Catecholamine levels with use of electronic and combustible cigarettes.

INTRODUCTION: Smoking elevates catecholamines that increase the risk for cardiovascular disease. Sparse evidence exists about the effects of e-cigarettes and catecholamines. Higher levels of catecholamines could trigger the increased heart rate, blood pressure, and decreased vascular function reported with the use of e-cigarettes. We investigated the difference in urinary catecholamines and their metabolites before and after the use of an e-cigarette containing nicotine or cigarettes compared to no tobacco use. METHODS: In our observational cohort exposure study, healthy adults aged 21-45 years who were currently using e-cigarettes, cigarettes, or had never used tobacco, participated in an acute exposure visit using their most common tobacco product. Urine was collected before, 1, and 2 hours after a 3-second puff every 30 seconds for 10 minutes on an e-cigarette or straw or use of 1 cigarette. Urinary catecholamines and their metabolites were measured by ultra-high-performance liquid chromatography. Participants (n=323) were grouped by the product used at the visit. We compared levels of creatinine normalized log-transformed urinary catecholamines and their metabolites across groups using Dunn's test following a Kruskal-Wallis test in unadjusted and demographically adjusted models. RESULTS: Prior to use, individuals who used cigarettes (n=70) had lower urinary metabolites from epinephrine, serotonin, and norepinephrine. No differences were seen in those who used e-cigarettes (n=171) and those who did not use tobacco (n=82). In fully adjusted models, 1 h after the use of a combustible or e-cigarette, log-transformed urinary metabolites from norepinephrine (ß=1.22; 95% CI: 0.39-2.05, p=0.004 and ß=1.06; 95% CI: 0.39-1.74, p=0.002), dopamine (ß=0.37; 95% CI: 0.24-0.5, p<0.001 and ß=0.15; 95% CI: 0.05-0.26, p<0.001), and epinephrine (ß=1.89; 95% CI: 0.51-3.27, p=0.008 and ß=1.49; 95% CI: 0.38-2.61, p=0.009) were elevated. In fully adjusted models, combustible cigarette use was associated with elevated urinary norepinephrine (ß=0.46; 95% CI: 0.13-0.81, p=0.007) and dopamine (ß=0.19; 95% CI: 0.06-0.31, p=0.003) 1 h after use. CONCLUSIONS: We found that the use of both e-cigarettes and cigarettes was associated with elevated urinary catecholamines or their metabolites. Catecholamines could be useful as a biomarker of harm for tobacco use and considered by tobacco regulatory scientists in future research.

Formaldehyde and the transient receptor potential ankyrin-1 contribute to electronic cigarette aerosol-induced endothelial dysfunction in mice.

Electronic nicotine delivery systems (ENDS) aerosol exposures can induce endothelial dysfunction (ED) in healthy young humans and animals. Thermal degradation of ENDS solvents, propylene glycol, and vegetable glycerin (PG: VG), generates abundant formaldehyde (FA) and other carbonyls. Because FA can activate the transient receptor potential ankyrin-1 (TRPA1) sensor, we hypothesized that FA in ENDS aerosols provokes TRPA1-mediated changes that include ED and "respiratory braking"-biomarkers of harm. To test this, wild-type (WT) and TRPA1-null mice were exposed by inhalation to either filtered air, PG: VG-derived aerosol, or FA (5 ppm). Short-term exposures to PG: VG and FA-induced ED in female WT but not in female TRPA1-null mice. Moreover, acute exposures to PG: VG and FA stimulated respiratory braking in WT but not in TRPA1-null female mice. Urinary metabolites of FA (ie, N-1,3-thiazolidine-4-carboxylic acid, TCA; N-1,3-thiazolidine-4-carbonyl glycine, TCG) and monoamines were measured by LC-MS/MS. PG: VG and FA exposures significantly increased urinary excretion of both TCA and TCG in both WT and TRPA1-null mice. To confirm that inhaled FA directly contributed to urinary TCA, mice were exposed to isotopic 13C-FA gas (1 ppm, 6 h). 13C-FA exposure significantly increased the urine level of 13C-TCA in the early collection (0 to 3 h) supporting a direct relationship between inhaled FA and TCA. Collectively, these data suggest that ENDS use may increase CVD risk dependent on FA, TRPA1, and catecholamines, yet independently of either nicotine or flavorants. This study supports that levels of FA in ENDS-derived aerosols should be lowered to mitigate CVD risk in people who use ENDS.

Nicotine Formulation Influences the Autonomic and Arrhythmogenic Effects of Electronic Cigarettes.

INTRODUCTION: Evidence is mounting that electronic cigarette (e-cig) use induces cardiac sympathetic dominance and electrical dysfunction conducive to arrhythmias and dependent upon nicotine. A variety of nicotine types and concentrations are available in e-cigs, but their relative cardiovascular effects remain unclear. Here we examine how different nicotine forms (racemic, free-base, and salt) and concentrations influence e-cig-evoked cardiac dysfunction and arrhythmogenesis and provide a mechanism for nicotine-salt-induced autonomic imbalance. METHODS: ECG-telemetered C57BL/6J mice were exposed to filtered air (FA) or e-cig aerosols from propylene glycol and vegetable glycerin solvents either without nicotine (vehicle) or with increasing nicotine concentrations (1%, 2.5%, and 5%) for three 9-min puff sessions per concentration. Spontaneous ventricular premature beat (VPB) incidence rates, heart rate, and heart rate variability (HRV) were compared between treatments. Subsequently, to test the role of ß1-adrenergic activation in e-cig-induced cardiac effects, mice were pretreated with atenolol and exposed to either FA or 2.5% nicotine salt. RESULTS: During puffing and washout phases, ≥ 2.5% racemic nicotine reduced heart rate and increased HRV relative to FA and vehicle controls, indicating parasympathetic dominance. Relative to both controls, 5% nicotine salt elevated heart rate and decreased HRV during washout, suggesting sympathetic dominance, and also increased VPB frequency. Atenolol abolished e-cig-induced elevations in heart rate and declines in HRV during washout, indicating e-cig-evoked sympathetic dominance is mediated by ß1-adrenergic stimulation. CONCLUSIONS: Our findings suggest that inhalation of e-cig aerosols from nicotine salt-containing e-liquids could increase the cardiovascular risks of vaping by inducing sympathetic dominance and cardiac arrhythmias. IMPLICATIONS: Exposure to e-cig aerosols containing commercially relevant concentrations of nicotine salts may increase nicotine delivery and impair cardiac function by eliciting ß1-adrenoceptor-mediated sympathoexcitation and provoking ventricular arrhythmias. If confirmed in humans, our work suggests that regulatory targeting of nicotine salts through minimum pH standards or limits on acid additives in e-liquids may mitigate the public health risks of vaping.

Effects of Environmental Polycyclic Aromatic Hydrocarbons Exposure and Pro-Inflammatory Activity on Type 2 Diabetes Mellitus in US Adults.

Polycyclic aromatic hydrocarbons (PAHs) are formed due to natural and anthropogenic activities and known for their potential impact and persistence in the environment. PAHs exposure has been linked to cause adverse health effect including lung cancer, heart conditions and genetic mutations. The understanding of metabolic effects of PAHs exposure is less clear especially in the presence of pro-inflammatory stress like alcoholism or diabetes. The aim of this article is to understand the metabolic effects of PAHs exposure on Type 2 Diabetes Mellitus (T2DM) by analyzing the clinical biomarkers data retrieved from the National Health and Nutrition Examination Survey, Center for Disease Control (CDC NHANES) (2015-16). This study has also accessed the interactive impact of PAHs and other proinflammatory factors, like alcohol intake on the metabolic syndrome on T2DM. We investigated urinary levels of hydroxylated PAHs metabolites (OH-PAHs) along with demographic, clinical and laboratory data. Generalize linear model Univariate factorial ANOVA was used to evaluate the group differences in the demographics, PAH exposure, drinking patterns, clinical data, and biomarker levels. Linear regression model was used to analyze the association of biomarkers, PAH exposure and drinking data. Multivariable regression model was used for multi-independent model to assess comorbidity association and their effect sizes on the clinical outcomes. The results indicated that BMI (p = 0.002), and age (≤0.001) are independent demographic risk factors for T2DM in high PAHs exposure. Acute proinflammatory activity characterized by CRP, is augmented by elevated monocyte levels (p ≤ 0.001) and stepwise addition of 1-Hydroxynapthelene (p = 0.005), and 2-Hydroxynapthelene (p = 0.001) independently. Prevalence of highest average drinks over time is observed in the high PAHs exposure; with males drinking almost twice compared to females in highly exposed population. Pathway response of T2DM shows sexual dimorphism; with males showing association with triglycerides (p ≤ 0.001), and females with CRP (p = 0.015) independently with HbA1C. The arrangement of CRP, absolute monocyte levels, serum triglycerides and average drinks over time predict the HbA1C levels (adjusted R2 = 0.226, p ≤ 0.001) in individuals with high PAHs exposure. Findings from this investigation support the pathological role of high exposure of PAHs in the exacerbation of metabolic disorder syndrome involving T2DM. Sexual dimorphism is reflected in alcohol drinking, with males drinking more in the high PAHs exposure group. Alcohol drinking as an independent factor was associated with the T2DM indicator, HbA1C in individuals with high PAHs exposure.

Electronic cigarette solvents, pulmonary irritation, and endothelial dysfunction: role of acetaldehyde and formaldehyde.

After more than a decade of electronic cigarette (E-cig) use in the United States, uncertainty persists regarding E-cig use and long-term cardiopulmonary disease risk. As all E-cigs use propylene glycol and vegetable glycerin (PG-VG) and generate abundant saturated aldehydes, mice were exposed by inhalation to PG-VG-derived aerosol, formaldehyde (FA), acetaldehyde (AA), or filtered air. Biomarkers of exposure and cardiopulmonary injury were monitored by mass spectrometry (urine metabolites), radiotelemetry (respiratory reflexes), isometric myography (aorta), and flow cytometry (blood markers). Acute PG-VG exposure significantly affected multiple biomarkers including pulmonary reflex (decreased respiratory rate, -50%), endothelium-dependent relaxation (-61.8 ± 4.2%), decreased WBC (-47 ± 7%), and, increased RBC (+6 ± 1%) and hemoglobin (+4 ± 1%) versus air control group. Notably, FA exposure recapitulated the prominent effects of PG-VG aerosol on pulmonary irritant reflex and endothelial dysfunction, whereas AA exposure did not. To attempt to link PG-VG exposure with FA or AA exposure, urinary formate and acetate levels were measured by GC-MS. Although neither FA nor AA exposure altered excretion of their primary metabolite, formate or acetate, respectively, compared with air-exposed controls, PG-VG aerosol exposure significantly increased post-exposure urinary acetate but not formate. These data suggest that E-cig use may increase cardiopulmonary disease risk independent of the presence of nicotine and/or flavorings. This study indicates that FA levels in tobacco product-derived aerosols should be regulated to levels that do not induce biomarkers of cardiopulmonary harm. There remains a need for reliable biomarkers of exposure to inhaled FA and AA.NEW & NOTEWORTHY Use of electronic cigarettes (E-cig) induces endothelial dysfunction (ED) in healthy humans, yet the specific constituents in E-cig aerosols that contribute to ED are unknown. Our study implicates formaldehyde that is formed in heating of E-cig solvents (propylene glycol, PG; vegetable glycerin, VG). Exposure to formaldehyde or PG-VG-derived aerosol alone stimulated ED in female mice. As ED was independent of nicotine and flavorants, these data reflect a "universal flaw" of E-cigs that use PG-VG.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/e-cigarettes-aldehydes-and-endothelial-dysfunction/.

Comprehensive Review of Abdominopelvic Mesenchymal Tumors With Radiologic Pathologic Correlation and Update on Current Treatment Guidelines-Part 2.

Soft-tissue sarcomas are a diverse group of rare mesenchymal malignancies accounting for only 1% of all solid adult malignancies. These have been categorized in 12 broad groups by the World Health Organization (WHO) with their recent update in 2013. Majority of them lack specific imaging features serving as imaging conundrums for a radiologist. These are often large masses at presentation as they are asymptomatic or cause vague clinical symptoms. These tumors are challenging for surgeons as well as they find it difficult to achieve complete resection because of complex intra-abdominal anatomy and their close relationship with critical structures. Often, a multidisciplinary approach is required to decide on the most appropriate management for these complex cases so as to provide optimal patient care. Knowledge of the WHO classification, pathologic features, and treatment options available helps the radiologist make a meaningful contribution in multidisciplinary discussions of such cases and overall patient care. Liposarcoma (well-differentiated and dedifferentiated liposarcomas), leiomyosarcoma, and gastrointestinal stromal tumor are the 3 most common primary intra-abdominal sarcomas. In part 1 of this article, general features of soft-tissue sarcomas and some of the common tumors from WHO category 1-4 found in abdomen and pelvis are discussed. Part 2 will focus on common tumors from remainder of the WHO categories.

Association between residential greenness and exposure to volatile organic compounds.

Residential proximity to vegetation and plants is associated with many health benefits, including reduced risk of cardiovascular disease, diabetes and mental stress. Although the mechanisms by which proximity to greenness affects health remain unclear, plants have been shown to remove particulate air pollution. However, the association between residential-area vegetation and exposure to volatile organic chemicals (VOCs) has not been investigated. We recruited a cohort of 213 non-smoking individuals and estimated peak, cumulative, and contemporaneous greenery using satellite-derived normalized difference vegetation index (NDVI) near their residence. We found that the urinary metabolites of exposure to VOCs - acrolein, acrylamide, acrylonitrile, benzene, 1-bromopropane, propylene oxide were inversely associated (7-31% lower) with 0.1 higher peak NDVI values within 100 m radius of the participants' home. These associations were significant at radii ranging from 25 to 300 m. Strongest associations were observed within a 200 m radius, where VOC metabolites were 22% lower per 0.1 unit higher NDVI. Of the 18 measured urinary metabolites, 7 were positively associated with variation of greenness within a 200 m radius of homes. The percent of tree canopy and street trees around participants' residence were less strongly associated with metabolite levels. The associations between urinary VOC metabolites and residential NDVI values were stronger in winter than in summer, and in participants who were more educated, White, and those who lived close to areas of high traffic. These findings suggest high levels of residential greenness are associated with lower VOC exposure, particularly in winter.

Oral squamous cell carcinoma profile in North-Eastern regions of India from habits to histopathology: A hospital-based study.

BACKGROUND: Head and neck cancers constitute about 5%-8% of total body cancers in Europe, America, but in India, this figure is somewhat higher. The aim of this study is to evaluate the current burden of oral cancers in India, particularly North-East India. MATERIALS AND METHODS: A full-length study starting from patient counseling to clinical and histopathological examination and grading was planned. The study was conducted under the guidance of clinician, oral surgeon, oral pathologists, and statistician. RESULTS: In the 3 years study, all the patients with oral lesions are examined clinically, out of them suspected oral cancer patients were histopathologically confirmed as oral squamous cell carcinoma patient. The socioeconomic profile of oral cancer patients in relation to all examined patients was summarized, and results are drawn. CONCLUSION: The studied population is heavily indulgent tobacco consumption. Education for cancer prevention, early detection, and treatment is needed.

Role of Y Box Protein-1 in cancer: As potential biomarker and novel therapeutic target.

The Y-box binding protein (YB-1) is known to be a multifunctional transcription and translation factor during expression of several proteins. It is a vital oncoprotein that regulates cancer cell progression and proliferation. YB-1 is over-expressed in various human cancers such as breast cancer, colon cancer, lung cancer, gastric cancer, oesophageal cancer and glioblastoma. Nuclear expression of YB-1 is found to be associated with multidrug resistance and cancer cell progression. YB-1 is reported to regulate many cellular signalling pathways in different types of cancer proliferation. Knowledge about nuclear localization and nuclear level expression of YB-1 in different cancers has been correlated with prospective prognosis of cancer. This review discusses the prospects of YB-1 as a potential biomarker as well as therapeutic target in lieu of their role during cancer progression and multidrug resistance.

Imatinib mesylate resistance and mutations: An Indian experience.

The treatment of chronic myeloid leukemia (CML) has been revolutionized by the small molecule selective kinase inhibitor imatinib mesylate. Imanitib was the first BCR-ABL targeted agent approved for the treatment of CML patients and confers significant response in most patients; however, a substantial number of patients are initially refractory to the drug or may develop resistance during the course of treatment. Point mutations in the kinase domain (KD) of BCR-ABL that impact drug binding have been identified as one of the major mechanisms of resistance. We present here an overview of the current practice in monitoring for such mutations, including the methods used, criteria for investigating and guidelines for reporting the mutations. We further present and discuss the experience of our own laboratory in studying the KD mutations in Indian CML patients on imatinib treatment.

Vibrational dynamics of poly(L-isoleucine).

Normal mode analysis and their dispersion for poly(L-isoleucine) are reported by using Urey Bradley force field and Fourier transform IR. The calculated frequencies are found to be in reasonably good agreement with the Fourier transform IRspectra. Experimental measurements reported by Wunderlich et al. also support the calculated specific heat variation of poly(L-isoleucine).

Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis.

OBJECTIVE: To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. METHODS: Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0). RESULTS: A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well. CONCLUSION: Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis.