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Background: Oxidative stress is thought to be related to many diseases. Furthermore, it is hypothesized that radiofrequency electromagnetic fields (RF-EMF) may induce excessive oxidative stress in various cell types and thereby have the potential to compromise human and animal health. The objective of this systematic review (SR) is to summarize and evaluate the literature on the relation between the exposure to RF-EMF in the frequency range from 100 kHz to 300 GHz and biomarkers of oxidative stress. Methods: The SR framework was developed following the guidelines established in the WHO Handbook for Guideline Development and NTP/OHAT’s Handbook for Conducting a Literature-Based Health Assessment. We used the latter handbook’s methodology for implementing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for environmental health assessments.We searched the following databases up until June 30, 2023: PubMed, Embase, Web of Science Core Collection, Scopus, and the EMF-Portal. The reference lists of included studies and retrieved review articles were also manually searched.We rated Risk of Bias (RoB) using the OHAT RoB Rating Tool and assessed publication bias using funnel plots of included studies. We assessed the certainty of the evidence (high, moderate, low, or very low) for an association between RF-EMF and oxidative stress using an adapted version of the GRADE framework.Data were extracted according to a predefined set of forms developed in DistillerSR.Data were analysed after grouping them first as in vitro or in vivo and then according to outcome category, species category, and exposed tissue. We synthesized study results using a random effects meta-analysis when study characteristics were judged sufficiently similar to be combined and heterogeneity (I2) was lower than 75 %, otherwise we describe the findings narratively. Results: Fifty-six (56) studies, 45 in vivo and 11 in vitro, in which cells (in vitro) or animals (in vivo) were exposed to frequencies in the range 800–2450 MHz, were included in the systematic review after eliminating 12,353 publications because they did not meet the criteria defined in the published protocol (Henschenmacher et al., 2022). Of 56 studies 52 studies with 169 individual results were included in the meta-analysis. Together, these studies examined six human in vitro samples and fifty animal samples, including rodents (mice, rats, hamsters, and guinea pigs, (n = 46)) and rabbits (n = 4). RF-EMF were predominantly applied as continuous wave exposures in these studies. The outcome biomarkers for modified proteins and amino acids were measured in n = 30 studies, for oxidized DNA bases in n = 26 studies, for oxidized lipids in n = 3 studies and hydrogen peroxide production in 2 studies. Outcomes were mostly measured in the brain (n = 22), liver (n = 9), cells (n = 9), blood (n = 6), and testis (n = 2). RoB in studies was high, mainly due to biases in exposure and outcome assessment. In vivo studies: Brain: The effect on biomarkers for oxidized DNA bases in the rodent brain (five studies, n = 98) had an inconsistent effect, varying from a large decrease with a standardized mean difference (SMD) of −3.40 (95 % CI [−5.15, −1.64]) to a large increase with an SMD of 2.2 (95 % CI [0.78, 3.62]). In the brain of rabbits (two studies, n = 44), the effect sizes also varied, from an SMD of −1.06 (95 % CI [−2.13, 0.00]) to an SMD of 5.94 (95 % CI [3.14, 8.73]). The effect on biomarkers for modified proteins and amino acids in the rodent brain (15 studies, n = 328) also varied from a large decrease with an SMD of −6.11 (95 % CI [−8.16, −4.06]) to a large increase with an SMD of 5.33 (95 % CI [2.49, 8.17]).The effect on biomarkers for oxidized lipids in the brain of rodents (one study, n = 56) also varied from a large decrease with SMD = −4.10 (95 % CI [−5.48, −2.73]) to SMD = 1.27 (95 % CI [0.45, 2.10]).Liver: The effect on biomarkers for oxidized DNA bases in the rodent liver (two studies, n = 26) was inconsistent with effect sizes in both directions: SMD = −0.71 (95 % CI [−1.80, 0.38]) and SMD = 1.56 (95 % CI [0.19, 2.92]). The effect on biomarkers for oxidized DNA bases in the rabbits’ liver (two studies, n = 60) was medium with a pooled SMD of 0.39 (95 % CI [−0.79, 1.56]).Biomarkers for modified proteins and amino acids in the liver of rodents (six studies, n = 159) increased with a pooled SMD of 0.55 (95 % CI [0.06, 1.05]).Blood: The effect of RF-EMF on biomarkers for oxidized DNA bases in rodent blood (four studies, n = 104) was inconsistent, with SMDs ranging from −1.14 (95 % CI [−2.23, −0.06]) to 1.71 (95 % CI [−0.10, 3.53]).RF-EMF had no effect on biomarkers for modified proteins and amino acids in rodent blood (three studies, n = 40), with a pooled SMD of −0.08 (95 % CI [−1.32, 1.16]).There was a large increase in biomarkers for oxidized DNA bases in rodent plasma (two studies, n = 38) with a pooled SMD of 2.25 (95 % CI [1.27, 3.24]).Gonads: There was an increase in biomarkers for oxidized DNA bases in the rodent testis (two studies, n = 24) with a pooled SMD of 1.60 (95 % CI [0.62, 2.59]).The effect of RF-EMF on biomarkers for modified proteins and amino acids in the ovary of rodents (two studies, n = 52) was inconsistent with a medium effect, SMD = 0.24 (95 % CI [−0.74, 1.23])) and a large effect (SMD = 2.08 (95 % CI [1.22, 2.94])).Thymus: RF-EMF increased biomarkers for modified proteins and amino acids in the thymus of rodents (one study, n = 42) considerably with a pooled SMD of 6.16 (95 % CI [3.55, 8.76]).Cells: RF-EMF increased oxidized DNA bases in rodent cells with SMD of 2.49 (95 % CI [1.30, 3.67]) (one study, n = 27). There was a medium effect in oxidized lipids (one study, n = 18) but not statistically significant with SMD = 0.34 (95 % CI [−0.62, 1.29]). In vitro studies: In in vitro studies in human cells (three studies, n = 110), there were inconsistent increases in biomarkers for oxidized DNA bases, where the SMDs varied between 0.01 (95 % CI [−0.59, 0.62]) and 7.12 (95% CI [0.06, 14.18]) in 4 results (2 of them statistically significant). In rodent cells (three studies, n = 24), there was a not statistically significant large effect in biomarkers for oxidized DNA bases with SMD = 2.07 (95 % CI [−1.38, 5.52]).The RF-EMF biomarkers for modified proteins and amino acids in human cells (one study, n = 18) showed a large effect with SMD = 1.07 (95 % CI [−0.05, 2.19]). In rodent cells (two studies, n = 24) a medium effect of SMD = 0.56 (95 % CI [−0.29, 1.41]) was observed. Discussion: The evidence on the relation between the exposure to RF-EMF and biomarkers of oxidative stress was of very low certainty, because a majority of the included studies were rated with a high RoB level and provided high heterogeneity. This is due to inaccurate measurements of exposure and/or of measurement of oxidative stress biomarkers and missing information on the blinding of research personnel to exposure conditions or outcome measurements. There may be no or an inconsistent effect of RF-EMF on biomarkers of oxidative stress in the brain, liver, blood, plasma and serum, and in the female reproductive system in animal experiments but the evidence is of very low certainty. There may be an increase in biomarkers of oxidative stress in testes, serum and thymus of rodents but the evidence is of very low certainty. Future studies should improve experimental designs and characterization of exposure systems as well as the use of validated biomarker measurements with positive controls.Other: This review was partially funded by the World Health Organization.The protocol for this review is registered in PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021235573) and published in Environment International (https://doi.org/10.1016/j.envint.2021.106932) (Henschenmacher et al., 2022).

BackgroundThe COVID-19 pandemic propelled immunology into global news and social media, resulting in the potential for misinterpreting and misusing complex scientific concepts.ObjectiveTo study the extent to which immunology is discussed in news articles and YouTube videos in English and Italian, and if related scientific concepts are used to support specific political or ideological narratives in the context of COVID-19.MethodsIn English and Italian we searched the period 11/09/2019 to 11/09/2022 on YouTube, using the software Mozdeh, for videos mentioning COVID-19 and one of nine immunological concepts: antibody-dependent enhancement, anergy, cytokine storm, herd immunity, hygiene hypothesis, immunity debt, original antigenic sin, oxidative stress and viral interference. We repeated this using MediaCloud for news articles.Four samples of 200 articles/videos were obtained from the randomised data gathered and analysed for mentions of concepts, stance on vaccines, masks, lockdown, social distancing, and political signifiers.ResultsVaccine-negative information was higher in videos than news (8-fold in English, 6-fold in Italian) and higher in Italian than English (4-fold in news, 3-fold in videos). We also observed the existence of information bubbles, where a negative stance towards one intervention was associated with a negative stance to other linked ideas. Some immunological concepts (immunity debt, viral interference, anergy and original antigenic sin) were associated with anti-vaccine or anti-NPI (non-pharmacological intervention) views. Videos in English mentioned politics more frequently than those in Italian and, in all media and languages, politics was more frequently mentioned in anti-guidelines and anti-vaccine media by a factor of 3 in video and of 3–5 in news.ConclusionThere is evidence that some immunological concepts are used to provide credibility to specific narratives and ideological views. The existence of information bubbles supports the concept of the “rabbit hole” effect, where interest in unconventional views/media leads to ever more extreme algorithmic recommendations.

Abstract Background There is a growing literature on the potential medical uses of Cannabis sativa and cannabinoid compounds. Although these have only been approved by regulatory agencies for a few indications, there is a hype about their possible benefits in a variety of conditions and a large market in the wellness industry. As in many cases patients search for information on cannabis products online, we have analyzed the information on medical cannabis available on the Internet. Therefore, this study aims at assessing the quality of the information available online on medical cannabis. Methods We searched “medical cannabis” on June 2019 using google.com and downloaded the first 243 websites. After excluding dead links or websites with no information about cannabis, 176 websites were included. They were then classified for their typology (e.g., commercial, government, news outlets). As an indicator of trustworthiness, we used the Journal of American Medical Association (JAMA) score, which assesses the indication of date, author, ownership of the website, and the presence of references. We also considered if a website is certified by Health-On-the-Net (HON), an independent organization, by displaying a HONCode symbol. Subsequently, we performed a content analysis to assess both the medical cannabis indications mentioned by webpages and the completeness of the information provided (whether they mentioned potential side effects and legal/regulatory issues or not). Results Analyzing 176 webpages returned by a search engine, we found that 52% of them were news websites. Pain, epilepsy, and multiple sclerosis were the most frequently mentioned therapeutic areas (cited in 92, 84 and 80 webpages, respectively), which did not always match those for which there is regulatory approval. Information was also incomplete, with only 22% of the webpages mentioning potential side effects. Health portal websites provided the most complete information, with all of them (n = 7) reporting side effects. On average, 80% of webpages had a neutral stance on the potential benefits of medical cannabis, with commercial websites having more frequently a positive stance (67%). Conclusions We conclude that the information that can be found online is not always aligned in terms of the therapeutic areas for which science-based evidence is often still weak.

This Perspective highlights the work of Dr. Daniela Novick in the field of cytokine biology. Using affinity chromatography to characterize cytokine-binding proteins, she identified soluble forms of the receptors as well as binding proteins for several cytokines, including tumor necrosis factor, interleukin (IL) 6, IL-18 and IL-32. Importantly, her work has been key in the development of monoclonal antibodies against interferons and cytokines. This Perspective discusses her contribution to the field and highlights her recent review on this topic.

Objective: There is an association between frailty and arterial stiffness. However, arterial stiffness does not uniformly correlate with the spectrum of frailty states. Both oxidative stress and inflammaging contribute to vascular ageing. There are no human studies exploring links between arterial stiffness, oxidative stress, inflammaging and frailty. Our objective is to investigate arterial stiffness and inflammaging as predictors of frailty states. Methods: An observational longitudinal cohort study will be used to examine the association between arterial stiffness, oxidative stress and inflammation in 50 older adults (⩾70 years) with clinical frailty scores (CFS) ⩽6 over 6 months. All study measurements will be taken at baseline. Frailty assessment will include hand-grip strength, timed-up and go test, mini-mental state examination, geriatric depression scale and sarcopenia using body composition measurements with Tanita ® . Arterial stiffness measurements will include carotid-femoral pulse wave velocity (cfPWV) and carotid-radial pulse wave velocity (crPWV) using Complior (Alam Medical, France). CAVI device will measure Cardio-ankle vascular index and ankle brachial index (ABI). Oxidative stress blood markers nitrotyrosine (NT) and 8-hydroxy-2’-deoxyguanosin (8-oxo-dG) and inflammation markers high-sensitive C-reactive protein (hs-CRP) and interlukin-6(IL-6) will be measured at baseline and 6 month along with lipid profile and glycated haemoglobin. Results (data analysis plan): Descriptive statistics for continuous data using means and standard deviations for normality distributed variables or medians and inter-quartile ranges for skewed variables will be used. Participants will be categorised into CFS 1-3, and CFS 4-6. Categorical data will use frequencies and comparison between groups. Change in frailty between the groups over 6 months will be compared using paired t-test. Simple linear regression will be done between frailty measures, arterial stiffness, inflammation and oxidative stress biomarkers. Significance will be at P < .05. Conclusion: This study data will inform a larger, multi-centre study exploring further the interplay between frailty, biomarkers and arterial stiffness parameters.

Abstract Background Vitamin D deficiency increases the risk of developing multiple sclerosis (MS) but it is unclear whether vitamin D supplementation improves the clinical course of MS, and there is uncertainty about the dose and form of vitamin D (D2 or D3) to be used. The mechanisms underlying the effects of vitamin D in MS are not clear. Vitamin D3 increases the rate of differentiation of primary oligodendrocyte precursor cells (OPCs), suggesting that it might help remyelination in addition to modulating the immune response. Here we analyzed the transcriptome of differentiating rat CG4 OPCs treated with vitamin D2 or with vitamin D3 at 24 h and 72 h following onset of differentiation. Methods Gene expression in differentiating CG4 cells in response to vitamin D2 or D3 was quantified using Agilent DNA microarrays (n = 4 replicates), and the transcriptome data were processed and analysed using the R software environment. Differential expression between the experimental conditions was determined using LIMMA, applying the Benjamini and Hochberg multiple testing correction to p-values, and significant genes were grouped into co-expression clusters by hierarchical clustering. The functional significance of gene groups was explored by pathway enrichment analysis using the clusterProfiler package. Results Differentiation alone changed the expression of about 10% of the genes at 72 h compared to 24 h. Vitamin D2 and D3 exerted different effects on gene expression, with D3 influencing 1272 genes and D2 574 at 24 h. The expression of the vast majority of these genes was either not changed in differentiating cells not exposed to vitamin D or followed the same trajectory as the latter. D3-repressed genes were enriched for Gene Ontology (GO) categories including transcription factors and the Notch pathway, while D3-induced genes were enriched for the Ras pathway. Conclusions This study shows that vitamin D3, compared with D2, changes the expression of a larger number of genes in OLs. Identification of genes affected by D3 in OLs should help to identify mechanisms mediating its action in MS.

Background: Oxidative stress is conjectured to be related to many diseases. Furthermore, it is hypothesized that radiofrequency fields may induce oxidative stress in various cell types and thereby compromise human and animal health. This systematic review (SR) aims to summarize and evaluate the literature related to this hypothesis. Objectives: The main objective of this SR is to evaluate the associations between the exposure to radiofrequency electromagnetic fields and oxidative stress in experimental models (in vivo and in vitro). Methods: The SR framework has been developed following the guidelines established in the WHO Handbook for Guideline Development and the Handbook for Conducting a Literature-Based Health Assessment). We will include controlled in vivo and in vitro laboratory studies that assess the effects of an exposure to RF-EMF on valid markers for oxidative stress compared to no or sham exposure. The protocol is registered in PROSPERO.We will search the following databases: PubMed, Embase, Web of Science Core Collection, Scopus, and the EMF-Portal. The reference lists of included studies and retrieved review articles will also be manually searched. Study appraisal and synthesis method: Data will be extracted according to a pre-defined set of forms developed in the DistillerSR online software and synthesized in a meta-analysis when studies are judged sufficiently similar to be combined. If a meta-analysis is not possible, we will describe the effects of the exposure in a narrative way. Risk of bias: The risk of bias will be assessed with the NTP/OHAT risk of bias rating tool for human and animal studies.We will use GRADE to assess the certainty of the conclusions (high, moderate, low, or inadequate) regarding the association between radiofrequency electromagnetic fields and oxidative stress. Funding: This work was funded by the World Health Organization (WHO). Registration: The protocol was registered on the PROSPERO webpage on July 8, 2021.

It is thought that excessive production of reactive oxygen species (ROS) can be a causal component in many diseases, some of which have an inflammatory component. This led to an oversimplification whereby ROS are seen as inflammatory and antioxidants anti-inflammatory. This paper aims at reviewing some of the literature on thiols in host defense. The review will first summarize the mechanisms by which we survive infections by pathogens. Then we will consider how the redox field evolved from the concept of oxidative stress to that of redox regulation and how it intersects the field of innate immunity. A third section will analyze how an oversimplified oxidative stress theory of disease led to a hypothesis on the role of ROS and glutathione (GSH) in immunity, respectively as pro- and anti-inflammatory mediators. Finally, we will discuss some recent research and how to think out of the box of that oversimplification and link the role of thiols in redox regulation to the mechanisms by which we survive an infection outlined in the first section.

Objective Countries have major differences in the acceptance of face mask use for the prevention of COVID-19. This work aims at studying the information online in different countries in terms of information quality and content.Design Content analysis.Method We analysed 450 webpages returned by searching the string ‘are face masks dangerous’ in Italy, the UK and the USA using three search engines (Bing, Duckduckgo and Google) in August 2020. The type of website and the stance about masks were assessed by two raters for each language and inter-rater agreement reported as Cohen’s kappa. The text of the webpages was collected from the web using WebBootCaT and analysed using a corpus analysis software to identify issues mentioned.Results Most pages were news outlets, and few (2%–6%) from public health agencies. Webpages with a negative stance on masks were more frequent in Italian (28%) than English (19%). Google returned the highest number of mask-positive pages and Duckduckgo the lowest. Google also returned the lowest number of pages mentioning conspiracy theories and Duckduckgo the highest. Webpages in Italian scored lower than those in English in transparency (reporting authors, their credentials and backing the information with references). When issues about the use of face masks were analysed, mask effectiveness was the most discussed followed by hypercapnia (accumulation of carbon dioxide), contraindication in respiratory disease and hypoxia, with issues related to their contraindications in mental health conditions and disability mentioned by very few pages.Conclusions This study suggests that: (1) public health agencies should increase their web presence in providing correct information on face masks; (2) search engines should improve the information quality criteria in their ranking; (3) the public should be more informed on issues related to the use of masks and disabilities, mental health and stigma arising for those people who cannot wear masks.

Long-term ingestion of arsenicals, a heterogeneous group of toxic compounds, has been associated with a wide spectrum of human pathologies, which include various malignancies. Although their mechanism of toxicity remains largely unknown, it is generally believed that arsenicals mainly produce their effects via direct binding to protein thiols and ROS formation in different subcellular compartments. The generality of these mechanisms most probably accounts for the different effects mediated by different forms of the metalloid in a variety of cells and tissues. In order to learn more about the molecular mechanisms of cyto- and genotoxicity, there is a need to focus on specific arsenic compounds under tightly controlled conditions. This review focuses on the mechanisms regulating the mitochondrial formation of ROS after exposure to low concentrations of a specific arsenic compound, NaAsO2, and their crosstalk with the nuclear factor (erythroid-2 related) factor 2 antioxidant signaling and the endoplasmic reticulum stress response.

Objective: Many online and printed media publish health news of questionable trustworthiness and it may be difficult for laypersons to determine the information quality of such articles. The purpose of this work was to propose a methodology for the automatic assessment of the quality of health-related news stories using natural language processing and machine learning.Materials and Methods: We used a database from the website HealthNewsReview.org that aims to improve the public dialogue about health care. HealthNewsReview.org developed a set of criteria to critically analyze health care interventions' claims. In this work, we attempt to automate the evaluation process by identifying the indicators of those criteria using natural language processing-based machine learning on a corpus of more than 1,300 news stories. We explored features ranging from simple n-grams to more advanced linguistic features and optimized the feature selection for each task. Additionally, we experimented with the use of pre-trained natural language model BERT.Results: For some criteria, such as mention of costs, benefits, harms, and “disease-mongering,” the evaluation results were promising with an F1 measure reaching 81.94%, while for others the results were less satisfactory due to the dataset size, the need of external knowledge, or the subjectivity in the evaluation process.Conclusion: These used criteria are more challenging than those addressed by previous work, and our aim was to investigate how much more difficult the machine learning task was, and how and why it varied between criteria. For some criteria, the obtained results were promising; however, automated evaluation of the other criteria may not yet replace the manual evaluation process where human experts interpret text senses and make use of external knowledge in their assessment.

The fact that Internet companies may record our personal data and track our online behavior for commercial or political purpose has emphasized aspects related to online privacy. This has also led to the development of search engines that promise no tracking and privacy. Search engines also have a major role in spreading low-quality health information such as that of anti-vaccine websites. This study investigates the relationship between search engines' approach to privacy and the scientific quality of the information they return. We analyzed the first 30 webpages returned searching “vaccines autism” in English, Spanish, Italian, and French. The results show that not only “alternative” search engines (Duckduckgo, Ecosia, Qwant, Swisscows, and Mojeek) but also other commercial engines (Bing, Yahoo) often return more anti-vaccine pages (10–53%) than Google.com (0%). Some localized versions of Google, however, returned more anti-vaccine webpages (up to 10%) than Google.com. Health information returned by search engines has an impact on public health and, specifically, in the acceptance of vaccines. The issue of information quality when seeking information for making health-related decisions also impact the ethical aspect represented by the right to an informed consent. Our study suggests that designing a search engine that is privacy savvy and avoids issues with filter bubbles that can result from user-tracking is necessary but insufficient; instead, mechanisms should be developed to test search engines from the perspective of information quality (particularly for health-related webpages) before they can be deemed trustworthy providers of public health information.

Environmental agents, including socioeconomic condition, and host factors can act as causal agents and risk factors in disease. We use biomarkers and sociomarkers to study causal factors, such as overproduction of reactive oxygen species (ROS) which could play a role in disease through oxidative stress. It is therefore important to define the exact meaning of the biomarker we measure. In this review we attempt a classification of biomarkers related to oxidative stress based on their biological meaning. We define as type zero biomarkers the direct measurement of ROS in vivo in patients. Type 1 biomarkers are the most frequently used indicators of oxidative stress, represented by oxidized lipids, proteins or nucleic acids and their bases. Type 2 biomarkers are indicators of the activation of biochemical pathways that can lead to the formation of ROS. Type 3 biomarkers are host factors such as small-molecular weight antioxidants and antioxidant enzymes, while type 4 biomarkers measure genetic factors and mutations that could modify the susceptibility of an individual to oxidative stress. We also discuss whether biomarkers are actionable or not, that is if the specific blockade of these molecules can ameliorate disease or if they are just surrogate markers.The proposed classification of biomarkers of oxidative stress based on their meaning and ambiguities, within the theoretical framework of the oxidative stress theory of disease may help identify those diseases, and individuals, where oxidative stress has a causal role, to allow targeted therapy and personalized medicine.

Patients who have experienced a first cerebral ischemic event are at increased risk of recurrent stroke. There is strong evidence that low-level inflammation as measured by high sensitivity C-reactive protein (hs-CRP) is a predictor of further ischemic events. Other mechanisms implicated in the pathogenesis of stroke may play a role in determining the risk of secondary events, including oxidative stress and the adaptive response to it and activation of neuroprotective pathways by hypoxia, for instance through induction of erythropoietin (EPO). This study investigated the association of the levels of CRP, peroxiredoxin 1 (PRDX1, an indicator of the physiological response to oxidative stress) and EPO (a neuroprotective factor produced in response to hypoxia) with the risk of a second ischemic event. Eighty patients with a diagnosis of lacunar stroke or transient ischemic attack (TIA) were included in the study and a blood sample was collected within 14 days from the initial event. Hs-CRP, PRDX1, and EPO were measured by ELISA. Further ischemic events were recorded with a mean follow-up of 42 months (min 24, max 64). Multivariate analysis showed that only CRP was an independent predictor of further events with an observed risk (OR) of 1.14 (P = 0.034, 95% CI 1.01–1.29). No association was observed with the levels of PRDX1 or EPO. A receiver operating curve (ROC) determined a cut-off CRP level of 3.25 μg/ml, with a 46% sensitivity and 81% specificity. Low-level inflammation as detected by hs-CRP is an independent predictor of recurrent cerebrovascular ischemic events.

Probiotics are over-the-counter products marketed for enhancing human health. Online information has been key in promoting probiotics worldwide. However, only few rigorous clinical studies have met the stringent criteria required to establish the efficacy and safety of probiotics. The present study was undertaken to assess the information quality of webpages referring to probiotics and to compare the recommendations available online with the information collected from trusted scientific sources. We evaluated 150 webpages returned by Google searching “probiotics” in terms of typology of website, health information quality based on the JAMA score and the HONcode certification, as well as completeness of the information based on the presence of four criteria: (1) links to scientific references supporting health claims, (2) cautionary notes about level of evidence for alleged benefits, (3) safety considerations, and (4) regulatory status. We then enumerated the health claims mentioned online and the corresponding clinical trials and reviews registered in the Cochrane library. Finally, the conclusions of Cochrane reviews were used to assess the level of scientific evidence of the information available through Google search. HON-certified websites were significantly more frequent in the top 10 websites than in the remaining websites. In terms of completeness of information, only 10% of webpages met all four criteria, 40% had a cautionary note on benefits, 35% referred to scientific literature, and only 25% mentioned potential side effects. The results of the content analysis led us to conclude that: (1) the most frequent typologies of webpages returned by Google are commercial and news, (2) commercial websites on average provide the least reliable information, and (3) significant numbers of claimed benefits of probiotics are not supported by scientific evidence. This study highlights important biases in the probiotics information available online, underlining the need to improve the quality and objectivity of information provided to the public.

Abstract Background The pro-myelinating effects of leukemia inhibitory factor (LIF) and other cytokines of the gp130 family, including oncostatin M (OSM) and ciliary neurotrophic factor (CNTF), have long been known, but controversial results have also been reported. We recently overexpressed erythropoietin receptor (EPOR) in rat central glia-4 (CG4) oligodendrocyte progenitor cells (OPCs) to study the mechanisms mediating the pro-myelinating effects of erythropoietin (EPO). In this study, we investigated the effect of co-treatment with EPO and LIF. Methods Gene expression in undifferentiated and differentiating CG4 cells in response to EPO and LIF was analysed by DNA microarrays and by RT-qPCR. Experiments were performed in biological replicates of N ≥ 4. Functional annotation and biological term enrichment was performed using DAVID (Database for Annotation, Visualization and Integrated Discovery). The gene-gene interaction network was visualised using STRING (Search Tool for the Retrieval of Interacting Genes). Results In CG4 cells treated with 10 ng/ml of EPO and 10 ng/ml of LIF, EPO-induced myelin oligodendrocyte glycoprotein (MOG) expression, measured at day 3 of differentiation, was inhibited ≥4-fold (N = 5, P

Abstract Background Endothelial injury is an early and enduring feature of cardiovascular disease. Inflammation and hypoxia may be responsible for this, and are often associated with the up-regulation of several transcriptional factors that include Hypoxia Inducible Factor-1 (HIF-1). Although it has been reported that HIF-1α is detectable in plasma, it is known to be unstable. Our aim was to optimize an assay for HIF-1α to be applied to in vitro and in vivo applications, and to use this assay to assess the release kinetics of HIF-1α following endothelial injury. Methods An ELISA for the measurement of HIF-1α in cell-culture medium and plasma was optimized, and the assay was used to determine the best conditions for sample collection and storage. The results of the ELISA were validated using Western blotting and immunohistochemistry (IHC). In vitro, a standardized injury was produced in a monolayer of rat aortic endothelial cells (RAECs) and intracellular HIF-1α was measured at intervals over 24 h. In vivo, a rat angioplasty model was used. The right carotid artery was injured using a 2F Fogarty balloon catheter. HIF-1α was measured in the plasma and in the arterial tissue (0, 1, 2, 3 and 5 days post injury). Results The HIF-1α ELISA had a limit of detection of 2.7 pg/mL and was linear up to 1000 pg/ mL. Between and within-assay, the coefficient of variation values were less than 15%. HIF-1α was unstable in cell lysates and plasma, and it was necessary to add a protease inhibitor immediately after collection, and to store samples at -80 °C prior to analysis. The dynamics of HIF-1α release were different for the in vitro and in vivo models. In vitro, HIF-1α reached maximum concentrations approximately 2 h post injury, whereas peak values in plasma and tissues occurred approximately 2 days post injury, in the balloon injury model. Conclusion HIF-1α can be measured in plasma, but this requires careful sample collection and storage. The carotid artery balloon injury model is associated with the transient release of HIF-1α into the circulation that probably reflects the hypoxia induced in the artery wall.

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.

Background: The concept that one can “boost” immunity is a popular one. Although the only evidence-based approach to this is vaccination, the lay public is exposed to a wide range of information on how to boost immunity. The aim of this study was to analyze such information available on the Internet.Methods and findings: We visited 185 webpages returned from a Google search on “boost immunity” and classified them by typology (blogs, commercial, government, no-profit, news, professional, scientific journals) and by using standard indicators of health information quality (JAMA score, HONCode). We then analyzed their content in terms of disease and “boosters” mentioned. Commercial and news websites represented one third of the results each. Of the 37 approaches to boost immunity recorded, the top ones were diet (77% of webpages), fruit (69%), vitamins (67%), antioxidants (52%), probiotics (51%), minerals (50%), and vitamin C (49%). Interestingly, vaccines ranked 27th, with only 12% of webpages mentioning them.Conclusions: Commercial websites are an important component of the information available to the public on the topic, and thus contribute providing biased information.

The pro-inflammatory cytokine interleukin-1β (IL-1β) plays important roles in immunity but is also implicated in autoimmune disease. The most well-established mechanism of IL-1β secretion is via activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome which requires an initial priming signal followed by an activating signal. However, the precise mechanism by which the inflammasome is activated remains unclear. The role of reactive oxygen species (ROS) in this process is contradictory, with some studies suggesting that ROS are crucial while others describe opposite effects. In this study, we evaluated the effects of oxidative stress on IL-1β secretion. Gout is a disease driven solely by IL-1β secretion in response to monosodium urate (MSU) crystals which form during periods of hyperuricemia and thus presents an opportunity to study factors contributing to IL-1β secretion. Sera and monocytes were isolated from patients with gout to determine whether differences in antioxidant status could explain the susceptibility of these individuals to gout attacks. In addition, sera and monocytes were collected from patients with chronic kidney disease (CKD) for comparison as this condition is associated with high levels of oxidative stress and disturbances in serum uric acid levels. There were differences in some aspects of antioxidant defenses in gout patients and these were mainly due to higher serum uric acid. Monocytes from gout patients were more responsive to priming, but not activation, of the NLRP3 inflammasome. However, expression of the components of the NLRP3 inflammasome were unaffected by priming or activation of the inflammasome, nor were these expression levels differentially regulated in gout patients. Inhibition of ROS by N-Acetyl Cysteine inhibited TLR2-induced priming of the NLRP3 inflammasome, but had no effect on MSU-induced activation. Together these findings demonstrate that oxidative stress only affects priming of the NLRP3 inflammasome but does not influence activation.

An amendment to this paper has been published and can be accessed via the original article.

An amendment to this paper has been published and can be accessed via the original article.

Introduction: The popularity of seeking health information online makes information quality (IQ) a public health issue. The present study aims at building a theoretical framework of health information quality (HIQ) that can be applied to websites and defines which IQ criteria are important for a website to be trustworthy and meet users' expectations.Methods: We have identified a list of HIQ criteria from existing tools and assessment criteria and elaborated them into a questionnaire that was promoted via social media and mainly the University. Responses (329) were used to rank the different criteria for their importance in trusting a website and to identify patterns of criteria using hierarchical cluster analysis.Results: HIQ criteria were organized in five dimensions based on previous theoretical frameworks as well as on how they cluster together in the questionnaire response. We could identify a top-ranking dimension (scientific completeness) that describes what the user is expecting to know from the websites (in particular: description of symptoms, treatments, side effects). Cluster analysis also identified a number of criteria borrowed from existing tools for assessing HIQ that could be subsumed to a broad “ethical” dimension (such as conflict of interests, privacy, advertising policies) that were, in general, ranked of low importance by the participants. Subgroup analysis revealed significant differences in the importance assigned to the various criteria based on gender, language and whether or not of biomedical educational background.Conclusions: We identified criteria of HIQ and organized them in dimensions. We observed that ethical criteria, while regarded highly in the academic and medical environment, are not considered highly by the public.

The 1998 Lancet paper by Wakefield et al., despite subsequent retraction and evidence indicating no causal link between vaccinations and autism, triggered significant parental concern. The aim of this study was to analyze the online information available on this topic. Using localized versions of Google, we searched “autism vaccine” in English, French, Italian, Portuguese, Mandarin, and Arabic and analyzed 200 websites for each search engine result page (SERP). A common feature was the newsworthiness of the topic, with news outlets representing 25–50% of the SERP, followed by unaffiliated websites (blogs, social media) that represented 27–41% and included most of the vaccine-negative websites. Between 12 and 24% of websites had a negative stance on vaccines, while most websites were pro-vaccine (43–70%). However, their ranking by Google varied. While in Google.com, the first vaccine-negative website was the 43rd in the SERP, there was one vaccine-negative webpage in the top 10 websites in both the British and Australian localized versions and in French and two in Italian, Portuguese, and Mandarin, suggesting that the information quality algorithm used by Google may work better in English. Many webpages mentioned celebrities in the context of the link between vaccines and autism, with Donald Trump most frequently. Few websites (1–5%) promoted complementary and alternative medicine (CAM) but 50–100% of these were also vaccine-negative suggesting that CAM users are more exposed to vaccine-negative information. This analysis highlights the need for monitoring the web for information impacting on vaccine uptake.

The systemic inflammatory response syndrome (SIRS) is a potentially lethal response triggered by diverse forms of tissue injury and infection. When systemic inflammation is triggered by infection, the term sepsis is used. Understanding how inflammation is mediated and regulated is of enormous medical importance. We previously demonstrated that circulating inflammatory-relevant microRNAs (CIR-miRNAs) are candidate biomarkers for differentiating sepsis from SIRS. Here, we set out to determine how CIR-miRNA levels reflect SIRS severity and whether they derive from activated immune cells. Clinical disease severity scores and markers of red blood cell (RBC) damage or immune cell activation were correlated with CIR-miRNA levels in patients with SIRS and sepsis. The release of CIR-miRNAs modulated during SIRS was assessed in immune cell cultures. We show that severity of non-infective SIRS, but not sepsis is reflected in the levels of miR-378a-3p, miR-30a-5p, miR-30d-5p, and miR-192-5p. These CIR-miRNA levels positively correlate with levels of the redox biomarker, peroxiredoxin-1 (Prdx-1), which has previously been shown to be released by immune cells during inflammation. Furthermore, in vitro activated immune cells produce SIRS-associated miR-378a-3p, miR-30a-5p, miR-30d-5p, and miR-192-5p. Our study furthers the understanding of the origin, role, and trafficking of CIR-miRNAs as potential regulators of inflammation.

Objective: To explore the role of biomarkers (hsCRP, sRANKL, PRDX1 and EPO) in arterial stiffness and in predicting further vascular events. Methods: Patients from the ongoing ASIST study each attended a laboratory visit within fourteen days of their diagnosed TIA or lacunar stroke. Arterial stiffness was calculated using cfPWV (carotid-femoral pulse wave velocity) measured with Complior ®Artech, France, and with the CAVI ®Fukuda, Japan (cardio-ankle vascular index) method. Blood samples were taken for ELISA assays. Analysis was completed with SPSS software Results: Forty patients were evaluated in this preliminary project (29 male/11 female, mean age 70.7±11.99), with four experiencing a further event during the six month follow up (10%). All biomarkers and both measurements for arterial stiffness had a higher mean value in patients with a further event (hsCRP 3.89 vs 1.42, P = 0.08; EPO 9.06 vs 9.01, P = 0.85; sRANKL 0.05 vs 0.03, P = 0.31; PRDX1 6.27 vs 6.21, P = 0.95; CAVI 11.13 vs 9.69, P = 0.15; cfPWV 10.82 vs 10.2, P = 0.55), however none were statistically significant. Levels of PRDX1 were elevated acutely post-event before falling significantly (R = −0.475, P = 0.002), while hsCRP and EPO continued to be elevated at >10 days post- event. In addition, CAVI correlated closely with hsCRP (R = 0.28, P = 0.09) and EPO (R = 0.29, P = 0.08), but cfPWV was not closely related to any of the biomarkers. Conclusions: This preliminary data suggests that biomarkers, particularly EPO and hsCRP, are more closely related to CAVI than cfPWV. hsCRP was the most relevant as an independent predictive factor for further vascular events.

Several studies have shown that erythropoietin (EPO) has neuroprotective or neuroreparative actions on diseases of the nervous system and that improves oligodendrocyte (OL) differentiation and myelination in vivo and in vitro. This study aims at investigating the early molecular mechanisms for the pro-myelinating action of EPO at the gene expression level. For this purpose, we used a differentiating OL precursor cell line, rat central glia-4 cells. Cells were differentiated or not, and then treated with EPO for 1 or 20 h. RNA was extracted and changes in the gene expression profile were assessed using microarray analysis. Experiments were performed in biological replicates of n = 4. Differentiation alone changed the expression of 11% of transcripts (2,663 out of 24,272), representing 2,436 genes, half of which were upregulated and half downregulated. At 20 h of treatment, EPO significantly affected the expression of 99 genes that were already regulated by differentiation and of 150 genes that were not influenced by differentiation alone. Analysis of the transcripts most upregulated by EPO identified several genes involved in lipid transport (e.g., Cd36) and lipid metabolism (Ppargc1a/Pgc1alpha, Lpin1, Pnlip, Lpin2, Ppard, Plin2) along with Igf1 and Igf2, growth factors known for their pro-myelinating action. All these genes were only induced by EPO and not by differentiation alone, except for Pnlip which was highly induced by differentiation and augmented by EPO. Results were validated by quantitative PCR. These findings suggest that EPO might increase remyelination by inducing insulin-like growth factors and increasing lipid metabolism.

Glutathione (GSH), a major cellular antioxidant, is considered an inhibitor of the inflammatory response involving reactive oxygen species (ROS). However, evidence is largely based on experiments with exogenously added antioxidants/reducing agents or pro-oxidants. We show that depleting macrophages of 99% of GSH does not exacerbate the inflammatory gene expression profile in the RAW264 macrophage cell line or increase expression of inflammatory cytokines in response to the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS); only two small patterns of LPS-induced genes were sensitive to GSH depletion. One group, mapping to innate immunity and antiviral responses (Oas2, Oas3, Mx2, Irf7, Irf9, STAT1, il1b), required GSH for optimal induction. Consequently, GSH depletion prevented the LPS-induced activation of antiviral response and its inhibition of influenza virus infection. LPS induction of a second group of genes (Prdx1, Srxn1, Hmox1, GSH synthase, cysteine transporters), mapping to nrf2 and the oxidative stress response, was increased by GSH depletion. We conclude that the main function of endogenous GSH is not to limit inflammation but to fine-tune the innate immune response to infection.

The idea that antioxidant supplements can prevent or cure many diseases is extremely popular. To study the public understanding of antioxidants on the Web, we searched the term “antioxidants” in http://Google.com and analyzed 200 websites in terms of typology (news, commercial, professional, health portal, no-profit or government organization, scientific journals), disease or biological process mentioned (aging, immunity, neurological disease, diabetes, arthritis, etc.), and stance toward antioxidants, whether neutral, positive, or negative. Commercial and news websites were prevalent (over half of the total) but not in the top 10 returned by Google, where the most frequent were health portals, government, and professional websites. Among the diseases mentioned, cancer was the first, followed by vascular and eye diseases. A negative stance toward supplements was prevalent in the whole search, and this was even more evident for cancer. Information on aging or immunity had the largest proportion of pro-supplement and commercial websites. This study shows that some diseases are highly associated with antioxidants on the Internet and that information on antioxidants in aging and immunity is more likely to describe the positive effects of antioxidant supplements.

Abstract Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in nonhematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP)). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by Western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects.

Traumatic brain injury (TBI) is a leading cause of death and disability in the modern society. Although primary prevention is the only strategy that can counteract the primary brain damage, numerous preclinical studies have been accumulated in order to find therapeutic strategies against the secondary damage. In this scenario erythropoietin (EPO) has been shown to be a promising candidate as neuroprotective agent. A recent clinical trial, however, has shown that EPO has not an overall effect on outcomes following TBI thus renewing old concerns. However, the results of a prespecified sensitivity analysis indicate that the effect of EPO on mortality remains still unclear. In the light of these observations, further investigations are needed to resolve doubts on EPO effectiveness in order to provide a more solid base for tailoring conclusive clinical trials.

Pietro GhezziBrighton and Sussex Medical School, Trafford Centre, Falmer, Brighton, UKAbstract: Reactive oxygen species and thiol antioxidants, including glutathione (GSH), regulate innate immunity at various levels. This review outlines the redox-sensitive steps of the cellular mechanisms implicated in inflammation and host defense against infection, and describes how GSH is not only important as an antioxidant but also as a signaling molecule. There is an extensive literature of the role of GSH in immunity. Most reviews are biased by an oversimplified picture where “bad” free radicals cause all sorts of diseases and “good” antioxidants protect from them and prevent oxidative stress. While this may be the case in certain fields (eg, toxicology), the role of thiols (the topic of this review) in immunity certainly requires wearing scientist’s goggles and being prepared to accept a more complex picture. This review aims at describing the role of GSH in the lung in the context of immunity and inflammation. The first part summarizes the history and basic concepts of this picture. The second part focuses on GSH metabolism/levels in pathology, the third on the role of GSH in innate immunity and inflammation, and the fourth gives 4 examples describing the importance of GSH in the response to infections.Keywords: antioxidants, oxidative stress, sepsis, infection, cysteine

Protein cysteines can form transient disulfides with glutathione (GSH), resulting in the production of glutathionylated proteins, and this process is regarded as a mechanism by which the redox state of the cell can regulate protein function. Most studies on redox regulation of immunity have focused on intracellular proteins. In this study we have used redox proteomics to identify those proteins released in glutathionylated form by macrophages stimulated with lipopolysaccharide (LPS) after pre-loading the cells with biotinylated GSH. Of the several proteins identified in the redox secretome, we have selected a number for validation. Proteomic analysis indicated that LPS stimulated the release of peroxiredoxin (PRDX) 1, PRDX2, vimentin (VIM), profilin1 (PFN1) and thioredoxin 1 (TXN1). For PRDX1 and TXN1, we were able to confirm that the released protein is glutathionylated. PRDX1, PRDX2 and TXN1 were also released by the human pulmonary epithelial cell line, A549, infected with influenza virus. The release of the proteins identified was inhibited by the anti-inflammatory glucocorticoid, dexamethasone (DEX), which also inhibited tumor necrosis factor (TNF)-α release, and by thiol antioxidants (N-butanoyl GSH derivative, GSH-C4, and N-acetylcysteine (NAC), which did not affect TNF-α production. The proteins identified could be useful as biomarkers of oxidative stress associated with inflammation, and further studies will be required to investigate if the extracellular forms of these proteins has immunoregulatory functions.

Glucocorticoids are potent inhibitors of inflammation and endotoxic shock. This probably occurs through an inhibition of the synthesis of pro-inflammatory cytokines as well as of many of their toxic activities. Therefore, endogenous glucocorticoids (GC) might represent a major mechanism in the control of cytokine mediated pathologies. GC inhibit the synthesis of cytokines in various experimental models. Adrenalectomy or GC antagonists potentiate TNF, IL-1 and IL-6 production in LPS treated mice. GC inhibit the formation of arachidonic acid metabolites and the induction of NO synthase. They also inhibit various activities of cytokines including toxicity, haemodynamic shock and fever. Adrenalectomy sensitizes to the toxic effects of LPS, TNF and IL-1. On the other hand, GC potentiate the synthesis of several cytokine induced APP by the liver. Since many of these proteins have anti-toxic activities (antioxidant, antiprotease etc.) or bind cytokines, this might well represent a GC mediated protective feedback mechanism involving the liver. Not only do GC inhibit cytokines, but in vivo LPS and various cytokines (TNF, IL-1, IL-6) increase blood GC levels through a central mechanism involving the activation of the HPA. Thus, this neuroendocrine response to cytokines constitutes an important immunoregulatory feedback involving the brain.