The analgesic effects of sigma-1 antagonists are undisputed, but the effects of sigma-1 agonists on pain are not well studied. Here, we used a mouse model to show that the administration of the ...sigma-1 agonists dextromethorphan (a widely used antitussive drug), PRE-084 (a standard sigma-1 ligand), and pridopidine (a selective drug being investigated in clinical trials for the treatment of neurodegenerative diseases) enhances PGE2-induced mechanical hyperalgesia. Superficial plantar incision induced transient weight-bearing asymmetry at early time points, but the mice appeared to recover at 24 h, despite noticeable edema and infiltration of neutrophils (a well-known cellular source of PGE2) at the injured site. Sigma-1 agonists induced a relapse of weight bearing asymmetry in a manner dependent on the presence of neutrophils. The effects of sigma-1 agonists were all reversed by administration of the sigma-1 antagonist BD-1063 in wild-type mice, and were absent in sigma-1 knockout mice, supporting the selectivity of the effects observed. The proalgesic effects of sigma-1 agonism were also abolished by the TRP antagonist ruthenium red and by in vivo resiniferatoxin ablation of TRPV1 + peripheral sensory neurons. Therefore, sigma-1 agonism exacerbates pain-like responses in mice with a mild inflammatory state through the action of TRPV1 + nociceptors. We also show that sigma-1 receptors are present in most (if not all) mouse and human DRG neurons. If our findings translate to humans, further studies will be needed to investigate potential proalgesic effects induced by sigma-1 agonism in patients treated with sigma-1 agonists.
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•Sigma-1 agonism potentiates PGE2-induced hyperalgesia.•Sigma-1 agonism enhances pain responses after plantar incision–induced inflammation.•These responses are due to an increase in the proalgesic actions of neutrophils.•The proalgesic actions of sigma-1 agonists are mediated by TRPV1 + neurons.•The sigma-1 receptor is present in all mouse and human DRG neurons.
This paper presents a new predictive current control for three-phase grid-connected inverters in the synchronous reference frame. The control combines a deadbeat control law with a diagonal ...Luenberger observer to estimate the future value of the grid currents. It provides a decoupled control of the active and reactive power and offers robustness against the computational delay inherent in the digital implementation and against filter and grid-impedance uncertainties. This control exhibits a very fast current response while widely improving the gain and phase margins of the traditional predictive controllers.
Evidence for a protective role of physical activity against development of stomach cancer is yet inconclusive. We studied the association of domain-specific physical activity and the risk of gastric ...adenocarcinoma (GAC), by site and histology, in the MCC-Spain case-control study.
428 histologically confirmed GAC cases (67% men) including the gastro-esophageal region and 3225 controls were included. Cases were recruited in hospitals from 10 different Spanish regions, whereas population controls were randomly selected within the respective hospitals' catchment areas. A physical activity (PA) questionnaire was used to gather information on household and recreational activities, allowing estimation of PA volume (in metabolic equivalents (MET)-min/week). Participants also reported the intensity of working PA and daily sitting time. Questionnaire data on diet, lifestyles and clinical variables including Helicobacter pylori serology were available. Adjusted odds ratios (OR) of GAC were estimated for domains of physical activity, stratifying by sex, site (cardia vs. non-cardia), and Lauren classification (intestinal vs. diffuse).
Household physical activity (HPA) showed a strong inverse association with GAC, observed for both cardia and non-cardia tumours. Risk of overall gastric cancer was 50% lower risk among participants in the highest HPA category (OR = 0.50, 95%CI: 0.38, 0.66). Recreational physical activity (RPA) was also associated with lower overall GAC risk (OR = 0.68, 95% CI: 0.52, 0.88), particularly at moderate levels of intensity such as walking (OR = 0.61, 95% CI: 0.46, 0.79). The protective effect of RPA was strongest for non-cardia tumours. Sedentary time was not related to GAC risk (p-trend = 0.392), but the potential protective effect of RPA was restricted to non-sedentary participants.
Both household and recreational physical activities were independently related to lower GAC risk in the MCC-Spain study.
ABSTRACT
Vibrio parahaemolyticus has been recognized as the causal agent of early mortality syndrome and is currently considered an emerging shrimp disease causing losses of millions in the ...aquaculture industry. Integral membrane proteins are widely recognized as pathogenicity factors involved in essential mechanisms for V. parahaemolyticus infection, which makes them attractive as therapeutic targets. However, their physico‐chemical properties and weak expression has resulted in under‐representation of these proteins in conventional bottom‐up proteomics, making integral membrane proteomics a challenging task. Integral membrane proteins from a bacterial strain isolated from the hepatopancreases of white shrimp with early mortality syndrome and identified by 16S rRNA sequencing as V. parahaemolyticus and an ATCC strain that is pathogenic for humans were obtained by a sequential extraction method and subjected to relative quantification and identification by isobaric Tags for Relative and Absolute Quantitation. A homology database search resulted in identification of more than two hundred proteins, 35 of which are recognized as pathogenic factors showed statistically significant differential accumulation between the strains. These proteins are mainly associated with adherence, secretion systems, cell division, transport, lysogenization, movement and virulence. Identification of pathogenicity‐related proteins in V. parahaemolyticus provides valuable information for developing strategies based on molecular mechanisms that inhibit these proteins, which may be useful therapeutic targets for assisting the shrimp and aquaculture industry.
Proinflammatory diets are associated with risk of developing colorectal cancer (CRC), however, inconsistencies exist in subsite‐ and sex‐specific associations. The relationship between CRC and ...combined lifestyle‐related factors that contribute toward a low‐grade inflammatory profile has not yet been explored. We examined the association between the dietary inflammatory potential and an inflammatory profile and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. This cohort included 476,160 participants followed‐up of 14 years and 5,991 incident CRC cases (3,897 colon and 2,094 rectal tumors). Dietary inflammatory potential was estimated using an Inflammatory Score of the Diet (ISD). An Inflammatory Profile Score (IPS) was constructed, incorporating the ISD, physical activity level and abdominal obesity. The associations between the ISD and CRC and IPS and CRC were assessed using multivariable regression models. More proinflammatory diets were related to a higher CRC risk, particularly for colon cancer; hazard ratio (HR) for highest versus lowest ISD quartile was 1.15 (95% confidence interval CI 1.04–1.27) for CRC, 1.24 (95% CI 1.09–1.41) for colon cancer and 0.99 (95% CI 0.83–1.17) for rectal cancer. Associations were more pronounced in men and not significant in women. The IPS was associated with CRC risk, particularly colon cancer among men; HRs for the highest versus lowest IPS was 1.62 (95% CI 1.31–2.01) for colon cancer overall and 2.11 (95% CI 1.50–2.97) for colon cancer in men. Our study shows that more proinflammatory diets and a more inflammatory profile are associated with higher risk of CRC, principally colon cancer and in men.
What's new?
Chronic inflammation has been implicated in colorectal cancer (CRC), and diet plays an important role in modulating systemic inflammation. Two additional factors that contribute to chronic inflammation and also increase CRC risk are adiposity and lack of physical activity. In this large prospective study, the authors gained further insight into these relationships. They found that pro‐inflammatory diets and a higher Inflammatory Profile Score (IPS, based on diet, physical activity, and abdominal obesity) are strong predictors of CRC, but principally of colon cancer and especially in men.
Recently, some US cohorts have shown a moderate association between red and processed meat consumption and mortality supporting the results of previous studies among vegetarians. The aim of this ...study was to examine the association of red meat, processed meat, and poultry consumption with the risk of early death in the European Prospective Investigation into Cancer and Nutrition (EPIC).
Included in the analysis were 448,568 men and women without prevalent cancer, stroke, or myocardial infarction, and with complete information on diet, smoking, physical activity and body mass index, who were between 35 and 69 years old at baseline. Cox proportional hazards regression was used to examine the association of meat consumption with all-cause and cause-specific mortality.
As of June 2009, 26,344 deaths were observed. After multivariate adjustment, a high consumption of red meat was related to higher all-cause mortality (hazard ratio (HR) = 1.14, 95% confidence interval (CI) 1.01 to 1.28, 160+ versus 10 to 19.9 g/day), and the association was stronger for processed meat (HR = 1.44, 95% CI 1.24 to 1.66, 160+ versus 10 to 19.9 g/day). After correction for measurement error, higher all-cause mortality remained significant only for processed meat (HR = 1.18, 95% CI 1.11 to 1.25, per 50 g/d). We estimated that 3.3% (95% CI 1.5% to 5.0%) of deaths could be prevented if all participants had a processed meat consumption of less than 20 g/day. Significant associations with processed meat intake were observed for cardiovascular diseases, cancer, and 'other causes of death'. The consumption of poultry was not related to all-cause mortality.
The results of our analysis support a moderate positive association between processed meat consumption and mortality, in particular due to cardiovascular diseases, but also to cancer.
To study whether the consumption of ultra-processed foods and drinks is associated with breast, colorectal, and prostate cancers.
Multicentric population-based case-control study (MCC-Spain) ...conducted in 12 Spanish provinces. Participants were men and women between 20 and 85 years of age with diagnoses of colorectal (n = 1852), breast (n = 1486), or prostate cancer (n = 953), and population-based controls (n = 3543) frequency-matched by age, sex, and region. Dietary intake was collected using a validated food frequency questionnaire. Foods and drinks were categorized according to their degree of processing based on the NOVA classification. Unconditional multivariable logistic regression was used to evaluate the association between ultra-processed food and drink consumption and colorectal, breast, and prostate cancer.
In multiple adjusted models, consumption of ultra-processed foods and drinks was associated with a higher risk of colorectal cancer (OR for a 10% increase in consumption: 1.11; 95% CI 1.04–1.18). The corresponding odds for breast (OR 1.03; 95% CI 0.96–1.11) and prostate cancer (OR 1.02; 95% CI 0.93–1.12) were indicative of no association.
Results of this large population-based case-control study suggest an association between the consumption of ultra-processed foods and drinks and colorectal cancer. Food policy and public health should include a focus on food processing when formulating dietary guidelines.
Sustained B-cell activation is an important mechanism contributing to B-cell lymphoma (BCL). We aimed to validate four previously reported B-cell activation markers predictive of BCL risk (sCD23, ...sCD27, sCD30, and CXCL13) and to examine their possible mediating effects on the association between anthropometric and lifestyle factors and major BCL subtypes. Pre-diagnostic serum levels were measured for 517 BCL cases and 525 controls in a nested case-control study. The odds ratios of BCL were 6.2 in the highest versus lowest quartile for sCD23, 2.6 for sCD30, 4.2 for sCD27, and 2.6 for CXCL13. Higher levels of all markers were associated with increased risk of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). Following mutual adjustment for the other immune markers, sCD23 remained associated with all subtypes and CXCL13 with FL and DLBCL. The associations of sCD23 with CLL and DLBCL and CXCL13 with DLBCL persisted among cases sampled > 9 years before diagnosis. sCD23 showed a good predictive ability (area under the curve = 0.80) for CLL, in particular among older, male participants. sCD23 and CXCL13 showed a mediating effect between body mass index (positive) and DLBCL risk, while CXCL13 contributed to the association between physical activity (inverse) and DLBCL. Our data suggest a role of B-cell activation in BCL development and a mediating role of the immune system for lifestyle factors.
This paper presents a new predictive control algorithm for grid-connected current-controlled inverters. The control combines a two-sample deadbeat control law with a Luenberger observer to estimate ...the future value of the grid currents. The resulting control offers robustness against the computational delay inherent in the digital implementation and considerably enhances the gain and phase margins of the previous predictive controls while maintaining the high-speed response typical of the deadbeat controllers.
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