The educational impact of technology-enhanced learning in regional anaesthesia: a scoping review.

BACKGROUND: Effective training in regional anaesthesia (RA) is paramount to ensuring widespread competence. Technology-based learning has assisted other specialties in achieving more rapid procedural skill acquisition. If applicable to RA, technology-enhanced training has the potential to provide an effective learning experience and to overcome barriers to RA training. We review the current evidence base for use of innovative technologies in assisting learning of RA. METHODS: Using scoping review methodology, three databases (MEDLINE, Embase, and Web of Science) were searched, identifying 158 relevant citations. Citations were screened against defined eligibility criteria with 27 studies selected for inclusion. Data relating to study details, technological learning interventions, and impact on learner experience were extracted and analysed. RESULTS: Seven different technologies were used to train learners in RA: artificial intelligence, immersive virtual reality, desktop virtual reality, needle guidance technology, robotics, augmented reality, and haptic feedback devices. Of 27 studies, 26 reported a positive impact of technology-enhanced RA training, with different technologies offering benefits for differing components of RA training. Artificial intelligence improved sonoanatomical knowledge and ultrasound skills for RA, whereas needle guidance technologies enhanced confidence and improved needling performance, particularly in novices. Immersive virtual reality allowed more rapid acquisition of needling skills, but its functionality was limited when combined with haptic feedback technology. User friendly technologies enhanced participant experience and improved confidence in RA; however, limitations in technology-assisted RA training restrict its widespread use. CONCLUSIONS: Technology-enhanced RA training can provide a positive and effective learning experience, with potential to reduce the steep learning curve associated with gaining RA proficiency. A combined approach to RA education, using both technological and traditional approaches, should be maintained as no single method has been shown to provide comprehensive RA training.

Stepping into the shoes of older people: a scoping review of simulating ageing experiences for healthcare professional students.

BACKGROUND: Ageing simulation suits and equipment give healthcare professional (HCP) students the opportunity to experience what it might feel like to be an older person with age-related disability or illness. Ageing simulation experiences, where students complete activities of daily living (ADL) tasks, aim to reproduce the challenges an older person may face. OBJECTIVES: We undertook a scoping literature review to establish, from the evidence base, what is known about simulating ageing experiences for HCP students and its impact on attitudes towards older patients. METHODS: We applied Arksey and O'Malley's scoping literature review framework to achieve relevant articles. Four databases (MEDLINE, Embase, Web of Science and Cumulative Index to Nursing and Allied Health Literature) were searched resulting in 114 citations. After screening and applying our exclusion criteria, 14 articles were selected for inclusion. RESULTS: Fifty percent of studies were mixed-methods, 35% quasi-experimental, 7% quantitative and 7% qualitative. Two types of simulation experience were identified: (i) workshop based and (ii) ageing games. Simulated impairments included vision, hearing and mobility issues. Most common ADLs simulated were managing medications, finances and functional ability. The majority of studies reported a positive impact on knowledge, attitudes and empathy towards older people. CONCLUSIONS: Teaching in Care of Older People is important in HCP undergraduate curricula and should be a positive experience promoting successful ageing while raising awareness of ageism. Ageing suits have a positive impact on students' attitudes and empathic skills towards older people. Future research should include interprofessional education with HCP students learning together throughout undergraduate training.

Fluvastatin enhances IL-33-mediated mast cell IL-6 and TNF production.

Statins are HMG-CoA reductase inhibitors prescribed for lowering cholesterol. They can also inhibit inflammatory responses by suppressing isoprenylation of small G proteins. Consistent with this, we previously found that fluvastatin suppresses IgE-mediated mast cell function. However, some studies have found that statins induced pro-inflammatory cytokines in macrophages and NK cells. In contrast to IgE signaling, we show that fluvastatin augments IL-33-induced TNF and IL-6 production by mast cells. This effect required the key mast cell growth factor, stem cell factor (SCF). Treatment of IL-33-activated mast cells with mevalonic acid or isoprenoids reduced fluvastatin effects, suggesting fluvastatin acts at least partly by reducing isoprenoid production. Fluvastatin also enhanced IL-33-induced NF-κB transcriptional activity and promoted neutrophilic peritonitis in vivo, a response requiring mast cell activation. Other statins tested did not enhance IL-33 responsiveness. Therefore, this work supports observations of unexpected pro-inflammatory effects of some statins and suggests mechanisms by which this may occur. Because statins are candidates for repurposing in inflammatory disorders, our work emphasizes the importance of understanding the pleiotropic and possible unexpected effects of these drugs.

Number of Months of Baseball in the Previous Year and Preseason Olecranon Tenderness: Risk Factors for Shoulder and Elbow Injuries in High-School Baseball Players.

OBJECTIVE: To identify risk factors for shoulder and elbow injuries in high-school baseball position players and pitchers in the preseason history and physical examination. DESIGN: Retrospective cohort study. SETTING: Community high-school baseball. PARTICIPANTS: Three hundred seventy-one male baseball players' mean age 15.0 ± 1.8 years. OUTCOME MEASURES: A preseason history and physical examination was performed on all athletes. Injury information was collected by weekly self-report and athletic trainer injury logs throughout the season. Comparisons between injured and noninjured players were performed using t tests and χ 2 analyses. Binary logistic regression models were developed to identify risk factors for injury. RESULTS: Seventy-six injuries were recorded over the season. In univariate analysis, the injured group had greater months of baseball participation ( P = 0.007) and shoulder visual analog scale for the past year ( P = 0.003). The injured group also had more olecranon tenderness ( P < 0.0001, odds ratio [OR] 2.9) and decreased elbow arc of motion. All other factors were not significantly different ( P > 0.05). In multivariable logistic regression, months per year of baseball participation was the only factor significantly associated with injuries ( P = 0.010, OR = 1.21). CONCLUSIONS: Baseball players who developed arm injuries during a season were more likely to play more months of baseball and report shoulder pain in the previous year. The presence of preseason olecranon tenderness was associated with nearly triple the risk of injury during the season. Every additional month of baseball participation in the previous year was associated with a 1.2× increased odds of injury. The presence of glenohumeral internal rotation deficit was not a predictor of injury.

Information on Genetic Variants Does Not Increase Identification of Individuals at Risk of Esophageal Adenocarcinoma Compared to Clinical Risk Factors.

We previously developed a tool that identified individuals who later developed esophageal adenocarcinoma (based on age, sex, body mass index, smoking status, and prior esophageal conditions) with an area under the curve of 0.80. In this study, we collected data from 329,463 individuals in the UK Biobank cohort who were tested for genetic susceptibility to esophageal adenocarcinoma (a polygenic risk score based on 18 recognized genetic variants). We found that after inclusion of this genetic information, the area under the curve for identification of individuals who developed esophageal adenocarcinoma remained at 0.80. Testing for genetic variants associated with esophageal adenocarcinoma therefore seems unlikely to improve identification of individuals at risk of esophageal adenocarcinoma.

The role of 5α-reductase inhibitors in gastro-oesophageal cancer risk: A nested case-control study.

PURPOSE: The strong male predominance of gastro-oesophageal cancer suggests that sex hormones play an important role. 5α-Reductase (5AR) inhibitors have antiandrogen effects and have been shown to decrease cancer cell proliferation and metastasis. We conducted the first epidemiologic investigation into the association between 5AR inhibitor use and gastro-oesophageal cancer risk. METHODS: We conducted a nested case-control study within the Scottish Primary Care Clinical Information Unit Research database. Male cases diagnosed with oesophageal or gastric cancer between 1999 and 2011 were matched to up to five male controls based on birth year, diagnosis year, and general practice. We used electronic prescribing records to ascertain medication use. We used conditional logistic regression to calculate odds ratios (ORs) for the association between 5AR inhibitor use and cancer risk, after adjusting for comorbidities and aspirin, statin, or proton pump inhibitor use. RESULTS: The study included 2003 gastro-oesophageal cancer cases and 9650 controls. There was some evidence of reduced gastro-oesophageal cancer risk among 5AR inhibitor users (adjusted OR = 0.75; 95% CI, 0.56-1.02), particularly for finasteride (adjusted OR = 0.68; 95% CI, 0.50-0.94). These decreases were more marked among those who received at least 3 years of 5AR inhibitors (adjusted OR = 0.54; 95% CI, 0.27-1.05; P value = .071) or finasteride (adjusted OR = 0.49; 95% CI, 0.24-0.99; P value = .046). CONCLUSIONS: We found evidence of reduced gastro-oesophageal cancer risk among users of 5AR inhibitors, particularly finasteride. However, larger epidemiological studies are required before randomised controlled trials are considered.

Low-Dose Aspirin Use Does Not Increase Survival in 2 Independent Population-Based Cohorts of Patients With Esophageal or Gastric Cancer.

BACKGROUND & AIMS: Preclinical studies have shown aspirin to have anticancer properties and epidemiologic studies have associated aspirin use with longer survival times of patients with cancer. We studied 2 large cohorts to determine the association between aspirin use and cancer-specific mortality in patients with esophageal or gastric cancer. METHODS: We performed a population-based study using cohorts of patients newly diagnosed with esophageal or gastric cancer, identified from cancer registries in England from 1998 through 2012 and the Scottish Cancer Registry from 2009 through 2012. Low-dose aspirin prescriptions were identified from linkages to the United Kingdom Clinical Research Practice Datalink in England and the Prescribing Information System in Scotland. Deaths were identified from linkage to national mortality records, with follow-up until September 2015 in England and January 2015 in Scotland. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific mortality by low-dose aspirin use after adjusting for potential confounders. Meta-analysis was used to pool results across the 2 cohorts. RESULTS: The combined English and Scottish cohorts contained 4654 patients with esophageal cancer and 3833 patients with gastric cancer, including 3240 and 2392 cancer-specific deaths, respectively. The proportions surviving 1 year, based on cancer-specific mortality, were similar in aspirin users vs non-users after diagnosis with esophageal cancer (48% vs 50% in England and 49% vs 46% in Scotland, respectively) or gastric cancer (58% vs 57% in England and 59% vs 55% in Scotland, respectively). There was no association between postdiagnosis use of low-dose aspirin and cancer-specific mortality among patients with esophageal cancer (pooled adjusted HR, 0.98; 95% CI, 0.89-1.09) or gastric cancer (pooled adjusted HR, 0.96; 95% CI, 0.85-1.08). Long-term aspirin use was not associated with cancer-specific mortality after diagnosis of esophageal cancer (pooled adjusted HR, 1.03; 95% CI, 0.85-1.25) or gastric cancer (pooled adjusted HR, 1.06; 95% CI, 0.85-1.32). CONCLUSIONS: In analyses of 2 large independent cohorts in the United Kingdom, low-dose aspirin usage was not associated with increased survival of patients diagnosed with esophageal or gastric cancer.

Lactic acid suppresses IgE-mediated mast cell function in vitro and in vivo.

Mast cells have functional plasticity affected by their tissue microenvironment, which greatly impacts their inflammatory responses. Because lactic acid (LA) is abundant in inflamed tissues and tumors, we investigated how it affects mast cell function. Using IgE-mediated activation as a model system, we found that LA suppressed inflammatory cytokine production and degranulation in mouse peritoneal mast cells, data that were confirmed with human skin mast cells. In mouse peritoneal mast cells, LA-mediated cytokine suppression was dependent on pH- and monocarboxylic transporter-1 expression. Additionally, LA reduced IgE-induced Syk, Btk, and ERK phosphorylation, key signals eliciting inflammation. In vivo, LA injection reduced IgE-mediated hypothermia in mice undergoing passive systemic anaphylaxis. Our data suggest that LA may serve as a feedback inhibitor that limits mast cell-mediated inflammation.

High PTGS2 expression in post-neoadjuvant chemotherapy-treated oesophageal adenocarcinoma is associated with improved survival: a population-based cohort study.

AIMS: High prostaglandin endoperoxide synthase-2 (PTGS2) enzyme expression in oesophageal adenocarcinoma has been shown to independently predict poor prognosis; however, the evidence is inconsistent. The aim of this study was to investigated the association between PTGS2 expression and prognosis in patients with oesophageal adenocarcinoma. METHODS AND RESULTS: A cohort of 135 patients with oesophageal adenocarcinoma who received neoadjuvant chemotherapy and surgery from 2004 to 2012 was identified in the Northern Ireland Cancer Centre. Tissue microarrays were created in the Northern Ireland Biobank, with triplicate cores being sampled from each tumour. Immunohistochemical PTGS2 expression was scored by two independent assessors, with intensity and proportion of tumour staining being used to calculate H-scores for each patient. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and cancer-specific survival, and recurrence-free survival by PTGS2 expression, with adjustment for potential confounders. Patients were followed up for a mean of 3.0 years (standard deviation 1.8 years). The PTGS2 expression cut-off value was determined from the median H-score of the cohort (270/300). High (n = 79), as compared with low (n = 56), PTGS2 expression was associated with improved cancer-specific survival (adjusted HR 0.56, 95% CI 0.33-0.94; P = 0.03). PTGS2 expression was not significantly associated with recurrence-free survival (adjusted HR 0.85, 95% CI 0.52-1.38; P = 0.51). CONCLUSIONS: High PTGS2 expression in oesophageal adenocarcinoma tissue was associated with improved overall and cancer-specific survival, in contrast to previous evidence. As this is the first study of its kind to include patients who had undergone neoadjuvant chemotherapy, further studies are needed to clarify these associations.

Furosemide use and survival in patients with esophageal or gastric cancer: a population-based cohort study.

BACKGROUND: Pre-clinical studies have shown that furosemide slows cancer cell growth by acting on the Na-K-2Cl transporter, particularly for gastric cancer cells. However, epidemiological studies have not investigated furosemide use and mortality in gastroesophageal cancer patients. Consequently, we conducted a population-based study to investigate whether furosemide use is associated with reduced cancer-specific mortality in esophageal/gastric cancer patients. METHODS: A cohort of patients newly diagnosed with esophageal or gastric cancer between 1998 and 2013 were identified from English cancer registries and linked to the Clinical Practice Research Datalink to provide prescription records and the Office of National Statistics to provide death data up to September 2015. Time-dependant Cox-regression models were used to calculate hazard ratios (HRs) comparing cancer-specific mortality in furosemide users with non-users. Analyses were repeated restricting to patients with common furosemide indications (heart failure, myocardial infarction, edema or hypertension) to reduce potential confounding. RESULTS: The cohort contained 2708 esophageal cancer patients and 2377 gastric cancer patients, amongst whom 1844 and 1467 cancer-specific deaths occurred, respectively. Furosemide use was not associated with reduced cancer-specific mortality overall (adjusted HR in esophageal cancer = 1.28, 95% CI 1.10, 1.50 and in gastric cancer = 1.27, 95% CI 1.08, 1.50) or when restricted to patients with furosemide indications before cancer diagnosis (adjusted HR in esophageal cancer = 1.07, 95% CI 0.88, 1.30 and in gastric cancer = 1.18, 95% CI 0.96, 1.46). CONCLUSIONS: In this large population-based cohort study, furosemide was not associated with reduced cancer-specific mortality in patients with esophageal or gastric cancer.

Ground reaction forces of overground galloping in ridden Thoroughbred racehorses.

The horse has evolved to gallop economically at high speed. Limb force increases with speed but direct measures of limb ground reaction forces (GRFs) at gallop are sparse. This study reports GRFs for multiple limbs, using force plates, across seven Thoroughbred racehorses during ridden galloping. The results show peak vertical GRF values of 13.6 N kg-1 (non-lead hindlimb), 12.3 N kg-1 (lead hindlimb), 14.0 N kg-1 (non-lead forelimb) and 13.6 N kg-1 (lead forelimb) at 11.4 m s-1 and recorded values are consistent with those predicted from duty factor. The distribution of body weight between the forelimbs and hindlimbs is approximated to 50:50, and is variable with speed, unlike the 60:40 commonly stated for cursorial quadrupeds in the literature. An even distribution of load on all limbs may help minimise accumulation of fatigue and assist in injury avoidance. Cranio-caudal force data concur with the observation that horses apply a net accelerative impulse with the hindlimbs and a net decelerative impulse with the forelimbs. Capturing GRFs enhances our knowledge on the mechanics of galloping in fast-moving species and provides insight into injury risk and factors limiting athletic performance.

TGF-ß1 Suppresses IL-33-Induced Mast Cell Function.

TGF-ß1 is involved in many pathological conditions, including autoimmune disorders, cancer, and cardiovascular and allergic diseases. We have previously found that TGF-ß1 can suppress IgE-mediated mast cell activation of human and mouse mast cells. IL-33 is a member of the IL-1 family capable of inducing mast cell responses and enhancing IgE-mediated activation. In this study, we investigated the effects of TGF-ß on IL-33-mediated mast cell activation. Bone marrow-derived mast cells cultured in TGF-ß1, ß2, or ß3 showed reduced IL-33-mediated production of TNF, IL-6, IL-13, and MCP-1 in a concentration-dependent manner. TGF-ß1 inhibited IL-33-mediated Akt and ERK phosphorylation as well as NF-κB- and AP-1-mediated transcription. These effects were functionally important, as TGF-ß1 injection suppressed IL-33-induced systemic cytokines in vivo and inhibited IL-33-mediated cytokine release from human mast cells. TGF-ß1 also suppressed the combined effects of IL-33 and IgE-mediated activation on mouse and human mast cells. The role of IL-33 in the pathogenesis of allergic diseases is incompletely understood. These findings, consistent with our previously reported effects of TGF-ß1 on IgE-mediated activation, demonstrate that TGF-ß1 can provide broad inhibitory signals to activated mast cells.

Statin use and survival in patients with gastric cancer in two independent population-based cohorts.

PURPOSE: Preclinical studies show statins inhibit pathways involved in gastric cancer progression, with observational studies demonstrating reduced gastric cancer risk in statin users. However, few studies have investigated statin use and survival in gastric cancer. We investigated statin use and survival in two large population-based gastric cancer cohorts. METHODS: Patients diagnosed with gastric cancer from 1998 to 2012 were identified from English and Scottish cancer registries. Statin prescriptions were identified from linkages to the UK Clinical Practice Research Datalink in England and the Prescribing Information System in Scotland, and deaths identified from national mortality records. Time-dependent Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) for cancer-specific mortality by statin use in multivariate analysis. Meta-analysis techniques pooled results across the cohorts. RESULTS: The combined cohorts contained 3833 patients with gastric cancer and 2392 cancer-specific deaths. Statin use after diagnosis was associated with reduced cancer-specific mortality (adjusted HR 0.83; 95% CI, 0.74-0.92). HRs for less than 1 year and over 1 year of statin use were similar (adjusted HR 0.83; 95% CI, 0.73-0.94 and adjusted HR 0.83; 95% CI, 0.64-1.01, respectively). Statin use prior to diagnosis was also associated with reduced cancer-specific mortality (adjusted HR 0.91; 95% CI, 0.84-0.98). CONCLUSIONS: In two independent UK cohorts, there was some evidence that statin use was associated with reduced cancer-specific mortality. However, these associations were weak in magnitude and did not follow a clear dose response, and we cannot rule out confounding by stage.

Hormonal and reproductive factors and risk of upper gastrointestinal cancers in men: A prospective cohort study within the UK Biobank.

Incidence of upper gastrointestinal cancers of the oesophagus and stomach show a strong unexplained male predominance. Hormonal and reproductive factors have been associated with upper gastrointestinal cancers in women but there is little available data on men. To investigate this, we included 219,425 men enrolled in the UK Biobank in 2006-2010. Baseline assessments provided information on hormonal and reproductive factors (specifically hair baldness, number of children fathered, relative age at first facial hair and relative age voice broke) and incident oesophageal or gastric cancers were identified through linkage to U.K. cancer registries. Unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. During 8 years of follow-up, 309 oesophageal 210 gastric cancers occurred. There was some evidence that male pattern baldness, was associated with gastric cancer risk (adjusted HR 1.35, 95% CI 0.97, 1.88), particularly for frontal male pattern baldness (adjusted HR 1.52, 95% CI 1.02, 2.28). There was little evidence of association between other hormonal and reproductive factors and risk of oesophageal or gastric cancer, overall or by histological subtype. In the first study of a range of male hormonal and reproductive factors and gastric cancer, there was a suggestion that male pattern baldness, often used as a proxy of sex hormone levels, may be associated with gastric cancer. Future prospective studies that directly test circulating sex steroid hormone levels in relation to upper gastrointestinal cancer risk are warranted.

Medications that relax the lower oesophageal sphincter and risk of oesophageal cancer: An analysis of two independent population-based databases.

Excessive lower oesophageal sphincter relaxation increases gastro-oesophageal acid reflux, an oesophageal adenocarcinoma risk factor. Medications that relax this sphincter (benzodiazepines, calcium channel blockers, nitrates, ß2 agonists and xanthines) could promote cancer. These medications were investigated in two independent datasets. In the Scottish Primary Care Clinical Informatics Unit (PCCIU) database, a nested case-control study of oesophageal cancer was performed using GP prescription records. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for medication use and oesophageal cancer. In UK Biobank, a cohort study was conducted using self-reported medication use. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs for medication use and oesophageal cancer, and by tumour subtype. Overall, 1,979 oesophageal cancer patients were matched to 9,543 controls in PCCIU, and 355 of 475,768 participants developed oesophageal cancer in UK Biobank. None of the medications investigated were significantly associated with oesophageal cancer risk apart from ß2 agonists, which were associated with increased oesophageal cancer risk in PCCIU (adjusted OR 1.38, 95% CI 1.12, 1.70) but not in UK Biobank (adjusted HR 1.21, 95% CI 0.70, 2.08). Medications that relax the lower oesophageal sphincter were not associated with oesophageal cancer, apart from ß2 agonists. This increased cancer risk in ß2 agonist users merits further investigation.

Model for Identifying Individuals at Risk for Esophageal Adenocarcinoma.

BACKGROUND & AIMS: The prognosis for most patients with esophageal adenocarcinoma (EAC) is poor because they present with advanced disease. Models developed to identify patients at risk for EAC and increase early detection have been developed based on data from case-control studies. We analyzed data from a prospective study to identify factors available to clinicians that identify individuals with a high absolute risk of EAC. METHODS: We collected data from 355,034 individuals (all older than 50 years) without a prior history of cancer enrolled in the UK Biobank prospective cohort study from 2006 through 2010; clinical data were collected through September 2014. We identified demographic, lifestyle, and medical factors, measured at baseline, that associated with development of EAC within 5 years using logistic regression analysis. We used these data to create a model to identify individuals at risk for EAC. Model performance was assessed using area under the receiver operating characteristics curve (AUROC), sensitivity, and specificity analyses. RESULTS: Within up to 5 years of follow up, 220 individuals developed EAC. Age, sex, smoking, body mass index, and history of esophageal conditions or treatments identified individuals who developed EAC (AUROC, 0.80; 95% CI, 0.77-0.82). We used these factors to develop a scoring system and identified a point cut off that 104,723 individuals (29.5%), including 170 of the 220 cases with EAC, were above. The scoring system identified individuals who developed EAC with 77.4% sensitivity and 70.5% specificity. The 5-year risk of EAC was 0.16% for individuals with scores above the threshold and 0.02% for individuals with scores below the threshold. CONCLUSION: We combined data on several well-established risk factors that are available to clinicians to develop a system to identify individuals with a higher absolute risk of EAC within 5 years. Studies are needed to evaluate the utility of these factors in a multi-stage, triaged, screening program.

Limping following limb loss increases locomotor stability.

Although many arthropods have the ability to voluntarily lose limbs, how these animals rapidly adapt to such an extreme perturbation remains poorly understood. It is thought that moving with certain gaits can enable efficient, stable locomotion; however, switching gaits requires complex information flow between and coordination of an animal's limbs. We show here that upon losing two legs, spiders can switch to a novel, more statically stable gait, or use temporal adjustments without a gait change. The resulting gaits have higher overall static stability than the gaits that would be imposed by limb loss. By decreasing the time spent in a low-stability configuration - effectively 'limping' over less-stable phases of the stride - spiders increased the overall stability of the less statically stable gait with no observable reduction in speed, as compared with the intact condition. Our results shed light on how voluntary limb loss could have persisted evolutionarily among many animals, and provide bioinspired solutions for robots when they break or lose limbs.

Automated calibration of laser spectrometer measurements of δ18 O and δ2 H values in water vapour using a Dew Point Generator.

RATIONALE: Continuous measurement of stable O and H isotope compositions in water vapour requires automated calibration for remote field deployments. We developed a new low-cost device for calibration of both water vapour mole fraction and isotope composition. METHODS: We coupled a commercially available dew point generator (DPG) to a laser spectrometer and developed hardware for water and air handling along with software for automated operation and data processing. We characterised isotopic fractionation in the DPG, conducted a field test and assessed the influence of critical parameters on the performance of the device. RESULTS: An analysis time of 1 hour was sufficient to achieve memory-free analysis of two water vapour standards and the δ18 O and δ2 H values were found to be independent of water vapour concentration over a range of ≈20,000-33,000 ppm. The reproducibility of the standard vapours over a 10-day period was better than 0.14 ‰ and 0.75 ‰ for δ18 O and δ2 H values, respectively (1 σ, n = 11) prior to drift correction and calibration. The analytical accuracy was confirmed by the analysis of a third independent vapour standard. The DPG distillation process requires that isotope calibration takes account of DPG temperature, analysis time, injected water volume and air flow rate. CONCLUSIONS: The automated calibration system provides high accuracy and precision and is a robust, cost-effective option for long-term field measurements of water vapour isotopes. The necessary modifications to the DPG are minor and easily reversible.

Lactic Acid Suppresses IL-33-Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1α-Dependent miR-155 Suppression.

Lactic acid (LA) is present in tumors, asthma, and wound healing, environments with elevated IL-33 and mast cell infiltration. Although IL-33 is a potent mast cell activator, how LA affects IL-33-mediated mast cell function is unknown. To investigate this, mouse bone marrow-derived mast cells were cultured with or without LA and activated with IL-33. LA reduced IL-33-mediated cytokine and chemokine production. Using inhibitors for monocarboxylate transporters (MCT) or replacing LA with sodium lactate revealed that LA effects are MCT-1- and pH-dependent. LA selectively altered IL-33 signaling, suppressing TGF-ß-activated kinase-1, JNK, ERK, and NF-κB phosphorylation, but not p38 phosphorylation. LA effects in other contexts have been linked to hypoxia-inducible factor (HIF)-1α, which was enhanced in bone marrow-derived mast cells treated with LA. Because HIF-1α has been shown to regulate the microRNA miR-155 in other systems, LA effects on miR-155-5p and miR-155-3p species were measured. In fact, LA selectively suppressed miR-155-5p in an HIF-1α-dependent manner. Moreover, overexpressing miR-155-5p, but not miR-155-3p, abolished LA effects on IL-33-induced cytokine production. These in vitro effects of reducing cytokines were consistent in vivo, because LA injected i.p. into C57BL/6 mice suppressed IL-33-induced plasma cytokine levels. Lastly, IL-33 effects on primary human mast cells were suppressed by LA in an MCT-dependent manner. Our data demonstrate that LA, present in inflammatory and malignant microenvironments, can alter mast cell behavior to suppress inflammation.

IL-10-Induced miR-155 Targets SOCS1 To Enhance IgE-Mediated Mast Cell Function.

IL-10 is an important regulatory cytokine that modulates a wide range of immune cells. Whereas it is best known for its ability to suppress immune responses, IL-10 has been found to be pathogenic in several human and animal studies of immune-mediated diseases. There is a considerable gap in our understanding of the molecular mechanisms behind the stimulatory effects of IL-10 during allergic inflammation. IL-10 treatment has been shown to suppress mast cell TNF production. In this study, we report that whereas TNF secretion was reduced, IL-10 surprisingly enhanced IgE-mediated protease and cytokine production both in vitro and in vivo. This stimulatory effect was consistent in mouse and human skin mast cells. IL-10 enhanced activation of the key FcεRI signaling proteins Stat5, JNK, and ERK. We demonstrate that IL-10 effects are dependent on Stat3 activation, eliciting miR-155 expression, with a resulting loss of suppressor of cytokine signaling-1. The importance of miR-155 was demonstrated by the inability of IL-10 to enhance anaphylaxis in miR-155-deficient mice. Taken together, our results reveal an IL-10-induced, Stat3-miR-155 signaling pathway that can promote mast cell responses.