reticular formation and during natural arousal. Sensory suppression occurred at the thalamocortical connection and was a consequence of the activity-dependent depression of thalamocortical synapses caused by increased thalamocortical tonic firing during arousal. Thalamocortical suppression may serve as a mechanism to focus sensory inputs to their appropriate representations in neocortex, which is helpful for the spatial processing of sensory information

An overview of twenty years of research at the Faculty of Forestry and Environmental Management, University of New Brunswick, Canada on fuel moisture estimation using optical, thermal infrared and radar remote sensing in boreal forests in Alberta, the Northwest Territories, and Alaska.

This paper presents an overview of 20 years of research at the Faculty of Forestry and Environmental Management, University of New Brunswick, Canada, on fuel moisture estimation using optical, thermal infrared and radar remote sensing in the boreal forests of Alberta, the Northwest Territories, and Alaska. In collaboration with Canadian Forest Service (CFS), the first studies tested the use of NOAA-AVHRR NDVI and surface temperature images over the boreal forests of the Northwest Territories and Alberta. Over the boreal forests in the Northwest Territories, we observed that mean surface temperature values increased as ignition dates approached and high fire weather index (FWI) areas corresponded to high surface temperature values (Oldford et al. 2003). A modelling approach showed that FWI was related to the ratio between actual and potential evapotranspirations estimated from NOAA-AVHRR images (Strickland et al. 2001). Over boreal forests in Alberta, significant relationships were established between the drought code (DC) and NOAA-AVHRR NDVI and surface temperature images, Satellite-based DC estimations were more reliable than weather station-based DC in the detection of fire starts (Oldford et al. 2006). More recently, SAR images from ERS-1 C-VV (Leblon et al. 2002) and RADSARSAT-1 C-HH (Abbott et al. 2007) were tested over forests in the Northwest Territories for the estimation of fuel moisture codes such as DC and FWI. Relationships with foliar moisture content (FMC) were also established. These studies also showed that biomass and canopy had an influence on the moisture code or FMC estimation. Finally, over a chronosequence of Alaskan boreal black spruce ecosystems (recent burns, regenerating forests dominated by shrubs, open canopied and moderately dense forest cover), RADARSAT-2 and ALOS-PALSAR polarimetric images were tested to assess DC variations (Bourgeau-Chavez et al. 2013a). Several polarimetric variables from a multi-date RADARSAT-2 C-band image sequence that were acquired across a range of soil moisture conditions were used to develop empirical algorithms to estimate volumetric soil moisture maps over the Alaskan boreal test area (Bourgeau-Chavez et al. 2013b). A mean error of 6.7 % between observed and estimated values was achieved through a regression model that used the C-VH backscatter intensity, the maximum of degree of polarization (dmax) and the maximum of the completely unpolarised component (Unpolmax) as independent variables. The model also showed improvement from 27% to 33% in the accuracy of the soil volumetric moisture content retrieval by comparison with a model that used only single polarized C-HH data. By providing information on surface roughness and/or biomass, dmax appeared to be helpful for extracting surface soil moisture from SAR data. So far, only empirical relationships have been established and a more deterministic approach still needs to be developed. The various studies were funded by NSERC. ERS-1/2 images were provided by the European Space Agency, RADARSAT-1 and-2 images were provided by the Canadian Space Agency. ALOS-PALSAR images were provided by the Japanese Space Agency