Plasma Cotinine Concentrations Research Articles

A randomised controlled trial to evaluate the effectiveness of a culture and disease-specific, patient-centric multi-component tobacco cessation intervention package for the patients attending non-communicable disease clinics in Punjab, India

Background Developing an infrastructure to support tobacco cessation through existing systems and resources is crucial for ensuring the greatest possible access to cessation services. The present study aims to evaluate the effectiveness of a newly developed multi-component cessation among tobacco users in Non- Communicable Disease (NCD) clinics, functioning under the National Programme for Prevention & Control of Cancer, Diabetes, Cardiovascular Diseases, & Stroke (NPCDCS) of the Government of India. Methods The intervention package consisting of culture- and disease-specific four face-to-face counselling sessions, pamphlets, and short text messages (bilingual) with follow-ups at 3rd, 6th, and 9th months with an endline assessment at 12th months was delivered to the intervention arm of the two-arm- parallel group randomised controlled trial at two selected NCD clinics. Self-reported seven-day abstinence, frequency of use, expenditure in seven days at each follow-up, FTND score, stage of change and plasma cotinine values were assessed at baseline, follow-ups, and endline (using Liquid Chromatography –Mass Spectrometry), as applicable. Results The intervention arm reported a significantly more reduction in self-reported frequency of tobacco use at 6 months (mean: 13.6, 95% CI (7.8–19.4)), 9 months (mean: 20.3, 95% CI (12.2–28.4)) and 12 months (mean: 18.7, 95% CI (8.7–28.7)). The plasma cotinine concentration at endline in the intervention arm was statistically significantly lower than the baseline concentration. Conclusion Strengthening existing health systems is crucial for offering cessation support in the resource-restraint setting of LMICs to assist in quitting sustainably.

Transdermal Nicotine Patch Increases the Number and Function of Endothelial Progenitor Cells in Young Healthy Nonsmokers without Adverse Hemodynamic Effects.

Transdermal nicotine patches (TNPs), administering nicotine into the bloodstream through skin, have been widely used as nicotine replacement therapy, and exposure to nicotine can be detected by measurement of plasma cotinine concentration. In animal studies, nicotine treatment could increase the number of endothelial progenitor cells (EPCs), but the effect of TNPs on circulating EPCs and their activity in humans remained unclear. This study aimed to explore the influence of TNPs on circulating EPCs with surface markers of CD34, CD133, and/or KDR, and colony-forming function plus migration activity of early EPCs derived from cultured peripheral blood mononuclear cells before and after TNP treatments in young healthy nonsmokers. In parallel, pulse wave analysis (PWA) was applied to evaluate the vascular effect of TNP treatments. Twenty-one participants (25.8 ± 3.6 years old, 10 males) used TNP (nicotine: 4.2 mg/day) for 7 consecutive days. During the treatment, the CD34+ EPCs progressively increased in number. In addition, the number of EPCs positive for CD34/KDR, CD133, and CD34/CD133 were also increased on day 7 of the treatment. Furthermore, the early EPC colony-forming function and migration activity were increased with the plasma cotinine level positively correlating with change in colony-forming unit number. PWA analyses on day 7, compared with pretreatment, did not show significant change except diastolic pressure time index, which was prolonged and implied potential vascular benefit. In conclusion, 7-day TNP treatments could be a practical strategy to enhance angiogenesis of circulating EPCs to alleviate tissue ischemia without any hemodynamic concern.

Investigation of the relationship between nicotine and cotinine concentrations in human biological samples by a GC-MS method

In this study, a gas chromatography-mass spectrometry method was developed for the determination of nicotine and cotinine wherein human plasma, urine, and saliva. In addition, it was aimed to determine statistically the correlation between nicotine and cotinine levels in urine and saliva samples and nicotine and cotinine levels in blood samples. The limit of quantification was ≤0.83 ng/mL and precision were ≤4.91 and accuracy (RE%) was between (-4.93) and 4.90. Recovery was detected between 95.4% and 104.7%. The method was employed to determining the nicotine and cotinine concentrations in plasma, saliva, and urine total of 91 samples belong to non-smokers (n=37) and active smokers (n=54) who were healthy (n=65) and COPD patients (n=27) and the statistical relationship within the nicotine and cotinine values of the samples were investigated. It was found a correlation (r=0.752, p≤0.01) between plasma and saliva cotinine levels and estimation equation calculated as y=1.56x+43.24. Also, the correlation between plasma and urine cotinine levels was found (r=0.787, p≤0.01) by the equation that y=0.31x+34.59. The results show that by accurately determining the amount of cotinine in both saliva and urine, the exposure risks of both active smokers and those exposed to cigarette smoke with the ETS can be estimated.

Strawberry Additive Increases Nicotine Vapor Sampling and Systemic Exposure But Does Not Enhance Pavlovian-Based Nicotine Reward in Mice.

Nicotine is an addictive drug whose popularity has recently increased, particularly among adolescents, because of the availability of electronic nicotine devices (i.e., "vaping") and nicotine e-liquids containing additives with rich chemosensory properties. Some efforts to understand the role of these additives in nicotine reward suggest that they increase nicotine reward and reinforcement, but the sensory contributions of additives, especially in their vapor forms, are largely untested. Here, to better understand how a fruit-flavored (i.e., strawberry) additive influences nicotine reward and aversion, we used a conditioned place preference (CPP) procedure in which nicotine and a strawberry additive were delivered as a vapor to male and female adolescent mice. We found that nicotine vapor alone can lead to a dose-dependent CPP when using a biased design. The strawberry additive did not produce CPP on its own, and we did not observe an effect of the strawberry additive on nicotine vapor-induced reward. Nevertheless, mice exposed to nicotine plus strawberry additive vapor had higher plasma cotinine concentrations, which did not appear to reflect altered nicotine metabolism. Instead, by directly measuring vapor sampling through respiration monitoring, we uncovered an increase in the amount of sniffing toward strawberry-containing nicotine vapor compared with nicotine vapor alone. Together these data indicate that chemosensory-rich e-liquid additives may enhance the perceived sensory profile of nicotine vapors rather than the reward value per se, which leads to overall increased nicotine exposure.

Deconvolution of Systemic Pharmacokinetics Predicts Inhaled Aerosol Dosimetry of Nicotine

Absorption of inhaled compounds can occur from multiple sites based on upper and lower respiratory tract deposition, and clearance mechanisms leading to differential local and systemic pharmacokinetics. Deriving inhaled aerosol dosimetry and local tissue concentrations for nose-only exposure in rodents and inhaled products in humans is challenging. In this study we use inhaled nicotine as an example to identify regional respiratory tract deposition, absorption fractions, and their contribution toward systemic pharmacokinetics in rodents and humans. A physiologically based pharmacokinetic (PBPK) model was constructed to describe the disposition of nicotine and its major metabolite, cotinine. The model description for the lungs was simplified to include an upper respiratory tract region with active mucociliary clearance and a lower respiratory tract region. The PBPK model parameters such as rate of oral absorption, metabolism and clearance were fitted to the published nicotine and cotinine plasma concentrations post systemic administration and oral dosing. The fractional deposition of inhaled aerosol in the upper and lower respiratory tract regions was estimated by fitting the plasma concentrations. The model predicted upper respiratory tract deposition was 63.9% for nose-only exposure to nicotine containing nebulized aqueous aerosol in rats and 60.2% for orally inhaled electronic vapor product in humans. A marked absorption of nicotine from the upper respiratory tract and the gastrointestinal tract for inhaled aqueous aerosol contributed to the differential systemic pharmacokinetics in rats and humans. The PBPK model derived dosimetry shows that the current aerosol dosimetry models with their posteriori application using independent aerosol physicochemical characterization to predict aerosol deposition are insufficient and will need to consider complex interplay of inhaled aerosol evolutionary process. While the study highlights the needs for future research, it provides a preliminary framework for interpreting pharmacokinetics of inhaled aerosols to facilitate the analysis of in vivo exposure-responses for pharmacological and toxicological assessments.

Investigation of exposure biomarkers in human plasma following differing levels of tobacco-specific N-nitrosamines and nicotine in cigarette smoke

Tobacco-specific N-nitrosamines (TSNAs) are strong carcinogens widely found in tobacco products, environmental tobacco smoke, lake, and wastewater. The main objective of this study was to investigate the effects of cigarette smoke with different yields of TSNAs (NNK, NNN, NAT, NAB) and nicotine on the levels of biomarkers of exposure in smokers’ plasma. Three hundred healthy volunteers were recruited comprising 60 smokers of each of 3 mg, 8 mg and 10 mg ISO tar yield cigarettes and 60 smokers who smoked 10 mg, 8 mg, and 3 mg for 14 days sequentially and 60 non-smokers. All study participants were male, aged from 21 to 45 years old, and were recruited from a same unit in Hebei, China. We measured the levels of NNAL, NAT, NNN, NAB and cotinine in plasma from 240 smokers and 60 non-smokers using a novel method established by online two-dimensional solid phase extraction-liquid chromatography-tandem mass spectrometry. The results showed that NNAL, NAT, NNN, NAB and cotinine in the plasma of smokers smoking cigarette with low TSNAs and nicotine were lower than that with high TSNAs and nicotine. When smokers switched from higher to lower TSNA yields of cigarettes, their plasma NNAL, NAT, NNN, NAB levels significantly decreased. The plasma concentrations of NNAL were significantly correlated with those of cotinine, NNN, NAT and NAB for smokers (p < 0.001). Similarly, the plasma concentrations of cotinine were significantly correlated with those of NNN, NAT and NAB for smokers (p < 0.001). The plasma NNAL, NAT, NNN, NAB and cotinine levels for smokers were significantly higher than those for non-smokers. These findings suggested that the total NNAL, NNN, NAT, NAB and cotinine in plasma were valid and reliable biomarkers for human exposure to TSNAs and nicotine.

Association between early gestation passive smoke exposure and neonatal size among self-reported non-smoking women by race/ethnicity: A cohort study

Understanding implications of passive smoke exposure during pregnancy is an important public health issue under the Developmental Origins of Health and Disease paradigm. In a prospective cohort of low-risk non-smoking pregnant women (NICHD Fetal Growth Studies-Singletons, 2009-2013, N = 2055), the association between first trimester passive smoke exposure and neonatal size was assessed by race/ethnicity. Plasma biomarker concentrations (cotinine, nicotine) assessed passive smoke exposure. Neonatal anthropometric measures included weight, 8 non-skeletal, and 2 skeletal measures. Linear regression evaluated associations between continuous biomarker concentrations and neonatal anthropometric measures by race/ethnicity. Cotinine concentrations were low and the percent above limit of quantification varied by maternal race/ethnicity (10% Whites; 14% Asians; 15% Hispanics; 49% Blacks). The association between cotinine concentration and infant weight differed by race/ethnicity (Pinteraction = 0.034); compared to women of the same race/ethnicity, per 1 log-unit increase in cotinine, weight increased 48g (95%CI -44, 139) in White and 51g (95%CI -81, 183) in Hispanic women, but decreased -90g (95%CI -490, 309) in Asian and -93g (95%CI -151, -35) in Black women. Consistent racial/ethnic differences and patterns were found for associations between biomarker concentrations and multiple non-skeletal measures for White and Black women (Pinteraction<0.1). Among Black women, an inverse association between cotinine concentration and head circumference was observed (-0.20g; 95%CI -0.38, -0.02). Associations between plasma cotinine concentration and neonatal size differed by maternal race/ethnicity, with increasing concentrations associated with decreasing infant size among Black women, who had the greatest biomarker concentrations. Public health campaigns should advocate for reducing pregnancy exposure, particularly for vulnerable populations.

Plasma Cotinine Is Positively Associated with Homocysteine in Smokers but Not in Users of Smokeless Tobacco.

Plasma total homocysteine (tHcy) is a risk marker, and smoking is an established risk factor for cardiovascular disease. It is unclear if the effect of smoked tobacco on homocysteine is mediated by nicotine or other combustion products in smoked tobacco. Snus (moist smokeless tobacco) is high nicotine-containing tobacco, and little is known about the effect of snus on plasma homocysteine. Therefore, we studied, in a cross-section of subjects (n = 1375) from the Northern Sweden Health and Disease Study, with strictly defined current smokers (n = 194) and snus users (n = 47), the impact of tobacco exposure on tHcy, assessed by self-reported tobacco habits and plasma cotinine concentrations. The snus users had higher cotinine concentrations than the smokers. Cotinine, creatinine, methylmalonic acid, and the methylenetetrahydrofolate reductase genotype (MTHFR) T allele were positively associated with tHcy among the smokers, but not among the snus users. No association was observed between tHcy and the number of cigarettes/day. There was a positive association between cotinine and tHcy in the smokers, but not among the snus users. This indicates that substances other than nicotine in tobacco smoke could be responsible for the differential effects on homocysteine status. Self-reported smoking should be complemented by a cotinine assay whenever possible.

Nicotine formulations impact reinforcement-related behaviors in a mouse model of vapor self-administration

BackgroundElectronic nicotine delivery systems (ENDS) differ from combustible cigarettes given that nicotine-salt or nicotine-freebase may be used depending on the product. We have investigated how nicotine-salt and freebase formulations alter e-Vape® self-administration (EVSA) behavior and plasma cotinine levels in male and female mice. MethodsAdult C57/BL6 J mice were used in EVSA and assigned vaping e-liquids (50:50 PGVG, 6 mg/mL nicotine-freebase, or 6 mg/mL nicotine-salt). Mice were escalated on a fixed ratio 1 (FR1) schedule in daily 2 h sessions and then transitioned to a FR3 to examine reinforcement-related behaviors. ResultsHere we observed that mice assigned nicotine-salt exhibited increased EVSA on a FR3 schedule compared to nicotine-freebase. Additionally, mice assigned nicotine-salt exhibited higher plasma cotinine concentrations following delivery-controlled passive-inhalation sessions. ConclusionsThese data provide evidence nicotine-salt formulations may contribute to greater reinforcement-related behavior and highlight the need for further investigations regarding nicotine formulation in ENDS.

Elevated plasma cotinine is associated with an increased risk of developing IBD, especially among users of combusted tobacco.

Smoking has previously been associated with inflammatory bowel disease (IBD), but no study has reported on cotinine, an objective, biochemical measure of tobacco use. We aimed at testing the hypothesis that cotinine levels among healthy subjects are associated with an increased risk of developing IBD in later life. We analysed plasma cotinine and evaluated corresponding lifestyle questionnaires that included tobacco habits in subjects (n = 96) who later developed late-onset IBD (70 ulcerative colitis (UC) and 26 Crohn's disease (CD)) and in sex and age-matched controls (n = 191). Patients who later developed IBD had significantly higher plasma cotinine levels compared to controls. In multivariable analysis, higher log-cotinine was associated with a higher risk of developing IBD (OR 1.34 (95% CI 1.01-1.63)). After stratifying for time to diagnosis, the association was only significant in subjects with shorter time (< 5.1 years) to diagnosis (OR 1.45 (1.09-1.92)). The findings were similar for UC- and CD-cases, but did not reach statistical significance in CD-cases. Although plasma cotinine concentrations were higher in snuff users compared to combusted tobacco users, no increase in the risk of IBD and lower risk of developing IBD among subjects with shorter time (< 5.1 years) to diagnosis was seen among snuff users. Cotinine, a biomarker of tobacco use, is associated with increased risk of developing late-onset IBD in general, and UC in particular. No increased risk among snuff users indicates that other components in combusted tobacco than nicotine may be involved in the pathogenesis of IBD among smokers.

Comprehensive Parent-Metabolite PBPK/PD Modeling Insights into Nicotine Replacement Therapy Strategies.

BackgroundNicotine, the pharmacologically active substance in both tobacco and many electronic cigarette (e-cigarette) liquids, is responsible for the addiction that sustains cigarette smoking. With 8 million deaths worldwide annually, smoking remains one of the major causes of disability and premature death. However, nicotine also plays an important role in smoking cessation strategies.ObjectivesThe aim of this study was to develop a comprehensive, whole-body, physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of nicotine and its major metabolite cotinine, covering various routes of nicotine administration, and to simulate nicotine brain tissue concentrations after the use of combustible cigarettes, e-cigarettes, nicotine gums, and nicotine patches.MethodsA parent–metabolite, PBPK/PD model of nicotine for a non-smoking and a smoking population was developed using 91 plasma and brain tissue concentration–time profiles and 11 heart rate profiles. Among others, cytochrome P450 (CYP) 2A6 and 2B6 enzymes were implemented, including kinetics for CYP2A6 poor metabolizers.ResultsThe model is able to precisely describe and predict both nicotine plasma and brain tissue concentrations, cotinine plasma concentrations, and heart rate profiles. 100% of the predicted area under the concentration–time curve (AUC) and maximum concentration (Cmax) values meet the twofold acceptance criterion with overall geometric mean fold errors of 1.12 and 1.15, respectively. The administration of combustible cigarettes, e-cigarettes, nicotine patches, and nicotine gums was successfully implemented in the model and used to identify differences in steady-state nicotine brain tissue concentration patterns.ConclusionsOur PBPK/PD model may be helpful in further investigations of nicotine dependence and smoking cessation strategies. As the model represents the first nicotine PBPK/PD model predicting nicotine concentration and heart rate profiles after the use of e-cigarettes, it could also contribute to a better understanding of the recent increase in youth e-cigarette use.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00880-4) contains supplementary material, which is available to authorized users.

Effects of Gene‐Environment Interactions on Endothelial Function in Adolescents: GSTM1 and GSTT1 Polymorphisms and Tobacco Smoke Exposure

IntroductionSecond‐hand smoke (SHS) exposure is a significant risk factor for cardiovascular disease (CVD) and related CV complications. SHS exposure increases arterial endothelial damage and has been associated with impaired flow‐mediated vasodilation (FMD), an ultrasonic assessment of endothelial function. There are established ethnic and sex‐related CVD health disparities attributable to SHS exposure among African Americans (AAs). In disease‐free adolescents and adults, AAs also have earlier manifestations of vascular damage including impaired FMD. Furthermore, polymorphisms in glutathione S‐transferase genes GSTM1 and GSTT1 result in the absence of enzyme activity necessary to detoxify several toxins in tobacco smoke. There is a lack of research on the impact of these GST null genotypes on endothelial function, especially within the context of smoke exposure (exposure alone or actual smoker) among normotensive disease‐free adolescents. Also, we are unaware of other studies that have examined these gene‐environment interactions with adolescents who all have an established biological family history of CVD disease (i.e., hypertension and or early myocardial infarction &lt; 55 yrs. of age in at least one parent or grandparent).PurposeTo investigate the potential gene‐environment interactions (GSTM1, GSTT1) and SHS exposure and the moderating effects of ethnicity/race on the pre‐clinical CVD risk factor (i.e. FMD) in an adolescent at‐risk cohort based on family history.MethodsSubjects were 262 normotensive adolescents aged 16–22 yrs., with nearly equal distribution of Caucasians and AAs. SHS exposure was measured by plasma cotinine using liquid chromatography with mass‐spectrometric detection and FMD of the left superficial femoral artery was determined using established procedures. To examine the effect of race, SHS and genotype (i.e., GSTT1 or GSTM1) on FMD, analysis of covariance was used.ResultsCaucasians had higher mean plasma cotinine concentrations compared with AAs (42.2 and 24.6 ng/ml, respectively), and males had higher concentrations than females (73.78 and 31.88 ng/ml, respectively). A significant three‐factor interaction was found between SHS exposure and presence of GSTM1 and GSTT1 (p = 0.016 and 0.0304, respectively) after adjusting for pre‐occlusion arterial diameter. Among all participants, AAs with the GSTM1‐1 genotype and who were also smokers exhibited the poorest %FMD compared to all other subgroups (Adjusted Mean = 0.30; SE 2.28).ConclusionHigher SHS exposure may be particularly harmful based on gene‐environment interactions in African American youth and especially in those who are already at high‐risk of developing CVD based on a positive family history. Although further research is needed, the association between GSTM1‐1 and lower %FMD in AAs may be related to early endothelial dysfunction, which is an independent predictor of CVD risk and events.Support or Funding InformationNIH/National Institute of Nursing Research 03/01/06‐2/28/08R15NR008871; PI: MSTingenThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Nicotine Supplementation Does Not Influence Performance of a 1h Cycling Time-Trial in Trained Males.

The use of nicotine amongst professional and elite athletes is high, with anecdotal evidence indicating increased prevalence amongst cycling sports. However, previous investigations into its effects on performance have not used high-validity or -reliability protocols nor trained cyclists. Therefore, the present study determined whether nicotine administration proved ergogenic during a ∼1 h self-paced cycling time-trial (TT). Ten well-trained male cyclists (34 ± 9 years; 71 ± 8 kg; O2max: 71 ± 6 ml ⋅ kg−1 ⋅ min−1) completed three work-dependent TT following ∼30 min administration of 2 mg nicotine gum (GUM), ∼10 h administration of 7 mg ⋅ 24 h−1 nicotine patch (PAT) or color- and flavor-matched placebos (PLA) in a randomized, crossover, and double blind design. Measures of nicotine’s primary metabolite (cotinine), core body temperature, heart rate, blood biochemistry (pH, HCO3−, La−) and Borg’s rating of perceived exertion (RPE) accompanied performance measures of time and power output. Plasma concentrations of cotinine were highest for PAT, followed by GUM, then PLA, respectively (p < 0.01). GUM and PAT resulted in no significant improvement in performance time compared to PLA (62.9 ± 4.1 min, 62.6 ± 4.5 min, and 63.3 ± 4.1 min, respectively; p = 0.73), with mean power outputs of 264 ± 31, 265 ± 32, and 263 ± 33 W, respectively (p = 0.74). Core body temperature was similar between trials (p = 0.33) whilst HR averaged 170 ± 10, 170 ± 11, and 171 ± 11 beats ⋅ min−1 (p = 0.60) for GUM, PAT, and PLA, respectively. There were no differences between trials for any blood biochemistry (all p > 0.46) or RPE with mean values of 16.7 ± 0.9, 16.8 ± 0.7, and 16.8 ± 0.8 (p = 0.89) for GUM, PAT, and PLA, respectively. In conclusion: (i) nicotine administration, whether via gum or transdermal patch, did not exert an ergogenic or ergolytic effect on self-paced cycling performance of ∼1 h; (ii) systemic delivery of nicotine was greatest when using a transdermal patch; and (iii) nicotine administration did not alter any of the psycho-physiological measures observed.

Self-reported prenatal tobacco smoke exposure, AXL gene-body methylation, and childhood asthma phenotypes

BackgroundEpigenetic modifications, including DNA methylation, act as one potential mechanism underlying the detrimental effects associated with prenatal tobacco smoke (PTS) exposure. Methylation in a gene called AXL was previously reported to differ in response to PTS.MethodsWe investigated the association between PTS and epigenetic changes in AXL and how this was related to childhood asthma phenotypes. We tested the association between PTS and DNA methylation at multiple CpG loci of AXL at birth using Pyrosequencing in two separate study populations, the Children’s Health Study (CHS, n = 799) and the Newborn Epigenetic Study (NEST, n = 592). Plasma cotinine concentration was used to validate findings with self-reported smoking status. The inter-relationships among AXL mRNA and miR-199a1 expression, PTS, and AXL methylation were examined. Lastly, we evaluated the joint effects of AXL methylation and PTS on the risk of asthma and related symptoms at age 10 years old.ResultsPTS was associated with higher methylation level in the AXL gene body in both CHS and NEST subjects. In the pooled analysis, exposed subjects had a 0.51% higher methylation level in this region compared to unexposed subjects (95% CI 0.29, 0.74; p < 0.0001). PTS was also associated with 21.2% lower expression of miR-199a1 (95% CI − 37.9, − 0.1; p = 0.05), a microRNA known to regulate AXL expression. Furthermore, the combination of higher AXL methylation and PTS exposure at birth increased the risk of recent episodes of bronchitic symptoms in childhood.ConclusionsPTS was associated with methylation level of AXL and the combination altered the risk of childhood bronchitic symptoms.

Association between smoking status assessed with plasma-cotinine and inflammatory and endothelial biomarkers in HIV-positive and HIV-negative individuals.

Smoking is a major contributor to mortality and morbidity in HIV-positive individuals. Our primary objective was to evaluate the association between smoking status determined by plasma cotinine (P-cotinine) concentration and inflammatory and endothelial biomarkers in HIV-positive versus HIV-negative individuals. We studied eight inflammatory/endothelial biomarkers [high-sensitivity C-reactive protein (hsCRP), E-selectin, soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular adhesion molecule 1 (sICAM-1), matrix metallopeptidase 9 (MMP-9), myeloperoxidase (MPO), tissue type plasminogen activator inhibitor 1 (tPAI) and endothelin] in 105 HIV-positive individuals and 105 HIV-negative individuals matched on age, sex and self-reported smoking status. Smoking status was determined using P-cotinine (a concentration > 14 ng/mL was defined as demonstrating exposure to smoke). We used linear regression models to (1) examine the association between smoking status and inflammatory/endothelial biomarkers in HIV-positive compared with HIV-negative individuals, and (2) to determine whether there was evidence to suggest that the impact of smoking status on the biomarkers differed between HIV-positive and HIV-negative individuals. Of the eight biomarkers, smokers had increased hsCRP, sICAM-1 and MMP-9 concentrations irrespective of HIV status and increasing P-cotinine concentration was associated with increasing hsCRP concentration. We found no interaction between smoking and HIV status. HIV infection was associated with increased hsCRP, E-selectin, sVCAM-1, sICAM-1 and MMP-9 concentrations. Self-reported smoking status differed substantially from smoking status assessed with P-cotinine. Several biomarkers were associated with smoking status and HIV status. However, our data do not indicate that the effects of smoking on the biomarkers differ between HIV-positive and HIV-negative individuals.

Early-life home environment and risk of asthma among inner-city children

Environmental exposures in early life appear to play an important role in the pathogenesis of childhood asthma, but the potentially modifiable exposures that lead to asthma remain uncertain. We sought to identify early-life environmental risk factors for childhood asthma in a birth cohort of high-risk inner-city children. We examined the relationship of prenatal and early-life environmental factors to the occurrence of asthma at 7years of age among 442 children. Higher house dust concentrations of cockroach, mouse, and cat allergens in the first 3years of life were associated with lower risk of asthma (for cockroach allergen: odds ratio per interquartile range increase in concentration, 0.55; 95% CI, 0.36-0.86; P<.01). House dust microbiome analysis using 16S ribosomal RNA sequencing identified 202 and 171 bacterial taxa that were significantly (false discovery rate<0.05) more or less abundant, respectively, in the homes of children with asthma. Amajority of these bacteria were significantly correlated with 1 of more allergen concentrations. Other factors associated significantly positively with asthma included umbilical cord plasma cotinine concentration (odds ratio per geometric SD increase in concentration, 1.76; 95% CI, 1.00-3.09; P=.048) and maternal stress and depression scores. Among high-risk inner-city children, higher indoor levels of pet or pest allergens in infancy were associated with lower risk of asthma. The abundance of a number of bacterial taxa in house dust was associated with increased or decreased asthma risk. Prenatal tobacco smoke exposure and higher maternal stress and depression scores in early life were associated with increased asthma risk.

Genetic Relationship between Schizophrenia and Nicotine Dependence.

It is well known that most schizophrenia patients smoke cigarettes. There are different hypotheses postulating the underlying mechanisms of this comorbidity. We used summary statistics from large meta-analyses of plasma cotinine concentration (COT), Fagerström test for nicotine dependence (FTND) and schizophrenia to examine the genetic relationship between these traits. We found that schizophrenia risk scores calculated at P-value thresholds of 5 × 10−3 and larger predicted FTND and cigarettes smoked per day (CPD), suggesting that genes most significantly associated with schizophrenia were not associated with FTND/CPD, consistent with the self-medication hypothesis. The COT risk scores predicted schizophrenia diagnosis at P-values of 5 × 10−3 and smaller, implying that genes most significantly associated with COT were associated with schizophrenia. These results implicated that schizophrenia and FTND/CPD/COT shared some genetic liability. Based on this shared liability, we identified multiple long non-coding RNAs and RNA binding protein genes (DA376252, BX089737, LOC101927273, LINC01029, LOC101928622, HY157071, DA902558, RBFOX1 and TINCR), protein modification genes (MANBA, UBE2D3, and RANGAP1) and energy production genes (XYLB, MTRF1 and ENOX1) that were associated with both conditions. Further analyses revealed that these shared genes were enriched in calcium signaling, long-term potentiation and neuroactive ligand-receptor interaction pathways that played a critical role in cognitive functions and neuronal plasticity.

Predictors of folate status among pregnant Japanese women: the Hokkaido Study on Environment and Children's Health, 2002-2012.

The International Clearinghouse for Birth Defects, Surveillance and Research reports a rise in the prevalence rate of spina bifida in Japan. We determined first-trimester folate status of Hokkaido women and identified potential predictors. Participants were 15 266 pregnant women of the Hokkaido Study on Environment and Children's Health Cohort. Data were extracted from self-reported questionnaires and biochemical assay results. Demographic determinants of low folate status were younger maternal age (adjusted OR (AOR) 1·48; 95 % CI 1·32, 1·66), lower educational level (AOR 1·27; 95 % CI 1·17, 1·39) and lower annual income (AOR 1·11; 95 % CI 1·01, 1·22). Plasma cotinine concentrations of 1·19-65·21 nmol/l increased the risk of low folate status (AOR 1·20; 95 % CI 1·10, 1·31) and concentrations >65·21 nmol/l further increased the risk (AOR 1·91; 95 % CI 1·70, 2·14). The most favourable predictor was use of folic acid (FA) supplements (AOR 0·19; 95 % CI 0·17, 0·22). Certain socio-demographic factors influence folate status among pregnant Japanese women. Modifiable negative and positive predictors were active and passive tobacco smoking and use of FA supplements. Avoiding both active and passive tobacco smoking and using FA supplements could improve the folate status of Japanese women.

The effect of cotinine concentrations in seminal plasma and follicular fluid on the pregnancy outcomes of couples undergoing assisted reproductive techniques.

This study determined the effects of cotinine concentrations in follicular fluid (FF) and seminal plasma (SP) on the pregnancy outcome of couples using assisted reproductive techniques (ARTs). This study was conducted as a case-control study. A total of 217 couples were included in the study. Among these couples, there were nonsmokers (66 women and 40 men), passive smokers (106 women and 54 men), and active smokers (45 women and 123 men). Demographic and smoking data were collected by questionnaire at the onset of treatment. FF and SP samples were obtained from the couples on the day of oocyte retrieval. The cotinine concentrations in the FF and SP of nonsmokers were significantly lower than they were in the other groups (P = 0.001). The difference in cotinine concentrations detected in FF between women with positive pregnancy test results and women with negative pregnancy test results was statistically insignificant. It was also determined that the percentage of clinical pregnancy was lower in nonsmoker women than in passive smoker or smoker women (P > 0.05). Although we found there was no significant difference in the pregnancy outcome between nonsmoker and passive smoker or smoker women, smoking cessation should be an integral part of ARTs.

Adiponectin and Mortality in Smokers and Non-Smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.

Cardiovascular diseases (CVD) are an important cause of morbidity and mortality worldwide. A decreased concentration of adiponectin has been reported in smokers. The aim of this study was to analyze the effect of cigarette smoking on the concentration of adiponectin and potassium in active smokers (AS) and life-time non-smokers (NS) of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study, and the use of these two markers for risk prediction. Smoking status was assessed by a questionnaire and measurement of plasma cotinine concentration. The serum concentration of adiponectin was measured by ELISA. Adiponectin was binned into tertiles separately for AS and NS and the Cox regression was used to assess the effect on mortality. There were 777 AS and 1178 NS among the LURIC patients. Within 10 years (median) of follow-up 221 AS and 302 NS died. In unadjusted analyses, AS had lower concentrations of adiponectin. However, after adjustment for age and gender there was no significant difference in adiponectin concentration between AS and NS. In the Cox regression model adjusted for age and gender, adiponectin was significantly associated with mortality in AS, but not in NS, with hazard ratio (95 % CI) of 1.60 (1.14-2.24) comparing the third with first tertile. In a model further adjusted for the risk factors, such as diabetes mellitus, hypertension, coronary artery disease, body mass index, LDL-cholesterol and HDL-cholesterol, adiponectin was significantly associated with mortality with hazard ratio of 1.83 (1.28-2.62) and 1.56 (1.15-2.11) for AS and NS, respectively. We conclude that increased adiponectin is a strong and independent predictor of mortality in both AS and NS. The determination of adiponectin concentration could be used to identify individuals at increased mortality risk.