Follow-up study of veterans with white and red oral mucosal lesions at Veterans Affairs Dental Clinics.

OBJECTIVES: This analysis examined the clinical and histopathological characteristics of white and red oral mucosal lesions and patient lifestyle behaviors to understand how the lesions changed over 19-23 years, including among patients who developed oral and pharyngeal cancer. MATERIALS AND METHODS: Seventy-five individuals with red and/or white oral mucosal lesions with clinical diagnoses of smokeless tobacco lesions, leukoplakia, erythroplakia, lichen planus, ulcer, and virus-associated lesions were identified in six Veterans Affairs Medical Center Dental Clinics (VAMC) from 1996 to 2001. Biopsy results and patients' sociodemographic, medical, and tobacco/alcohol use characteristics were obtained. Study dentists used standardized forms to capture information about the lesions. Study participants were re-examined at intervals through January 2002. In 2020, a retrospective review of VAMC and public records ascertained whether participants developed oral cancer or died. RESULTS: The most common red or white oral mucosal lesions among the 75 study participants were leukoplakia (36.0%), smokeless tobacco lesions (26.7%), virus-associated lesions (18.7%), and lichen planus (16.0%). Lesions in 11% of participants with leukoplakia and one-third of participants with lichen planus persisted for 5 years or more. Dysplasia was present in four participants with leukoplakia. Seventeen percent of participants developed a new white or red oral mucosal lesion. Five patients (6.1%) developed oral or pharyngeal cancer, four among participants with leukoplakia (one with prior dysplasia) and one among participants with lichen planus. Four of the cancers developed 6-20 years after enrollment, and only one was at the original lesion site. CONCLUSIONS: The occurrence of oral and pharyngeal cancers in some study participants with white and red oral mucosal lesions many years after enrollment reinforces the need for patients, dentists, and health care systems to have better methods to identify and assess the malignant potential of oral lesions, monitor patients over time, and intercept high-risk oral lesions before they become cancerous.

Cancer patterns in nasopharyngeal carcinoma multiplex families over 15 years.

BACKGROUND: Genetic and environmental factors are important determinants of nasopharyngeal carcinoma (NPC). NPC is associated with Epstein-Barr virus (EBV) infection. Studies have reported familial aggregation of NPC, but evidence has been mixed for elevated rates of cancers other than NPC. METHODS: The authors reassessed their previous evaluation of familial aggregation of cancer in 348 high-risk Taiwanese multiplex families with 2 or more NPC cases enrolled between 1980 and 2003. Participants were linked to the Taiwan National Cancer Registry and National Death Registry to identify cancers. RESULTS: In all, 2590 individuals contributed 37,959 person-years over an average of 15 years of follow-up; 314 incident cancers were identified. The authors computed multiple primary standardized incidence ratios (MP-SIRs) to evaluate the overall risk and the risk of infection-associated, EBV-associated, and individual cancers. The overall MP-SIR was 1.24 (95% confidence interval [CI], 1.10-1.38). The exclusion of excess NPC risk led to an overall MP-SIR of 1.11 (95% CI, 0.98-1.25). Similarly, the risk of cancers associated with infectious agents was driven by the excess in NPC, and its exclusion led to an MP-SIR of 1.22 (95% CI, 0.99-1.48) for infection-associated cancers and to an MP-SIR of 1.18 (95% CI, 0.72-1.82) for EBV-associated cancers. The authors observed a significant excess of second cancers among NPC cases (oral cancer, mouth cancer, tongue cancer, gum cancer, nasal cavity cancer, bone cancer, and non-Hodgkin lymphoma). CONCLUSIONS: This reassessment of the largest NPC multiplex family study confirms the presence of NPC coaggregation within families in Taiwan but does not provide evidence for a broader familial syndrome involving NPC and other tumors. Among NPC cases, elevated rates of secondary cancers, mostly at the, head and neck and hematopoietic cancers suggest radiation treatment effects on subsequent cancer risk.

Genetic variation in catechol-O-methyltransferase is associated with individual differences in conditioned pain modulation in healthy subjects.

BACKGROUND: Genetic variation in the catechol-O-methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis. METHODS: We evaluated CPM in 77 healthy pain-free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26-g von Frey filament as the test stimulus with immersion of the non-dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva. RESULTS: SNP rs4680 (val158 met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender. CONCLUSIONS: We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5' regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations.

Code Review as a Simple Trick to Enhance Reproducibility, Accelerate Learning, and Improve the Quality of Your Team's Research.

Programming for data wrangling and statistical analysis is an essential technical tool of modern epidemiology, yet many epidemiologists receive limited formal training in strategies to optimize the quality of our code. In complex projects, coding mistakes are easy to make, even for skilled practitioners. Such mistakes can lead to invalid research claims that reduce the credibility of the field. Code review is a straightforward technique used by the software industry to reduce the likelihood of coding bugs. The systematic implementation of code review in epidemiologic research projects could not only improve science but also decrease stress, accelerate learning, contribute to team building, and codify best practices. In the present article, we argue for the importance of code review and provide some recommendations for successful implementation for 1) the research laboratory, 2) the code author (the initial programmer), and 3) the code reviewer. We outline a feasible strategy for implementation of code review, though other successful implementation processes are possible to accommodate the resources and workflows of different research groups, including other practices to improve code quality. Code review isn't always glamorous, but it is critically important for science and reproducibility. Humans are fallible; that's why we need code review.

Unique etiologic, demographic, and pathologic characteristics of localized aggressive periodontitis support classification as a distinct subcategory of periodontitis.

BACKGROUND: Localized aggressive periodontitis (LAgP) occurs in 2% of African-American adolescents but only 0.15% of white adolescents. First molars and incisors are affected by rapid onset and progression. METHODS: This nonsystematic critical review evaluated published data for LAgP and chronic periodontitis (CP), focusing on potential differences in epidemiology, microbiology, immunology, genetics, and response to therapy. RESULTS: LAgP differs from CP by localization to incisors and first molars, early onset and rapid progression in adolescents and young adults, and a 10-fold higher prevalence in populations of African or Middle Eastern origin, often with strong familial aggregation. The bacterium Aggregatibacter actinomycetemcomitans and hyperresponsive neutrophils are frequently observed. Antibiotic and nonsurgical therapies are highly effective. CONCLUSIONS: LAgP differs in many ways from the far more common CP that affects older adults. The substantial evidence of dissimilarities summarized in this review strongly supports the classification of LAgP as a distinct form of periodontitis. PRACTICAL IMPLICATIONS: Classifying LAgP as a distinct subcategory of periodontitis will encourage future research and does not conflict with the newly proposed "staging and grading" system. The silent onset and rapid progression of LAgP make early diagnosis and frequent follow-up with patients essential for effective treatment.

Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma.

Genetic susceptibility is likely involved in nasopharyngeal carcinoma (NPC), a cancer caused by Epstein-Barr virus (EBV) infection. Understanding of genetic factors involved in NPC and how they contribute to EBV-induced carcinogenesis is limited. We conducted whole-exome capture/sequencing among 251 individuals from 97 multiplex families from Taiwan (205 affected, 21 obligate carriers, and 25 unaffected) using SeqCap EZ Human Exome Library v3.0 and Illumina HiSeq. Aligned sequences were filtered to identify likely-to-be-functional deleterious variants that co-segregated with disease. Ingenuity Pathway analysis was performed. Circulating magnesium levels were measured in 13 individuals in 2 families with NIPAL1 mutations and in 197 sporadic NPC cases and 237 controls. We identified variants in 12 genes likely involved in cancer pathogenesis, viral infection or immune responses to infection. These included genes postulated to be involved in magnesium transport (NIPAL1), EBV cell entry (ITGB6), modulation of EBV infection (BCL2L12, NEDD4L), telomere biology (CLPTM1L, BRD2, HNRNPU), modulation of cAMP signaling (RAPGEF3), DNA repair (PRKDC, MLH1), and Notch signaling (NOTCH1, DLL3). Pathway based analysis demonstrated enrichment for Notch signaling genes (p-value = 0.0006). Evaluation of individuals within NIPAL1 families suggested lower serum magnesium in NPC compared to unaffected members. A significant reduction in serum magnesium levels was observed among sporadic NPC cases compared to controls (7.1% NPC/1.7% controls below normal range; OR = 4.5; 95% CI = 1.4,14) and is consistent with findings demonstrating a role for magnesium channeling in T-cell responses to EBV. We identified novel genes associated with NPC that point to new areas of inquiry to better understand genetic factors that determine the fate of viral infections and/or otherwise predisposes to NPC.

Elevated antibodies against Epstein-Barr virus among individuals predicted to carry nasopharyngeal carcinoma susceptibility variants.

Epstein-Barr virus (EBV) is an obligatory factor in the development of nasopharyngeal carcinoma (NPC), and anti-EBV IgA antibodies are elevated many years prior to the development of NPC. Nearly all adults are infected with EBV, but only a few develop cancer, suggesting that additional co-factors, including genetic susceptibility, must be required for the disease to manifest. Individuals were selected from the Taiwan Family Study, a cohort of 3389 individuals from NPC multiplex families. Primary analyses were conducted among 671 individuals from 69 pedigrees with the strongest family history of disease (>3 NPC-affected family members). The likelihood that a given family member carried a NPC susceptibility variant was estimated using Mendelian segregation rules, assuming a dominant mode of inheritance. We compared anti-EBV IgA antibody seropositivity between family members predicted to be carriers of NPC-linked genetic variants and those with a lower likelihood of carrying such variants. Obligate carriers of NPC susceptibility variants (100 % predicted probability of harbouring the genetic mutation) were nine-fold more likely to be anti-EBV IgA positive compared to family members predicted not to carry disease-causing variants (OR=9.2; P-trend<0.001). This elevated risk was confirmed in analyses restricted to both unaffected individuals and pedigrees with EBV-related pathway variants identified through exome sequencing. Our data indicate that family members who are more likely to carry NPC susceptibility variants are also more likely to be anti-EBNA1 IgA seropositive. Genetic susceptibility associated with control over this common herpes virus is likely a co-factor in determining which EBV-infected adults develop NPC.

Mouse model demonstrates strain differences in susceptibility to opioid side effects.

Individual differences have been observed in responses to opioid drugs, including common side effects. In this study, the inbred mouse strains A/J and C57BL/6J were used to determine whether their specific strain differences correlate with differences in susceptibility to respiratory depression and constipation. To measure the effects of morphine on respiration, morphine at 15 and 40 mg/kg was injected subcutaneously. Respiratory parameters were then measured 30 and 60 min later. To measure the effects on constipation, 5, 15, 40, and 60 mg/kg doses were administered subcutaneously three times daily for three days. Gastrointestinal transit distance was then measured using the charcoal bolus test. C57BL/6J mice showed a greater degree of change in several respiratory parameters, resulting in more pronounced respiratory depression. C57BL6J mice also showed significantly more constipation than A/J mice with 40 and 60 mg/kg morphine doses. This study demonstrates that the strain differences between A/J and C57BL/6J mice have a major effect on opioid-induced constipation and respiratory depression. These correlations are of great clinical interest, as they could lead to the development of methods for reducing side effects.

Altered pain modulation in patients with persistent postendodontic pain.

Persistent pain may follow nerve injuries associated with invasive therapeutic interventions. About 3% to 7% of the patients remain with chronic pain after endodontic treatment, and these are described as suffering from painful posttraumatic trigeminal neuropathy (PTTN). Unfortunately, we are unable to identify which patients undergoing such procedures are at increased risk of developing PTTN. Recent findings suggest that impaired endogenous analgesia may be associated with the development of postsurgical chronic pain. We hypothesized that patients with PTTN display pronociceptive pain modulation, in line with other chronic pain disorders. Dynamic (conditioned pain modulation, temporal summation) and static (response to mechanical and cold stimulation) psychophysical tests were performed intraorally and in the forearm of 27 patients with PTTN and 27 sex- and age-matched controls. The dynamic sensory testing demonstrated less efficient conditioned pain modulation, suggesting reduced function of the inhibitory endogenous pain-modulatory system, in patients with PTTN, mainly in those suffering from the condition for more than a year. The static sensory testing of patients with PTTN demonstrated forearm hyperalgesia to mechanical stimulation mainly in patients suffering from the condition for less than a year and prolonged painful sensation after intraoral cold stimulus mainly in patients suffering from the condition for more than a year. These findings suggest that PTTN is associated more with the inhibitory rather than the facilitatory arm of pain modulation and that the central nervous system has a role in PTTN pathophysiology, possibly in a time-dependent fashion.

Interleukin 1 genetic tests provide no support for reduction of preventive dental care.

BACKGROUND: It has been proposed that the PST and PerioPredict genetic tests that are based on polymorphisms in interleukin 1 (IL-1) genes identify a subset of patients who experience fewer tooth extractions if provided with 2 annual preventive visits. Economic analyses indicate rationing preventive care to only "high-risk" genotypes, smokers, patients with diabetes, or combinations of these risk factors would reduce the cost of dental care by $4.8 billion annually in the United States. METHODS: Data presented in the study that claimed clinical utility for the PST and PerioPredict tests were obtained for reanalysis using logistic regression to assess whether the PST genetic test, smoking, diabetes, or number of preventive visits were risk factors for tooth extraction during a span of 16 years. Consistency of risk classification by the PST (version 1) and PerioPredict (version 2) genetic tests was evaluated in different ethnic groups from the 1000 Genomes database. RESULTS: Multivariate analyses revealed association of tooth extraction with diabetes (P < .0001), smoking (P < .0001), and number of preventive visits (P = .004), but no support for the PST genetic test (P = .96) nor indication that the benefit of 2 preventive visits was affected by this genetic test (P = .58). Classification of risk was highly inconsistent between the PST (version 1) and PerioPredict (version 2) genetic tests. CONCLUSIONS: Two annual preventive visits were supported as beneficial for all patients, and there was no evidence that the IL-1 PST genetic test has any effect on tooth extraction risk or influences the benefits of 2 annual preventive visits. PRACTICAL IMPLICATIONS: Neither IL-1 PST nor PerioPredict genetic tests are useful for rationing preventive dental care. Further research is needed to identify genetic biomarkers with robust clinical validity and clinical utility to effectively personalize the practice of dentistry.

Genetics of chronic post-surgical pain: a crucial step toward personal pain medicine.

PURPOSE: Most patients who undergo surgery or experience a traumatic injury suffer from acute pain that subsides once tissues heal. Nevertheless, the pain remains in 15-30% of patients, sometimes for life, and this chronic post-surgical pain (CPSP) can result in suffering, depression, anxiety, sleep disturbance, physical incapacitation, and an economic burden. The incorporation of genetic knowledge is expected to lead to the development of more effective means to prevent and manage CPSP using tools of personalized pain medicine. The purpose of this review article is to provide an update on the current state of CPSP genetics and its future potential. PRINCIPLE FINDINGS: The large variability in CPSP amongst patients undergoing similar surgery suggests that individual factors are significant contributors to CPSP, raising the possibility that CPSP is influenced by genetic determinants. Heritability estimates suggest that about half of the variance in CPSP levels is attributable to genetic variation. These estimates suggest that identifying the genetic underpinnings of CPSP may lead to significant improvements in treatment. Analyzing patients' DNA sequences, blood and salivary pain biomarkers, as well as their analgesic responses to medications will facilitate developing insights into CPSP pathophysiology and inform predictive algorithms to determine a patient's likelihood of developing CPSP even prior to surgery. These algorithms could facilitate effective treatment regimens that will protect against the transition to chronicity in traumatically injured patients or those scheduled for surgery and lead to better therapy for patients who have already developed CPSP. CONCLUSIONS: Pharmacogenomic technologies and strategies provide an opportunity to expand our knowledge in CPSP treatment that may manifest in a personalized approach to diagnosis, prevention, and therapy. Capitalizing on this genomic knowledge will necessitate the analysis of many tens of thousands of study patients. This will require an international coordinated effort to which anesthesiologists and surgeons can contribute substantially.

The cardiopulmonary effects of ambient air pollution and mechanistic pathways: a comparative hierarchical pathway analysis.

Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2-3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system.

Cardiorespiratory biomarker responses in healthy young adults to drastic air quality changes surrounding the 2008 Beijing Olympics.

Associations between air pollution and cardiorespiratory mortality and morbidity have been well established, but data to support biologic mechanisms underlying these associations are limited. We designed this study to examine several prominently hypothesized mechanisms by assessing Beijing residents' biologic responses, at the biomarker level, to drastic changes in air quality brought about by unprecedented air pollution control measures implemented during the 2008 Beijing Olympics. To test the hypothesis that changes in air pollution levels are associated with changes in biomarker levels reflecting inflammation, hemostasis, oxidative stress, and autonomic tone, we recruited and retained 125 nonsmoking adults (19 to 33 years old) free of cardiorespiratory and other chronic diseases. Using the combination of a quasi-experimental design and a panel-study approach, we measured biomarkers of autonomic dysfunction (heart rate [HR*] and heart rate variability [HRV]), of systemic inflammation and oxidative stress (plasma C-reactive protein [CRP], fibrinogen, blood cell counts and differentials, and urinary 8-hydroxy-2'-deoxyguanosine [8-OHdG]), of pulmonary inflammation and oxidative stress (fractional exhaled nitric oxide [FeNO], exhaled breath condensate [EBC] pH, EBC nitrate, EBC nitrite, EBC nitrite+nitrate [sum of the concentrations of nitrite and nitrate], and EBC 8-isoprostane), of hemostasis (platelet activation [plasma sCD62P and sCD40L], platelet aggregation, and von Willebrand factor [vWF]), and of blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]). These biomarkers were measured on each subject twice before, twice during, and twice after the Beijing Olympics. For each subject, repeated measurements were separated by at least one week to avoid potential residual effects from a prior measurement. We measured a large suite of air pollutants (PM2.5 [particulate matter < or = 2.5 microm in aerodynamic diameter] and constituents, sulfur dioxide [SO2], carbon monoxide [CO], nitrogen dioxide [NO2], and ozone [O3]) throughout the study at a central Beijing site near the residences and workplaces of the subjects on a daily basis. Total particle number (TPN) was also measured at a separate site. We used a time-series analysis to assess changes in pollutant concentration by period (pre-, during-, and post-Olympics periods). We used mixed-effects models to assess changes in biomarker levels by period and to estimate changes associated with increases in pollutant concentrations, controlling for ambient temperature, relative humidity (RH), sex, and the day of the week of the biomarker measurements. We conducted sensitivity analyses to assess the impact of potential temporal confounding and exposure misclassification. We observed reductions in mean concentrations for all measured pollutants except O3 from the pre-Olympics period to the during-Olympics period. On average, elemental carbon (EC) changed by -36%, TPN by -22%, SO2 by -60%, CO by -48%, and NO2 by -43% (P < 0.05 for all these pollutants). Reductions were observed in mean concentrations of PM2.5 (by -27%), sulfate (SO4(2-)) (by -13%), and organic carbon (OC) (by -23%); however, these values were not statistically significant. Both 24-hour averages and 1-hour maximums of O3 increased (by 20% and 17%, respectively) from the pre-Olympics to the during-Olympics period. In the post-Olympics period after the pollution control measures were relaxed, mean concentrations of most pollutants (with the exception of SO4(2-) and O3) increased to levels similar to or higher than pre-Olympics levels. Concomitantly and consistent with the hypothesis, we observed, from the pre-Olympics to the during-Olympics period, statistically significant (P < or = 0.05) or marginally significant (0.05 < P < 0.1) decreases in HR (-1 bpm or -1.7% [95% CI, -3.4 to -0.1]), SBP (-1.6 mmHg or -1.8% [95% CI, -3.9 to 0.4]), 8-OHdG (-58.3% [95% CI, -72.5 to -36.7]), FeNO (-60.3% [95% CI, -66.0 to -53.6]), EBC nitrite (-30.0% [95% CI, -39.3 to -19.3]), EBC nitrate (-21.5% [95% CI, -35.5 to -4.5]), EBC nitrite+nitrate (-17.6% [95% CI, -28.4 to -5.1]), EBC hydrogen ions (-46% [calculated from EBC pH], or +3.5% in EBC pH [95% CI, 2.2 to 4.9]), sCD62P (-34% [95% CI, -38.4 to -29.2]), sCD40L (-5.7% [95% CI, -10.5 to -0.7]), and vWF (-13.1% [95% CI, -18.6 to -7.5]). Moreover, the percentages of above-detection values out of all observations were significantly lower for plasma CRP and EBC 8-isoprostane in the during-Olympics period compared with the pre-Olympics period. In the post-Olympics period, the levels of the following biomarkers reversed (increased, either with or without statistical significance) from those in the during-Olympics period: SBP (10.7% [95% CI, 2.8 to 18.6]), fibrinogen (4.3% [95% CI, -1.7 to 10.2), neutrophil count (4.7% [95% CI, -7.7 to 17.0]), 8-OHdG (315% [95% CI, 62.0 to 962]), FeNO (130% [95% CI, 62.5 to 225]), EBC nitrite (159% [95% CI, 71.8 to 292]), EBC nitrate (161% [95% CI, 48.0 to 362]), EBC nitrite+nitrate (124% [95% CI, 50.9 to 233]), EBC hydrogen ions (146% [calculated from EBC pH] or -4.8% in EBC pH [95% CI, -9.4 to -0.21), sCD62P (33.7% [95% CI, 17.7 to 51.8]), and sCD40L (9.1% [95% CI, -3.7 to 23.5]). Furthermore, these biomarkers also showed statistically significant associations with multiple pollutants across different lags after adjusting for meteorologic parameters. The associations were in the directions hypothesized and were consistent with the findings from the comparisons between periods, providing further evidence that the period effects were due to changes in air quality, independent of season and meteorologic conditions or other potential confounders. Contrary to our hypothesis, however, we observed increases in platelet aggregation, red blood cells (RBCs) and white blood cells (WBCs) associated with the during-Olympics period, as well as significant negative associations of these biomarkers with pollutant concentrations. We did not observe significant changes in any of the HRV indices and DBP by period. However, we observed associations between a few HRV indices and pollutant concentrations. Changes in air pollution levels during the Beijing Olympics were associated with acute changes in biomarkers of pulmonary and systemic inflammation, oxidative stress, and hemostasis and in measures of cardiovascular physiology (HR and SBP) in healthy, young adults. These changes support the prominently hypothesized mechanistic pathways underlying the cardiorespiratory effects of air pollution.

Malondialdehyde in exhaled breath condensate and urine as a biomarker of air pollution induced oxidative stress.

Underlying mechanisms by which air pollutants adversely affect human health remain poorly understood. Oxidative stress has been considered as a potential mechanism that may promote lipid peroxidation by reactive oxygen species, leading to the formation of malondialdehyde (MDA) that is excreted in biofluids (e.g., urine and exhaled breath condensate (EBC)). A panel study was conducted to examine whether concentrations of MDA in EBC and urine were associated, respectively, with changes in air pollution levels brought by the Beijing Olympic air pollution control measures. EBC and urine samples from 125 healthy adults were collected twice in each of the pre-, during-, and post-Olympic periods. Period-specific means of MDA and changes in MDA levels associated with increases in 24-h average pollutant concentrations were estimated using linear mixed-effects models. From the pre- to the during-Olympic period, when concentrations of most pollutants decreased, EBC MDA and urinary MDA significantly decreased by 24% (P<0.0001) and 28% (P=0.0002), respectively. From the during-Olympic to the post-Olympic period, when concentrations of most pollutants increased, EBC MDA and urinary MDA increased by 28% (P=0.094) and 55% (P=0.046), respectively. Furthermore, the largest increases in EBC MDA associated with one interquartile range (IQR) increases in all pollutants but ozone ranged from 10% (95% CI: 2%, 18%) to 19% (95% CI: 14%, 25%). The largest increases in urinary MDA associated with IQR increases in pollutant concentration ranged from 9% (95%: 0.3%, 19%) to 15% (95% CI: 3%, 28%). These findings support the utility of EBC MDA as a biomarker of oxidative stress in the respiratory tract and urinary MDA as a biomarker of systemic oxidative stress in relation to air pollution exposure in healthy young adults. Both EBC and urine samples can be collected noninvasively in the general population.

Inflammatory and oxidative stress responses of healthy young adults to changes in air quality during the Beijing Olympics.

RATIONALE: Unprecedented pollution control actions during the Beijing Olympics provided a quasi-experimental opportunity to examine biologic responses to drastic changes in air pollution levels. OBJECTIVES: To determine whether changes in levels of biomarkers reflecting pulmonary inflammation and pulmonary and systemic oxidative stress were associated with changes in air pollution levels in healthy young adults. METHODS: We measured fractional exhaled nitric oxide, a number of exhaled breath condensate markers (H(+), nitrite, nitrate, and 8-isoprostane), and urinary 8-hydroxy-2-deoxyguanosine in 125 participants twice in each of the pre- (high pollution), during- (low pollution), and post-Olympic (high pollution) periods. We measured concentrations of air pollutants near where the participants lived and worked. We used mixed-effects models to estimate changes in biomarker levels across the three periods and to examine whether changes in biomarker levels were associated with changes in pollutant concentrations, adjusting for meteorologic parameters. MEASUREMENTS AND MAIN RESULTS: From the pre- to the during-Olympic period, we observed significant and often large decreases (ranging from -4.5% to -72.5%) in levels of all the biomarkers. From the during-Olympic to the post-Olympic period, we observed significant and larger increases (48-360%) in levels of these same biomarkers. Moreover, increased pollutant concentrations were consistently associated with statistically significant increases in biomarker levels. CONCLUSIONS: These findings support the important role of oxidative stress and that of pulmonary inflammation in mediating air pollution health effects. The findings demonstrate the utility of novel and noninvasive biomarkers in the general population consisting largely of healthy individuals.

Association between changes in air pollution levels during the Beijing Olympics and biomarkers of inflammation and thrombosis in healthy young adults.

CONTEXT: Air pollution is a risk factor for cardiovascular diseases (CVD), but the underlying biological mechanisms are not well understood. OBJECTIVE: To determine whether markers related to CVD pathophysiological pathways (biomarkers for systemic inflammation and thrombosis, heart rate, and blood pressure) are sensitive to changes in air pollution. DESIGN, SETTING, AND PARTICIPANTS: Using a quasi-experimental opportunity offered by greatly restricted air pollution emissions during the Beijing Olympics, we measured pollutants daily and the outcomes listed below in 125 healthy young adults before, during, and after the 2008 Olympics (June 2-October 30). We used linear mixed-effects models to estimate the improvement in outcome levels during the Olympics and the anticipated reversal of outcome levels after pollution controls ended to determine whether changes in outcome levels were associated with changes in pollutant concentrations. MAIN OUTCOME MEASURES: C-reactive protein (CRP), fibrinogen, von Willebrand factor, soluble CD40 ligand (sCD40L), soluble P-selectin (sCD62P) concentrations; white blood cell count (WBC); heart rate; and blood pressure. RESULTS: Concentrations of particulate and gaseous pollutants decreased substantially (-13% to -60%) from the pre-Olympic period to the during-Olympic period. Using 2-sided tests conducted at the .003 level, we observed statistically significant improvements in sCD62P levels by -34.0% (95% CI, -38.4% to -29.2%; P < .001) from a pre-Olympic mean of 6.29 ng/mL to a during-Olympic mean of 4.16 ng/mL and von Willebrand factor by -13.1% (95% CI, -18.6% to -7.5%; P < .001) from 106.4% to 92.6%. After adjustments for multiple comparisons, changes in the other outcomes were not statistically significant. In the post-Olympic period when pollutant concentrations increased, most outcomes approximated pre-Olympic levels, but only sCD62P and systolic blood pressure were significantly worsened from the during-Olympic period. The fraction of above-detection-limit values for CRP (percentage ≥ 0.3 mg/L) was reduced from 55% in the pre-Olympic period to 46% in the during-Olympic period and reduced further to 36% in the post-Olympic period. Interquartile range increases in pollutant concentrations were consistently associated with statistically significant increases in fibrinogen, von Willebrand factor, heart rate, sCD62P, and sCD40L concentrations. CONCLUSIONS: Changes in air pollution levels during the Beijing Olympics were associated with acute changes in biomarkers of inflammation and thrombosis and measures of cardiovascular physiology in healthy young persons. These findings are of uncertain clinical significance.

Prognostic utility of anti-EBV antibody testing for defining NPC risk among individuals from high-risk NPC families.

PURPOSE: Epstein-Barr virus (EBV) infection and a family history of nasopharyngeal carcinoma (NPC) are associated with NPC risk. We examined the risk associated with EBV markers and their clinical utility to identify NPC susceptibles within high-risk NPC families. EXPERIMENTAL DESIGN: We evaluated antibody titers against viral capsid antigen (VCA) IgA, EBV nuclear antigen-1 (EBNA1) IgA, and DNase among unaffected relatives of NPC cases from 358 multiplex families in Taiwan. Incident NPC cases were identified via linkage to the National Cancer Registry. Clinical examinations of 924 individuals were also done to identify occult, asymptomatic NPC. Baseline EBV serology was used to estimate NPC risk using rate ratios with 95% CI. Associated sensitivity/specificity and receiver operating characteristic (ROC) curves were calculated. RESULTS: A total of 2,444 unaffected individuals with 15,519 person-years (6.5 years median follow-up) yielded 14 incident NPC cases (nearly 11 times the general population rate). The absolute rate of NPC among anti-EBV EBNA1 IgA seropositives using a standard positivity cutoff versus an optimized cutoff point defined by ROC analyses was 265/100,000 person-years with a 4.7-fold increased risk of NPC (95% CI: 1.4-16) and 166/100,000 person-years with a 6.6-fold increase (95% CI: 1.5-61), respectively. Sensitivity and specificity using the optimized positivity cutoff points were 85.7% and 51.2%, respectively. It is estimated that active evaluation of 49% of individuals from high-risk NPC families seropositive for this marker could lead to earlier detection of up to 86% of NPC cases. Risks associated with the other three EBV markers were weaker. CONCLUSIONS: Future efforts are needed to identify susceptibility markers among high-risk NPC families that maximize both sensitivity and specificity.

Familial tendency and risk of nasopharyngeal carcinoma in taiwan: effects of covariates on risk.

In the present study, the authors compared the long-term risk of nasopharyngeal carcinoma (NPC) of male participants in an NPC multiplex family cohort with that of controls in a community cohort in Taiwan after adjustment for anti-Epstein-Barr virus (EBV) seromarkers and cigarette smoking. A total of 43 incident NPC cases were identified from the 1,019 males in the NPC multiplex family cohort and the 9,622 males in the community cohort, for a total of 8,061 person-years and 185,587 person-years, respectively. The adjusted hazard ratio was 6.8 (95% confidence interval (CI): 2.3, 20.1) for the multiplex family cohort compared with the community cohort. In the evaluation of anti-EBV viral capsid antigen immunoglobulin A and anti-EBV deoxyribonuclease, the adjusted hazard ratios were 2.8 (95% CI: 1.3, 6.0) and 15.1 (95% CI: 4.2, 54.1) for those positive for 1 EBV seromarker and positive for both seromarkers, respectively, compared with those negative for both EBV seromarkers. The adjusted hazard ratio was 31.0 (95% CI: 9.7, 98.7) for participants who reported a family history of NPC and who were anti-EBV-seropositive compared with individuals without such a history who were anti-EBV-seronegative. The findings suggest that both family history of NPC and anti-EBV seropositivity are important determinants of subsequent NPC risk and that the effect of family history on NPC risk cannot be fully explained by mediation through EBV serologic responses.