Despite a rich neuroscience literature on sensitization, this phenomenon has been neglected in clinical nicotine research. This paper offers a primer on the neuroscience of nicotine sensitization for behavioral scientists, identifying key concepts, potential theoretical and clinical implications, and directions for future research. Sensitization to a drug occurs when repeated exposures to the same dose produce greater responses. In animals, sensitization to nicotine, morphine, alcohol, cocaine, amphetamine, and methamphetamine manifests as increased locomotor activity. In animals, sensitization to nicotine begins with the first dose and is maximal within 5-7 days. It involves multiple neurotransmitters, receptors, and brain structures and cannot be attributed to any single alteration. The processes involved in its induction and expression are not identical. The neurologic changes associated with sensitization are not consistent across drugs, suggesting that sensitization is not an accident of neurophysiology but perhaps an exaggerated adaptive response. Sensitization is incorporated into two theories of addiction: incentive-sensitization and sensitization-homeostasis. Whether sensitization occurs in humans and how it is expressed is unclear, as is its role in human addiction.
OBJECTIVES: As smoking is very common in R-rated films, we sought to determine if viewing R-rated films is associated with adolescent smoking.
METHODS: Three annual cross-sectional surveys conducted of 88,505 Year 10 students of largely European, Maori, Asian or Pacific Islander ethnicity in secondary schools in New Zealand between 2002 and 2004. Outcomes of interest were: intention to smoke among never smokers; past experimentation with smoking among current non-smokers; current smoking status; and current frequency of smoking.
RESULTS: Dose-response relationships were observed between the frequency of viewing R-rated films and all outcome measures controlling for age, gender, ethnicity, peer smoking, parental smoking, socioeconomic status, pocket money and household smoking rules. Compared to never viewing R-rated films, viewing at least weekly nearly tripled the relative risk (2.81; 95% confidence interval 2.57, 3.09) of never smokers being susceptible to smoking, and more than doubled the risk of both past experimentation (2.28; 95% CI 2.12, 2.45) and smoking > /=monthly (2.31; 95% CI 2.10, 2.54). Each of these risks was seen across all ethnic groups.
CONCLUSIONS: Our results extend the association that has been demonstrated between viewing R-rated films and current smoking in American youth by demonstrating the same association in youth of different ethnic and cultural backgrounds in New Zealand.
Individuals have lost full autonomy over their smoking when quitting becomes unpleasant or difficult. We examined autonomy in relation to smoking frequency and lifetime cigarette use. A self-administered questionnaire was completed by three convenience samples of Year 10 students (ages 14-15) in New Zealand between 2002 and 2004 (n=96,156). The Hooked On Nicotine Checklist was used to measure diminished autonomy. Diminished autonomy was reported by 46% of subjects who smoked less often than monthly and by 25%-30% of current smokers who had smoked only one cigarette in total. The prevalence of diminished autonomy increased with increasing frequency of current use and with increasing lifetime use. Symptoms developed earlier among girls than boys. The data confirm previous reports that diminished autonomy appears soon after the onset of intermittent tobacco use and extends this literature by providing the first description of how diminished autonomy develops in relation to the total number of cigarettes smoked. These data suggest that smoking one cigarette in total can prompt a loss of autonomy.
OBJECTIVE, PARTICIPANTS, AND METHODS: In this study, the authors explored the psychometric properties of the Hooked on Nicotine Checklist (HONC) among 300 college students who were current smokers. The HONC is a 10-item survey instrument designed to measure diminished autonomy over smoking, a key aspect of dependence. Autonomy is diminished when symptoms present a barrier to cessation.
RESULTS: Internal consistency was high (alpha = .89), as was concurrent validity. Students who began smoking earlier and heavier smokers reported more symptoms than did those who started later and smoked less. After controlling for smoking frequency, the HONC was predictive of the likelihood of a failed cessation attempt, with each additional symptom doubling that likelihood.
CONCLUSIONS: College health professionals could use the HONC to help new smokers recognize their symptoms of diminished autonomy. The HONC may serve as a recruiting tool for cessation programs, which could benefit such early-phase smokers.
BACKGROUND/AIMS: We investigated the psychometric properties of a German translation of the 12-item Autonomy over Tobacco Scale (AUTOS) among 1,195 eighth-grade students.
METHODS: Data for this study were collected as part of the fourth wave of data collection of the Smokefree Class Competition intervention in the Saxony-Anhalt region of Germany. Students from the control arm of the Smokefree Class Competition study who indicated that they had ever smoked 'at least a few puffs' on a cigarette were classified as ever-smokers. They self-completed questionnaires distributed by teachers.
RESULTS: AUTOS scores ranged from 0 to 36 with a distribution highly skewed toward lower-response categories. Inter-item correlations ranged from 0.65 to 0.89 (mean = 0.79, SD = 0.06). Composite reliability for the AUTOS was high (Omega = 0.96) and 3 lower-order factors were also reliable (withdrawal: 0.89, psychological dependence: 0.91, cue-induced cravings: 0.87). Concurrent validity was supported by strong relationships between the AUTOS and both lifetime cigarette consumption and current smoking frequency. Youths were 18 times more likely to be current smokers (95% CI = 11.9-27.2, p < 0.001) if they endorsed any AUTOS item.
CONCLUSION: The German AUTOS is reliable and valid, and the results are consistent with the English AUTOS for use with adolescents.
INTRODUCTION: Waterpipe smoking is increasingly popular among North American youth. However, the extent to which waterpipe use is sustained over time is not known. The objective of this study was to describe the frequency and the predictors of sustained waterpipe use over 4 years among young adults.
METHODS: Data were available in a prospective cohort investigation of 1,293 seventh-grade students recruited in a convenience sample of 10 secondary schools in Montreal, Canada, in 1999. Data on past-year waterpipe use were collected from 777 participants when they were age 20 years on average (in 2007-2008) and again when they were age 24 years (in 2011-2012) in mailed self-report questionnaires. Twenty potential predictors of sustained waterpipe use were tested, each in a separate multivariable logistic regression model.
RESULTS: About 51% of 182 waterpipe users at age 20 reported waterpipe use 4 years later. Most sustained users (88%) smoked a waterpipe less than once a month. Parental smoking, being currently employed, less frequent cigarette smoking, and more frequent marijuana use were associated with sustained waterpipe use.
CONCLUSIONS: Half of the young adults who used waterpipe during young adulthood reported use 4 years later. Young adults who sustain waterpipe use appear to do so as an activity undertaken occasionally to socialize with others.
BACKGROUND: Binge drinking occurs frequently among young adults, posing risks to health and safety. Little is known, however, about which drinkers continue to binge later into adulthood. We sought to identify predictors of sustained binge drinking behaviors in young adulthood.
METHODS: Participants from the Nicotine Dependence in Teens (NDIT) cohort (n = 609, 53% female) completed self-report questionnaires in 20 survey cycles (SCs) during secondary school between 1999 and 2005, and in 2 postsecondary school SCs in 2007 to 2008 (SC 21; Mage = 20 years) and 2011 to 2012 (SC 22; Mage = 24 years). Participants reporting past-year binge drinking in both SCs 21 and 22 were categorized as sustainers (n = 517). Using multivariable logistic regression, we investigated 25 potential predictors of sustained binge drinking, binge-drinking frequency, and change in frequency over time among sustainers.
RESULTS: Compared with stoppers, sustainers (85% of participants) were more likely to be younger, male, and to have no college/university education. Sustainers began drinking alcohol and binge drinking earlier, drank at least monthly during more secondary school grades, binged more frequently at age 20, and scored higher on impulsivity and novelty seeking in adolescence. Among sustainers, frequent binge drinkers were more likely to be male, to be nonstudents, to score higher on novelty seeking, and to have reported more depressive symptoms in adolescence. Sustainers who decelerated their binge frequency between SCs 21 and 22 were more likely to be female, to have achieved a higher level of education, and to report more depressive symptoms in SC 21.
CONCLUSIONS: The determinants of sustained binge drinking are similar to predictors of binge drinking reported in the literature. Early identification of, and intervention with, youth who are impulsive, inclined toward novelty seeking, and who report higher levels of early sub clinical depressive symptoms might forestall their involvement in risky alcohol use.
The Nicotine Dependence in Teens (NDIT) study is a prospective cohort investigation of 1294 students recruited in 1999-2000 from all grade 7 classes in a convenience sample of 10 high schools in Montreal, Canada. Its primary objectives were to study the natural course and determinants of cigarette smoking and nicotine dependence in novice smokers. The main source of data was self-report questionnaires administered in class at school every 3 months from grade 7 to grade 11 (1999-2005), for a total of 20 survey cycles during high school education. Questionnaires were also completed after graduation from high school in 2007-08 and 2011-12 (survey cycles 21 and 22, respectively) when participants were aged 20 and 24 years on average, respectively. In addition to its primary objectives, NDIT has embedded studies on obesity, blood pressure, physical activity, team sports, sedentary behaviour, diet, genetics, alcohol use, use of illicit drugs, second-hand smoke, gambling, sleep and mental health. Results to date are described in 58 publications, 20 manuscripts in preparation, 13 MSc and PhD theses and 111 conference presentations. Access to NDIT data is open to university-appointed or affiliated investigators and to masters, doctoral and postdoctoral students, through their primary supervisor (www.nditstudy.ca). behalf of the International Epidemiological Association.
BACKGROUND: The level of physical dependence is a measure of addiction that correlates highly with addiction-associated changes in brain structure. We sought to determine whether age at first inhalation and initial reactions to inhaling nicotine are related to level of physical dependence in early adulthood.
METHODS: Young adults (n=312; mean age=24 years; 51% female) from the Nicotine Dependence in Teens study who had smoked at least once in the preceding three months completed self-report questionnaires in 2011-12. We assessed level of physical dependence with three validated self-report items assessing 'wanting,' 'craving' and 'needing' triggered by nicotine deprivation. Survey items assessed smoking behavior, including age at first inhalation, and recalled first reactions to inhaling nicotine.
RESULTS: After adjusting for covariates, experiencing relaxation, heart racing/pounding, rush or "buzz" (OR=1.45; 95% CI: 1.08, 1.94) and dizziness (OR=1.58; 95% CI: 1.15, 2.18) at first nicotine inhalation were associated with an increased odds of being at a higher level of physical dependence in young adulthood; the association for experiencing relaxation (OR=1.78; 95% CI: 1.20, 2.64) and heart racing/pounding (OR=1.51; 95% CI: 1.00, 2.28) persisted after additionally controlling for all other first reactions. Neither age at first inhalation nor unpleasant first reactions predicted level of physical dependence.
CONCLUSIONS: In accordance with prior research, our findings suggest that smokers who are particularly sensitive to the pleasant, "buzz-related" and generally arousing effects of nicotine may be more likely to attain higher levels of physical dependence.
INTRODUCTION: The Autonomy over Tobacco Scale (AUTOS) is composed of 12-symptoms of nicotine dependence. While it has demonstrated excellent reliability and validity, several psychometric properties have yet to be investigated. We aimed to determine (1) whether items functioned differently across demographic groups, (2) the likelihood that individual symptoms would be endorsed by smokers at different levels of diminished autonomy, and (3) the degree of information provided by each item and the reliability of the full AUTOS across the range of diminished autonomy.
METHODS: Data for this study come from two convenience samples of American adult current smokers (n=777; 69% female; 88% white; Mage=34 years, range: 18-78), of whom 66% were daily smokers (Mcigarettes/smoking day=10.1, range: < 1-70). Participants completed the AUTOS online as part of "a research study about the experiences people have when they smoke."
RESULTS: After p value correction, items remained invariant across sex and minority status, while two items functioned differently according to age, with minimal impact on the total AUTOS score. Discriminative power of the items was high. The greatest amount of information is provided at just under one-half SD above the mean and the least at the extremes of diminished autonomy. The AUTOS maintains acceptable reliability ( > 0.70) across the range of diminished autonomy within which more than 95% of smokers' scores could be anticipated to fall.
CONCLUSION: The AUTOS is a versatile and psychometrically sound instrument for measuring the loss of autonomy over tobacco use.
Tobacco use and tobacco smoke exposure are among the most important preventable causes of premature disease, disability, and death and therefore constitute a major pediatric health concern. The pediatric primary care setting offers excellent opportunities to prevent tobacco use in youth and to deliver cessation-related treatment to youth and parents who use tobacco. This report updates a "state-of-the-art" article published a decade ago on office-based interventions to address these issues. Since then there has been marked progress in understanding the nature, onset, and trajectories of tobacco use and nicotine addiction in youth with implications for clinical practice. In addition, clinicians need to remain abreast of emerging nicotine delivery systems, such as electronic cigarettes, that may influence uptake or continuation of smoking. Although evidence-based practice guidelines for treating nicotine addiction in youth are not yet available, research continues to build the evidence base toward that goal. In the interim, practical guidelines are available to assist clinicians in addressing nicotine addiction in the pediatric clinical setting. This article reports current practices in addressing tobacco in pediatric primary care settings. It reviews our increasing understanding of youth nicotine addiction, summarizes research efforts on intervention in the past decade and additional research needed going forward, and provides practical guidelines for pediatric health care providers to integrate tobacco use prevention and treatment into their clinical practice. Pediatric providers can and should play an important role in addressing tobacco use and dependence, both in the youth they care for and in parents who use tobacco.
Comment on: Age of smoking milestones: longitudinal inconsistencies and recanting. [J Adolesc Health. 2015]
The CBFbeta-SMMHC fusion protein is expressed in acute myeloid leukemia (AML) samples with the chromosome inversion inv(16)(p13;q22). This fusion protein binds the transcription factor RUNX with higher affinity than its physiological partner CBFbeta and disrupts the core binding factor (CBF) activity in hematopoietic stem and progenitor cells. Studies in the Castilla laboratory have shown that CBFbeta-SMMHC expression blocks differentiation of hematopoietic progenitors, creating a pre-leukemic progenitor that progresses to AML in cooperation with other mutations. However, the combined function of cumulative cooperating mutations in the pre-leukemic progenitor cells that enhance their expansion to induce leukemia is not known. The standard treatment for inv(16) AML is based on the use of non-selective cytotoxic chemotherapy, resulting in a good initial response, but with limited long-term survival. Therefore, there is a need for developing targeted therapies with improved efficacy in leukemic cells and minimal toxicity for normal cells.
Here, we used conditional Nras+/LSL-G12D; Cbfb+/56M; Mx1Cre knock-in mice to show that allelic expression of oncogenic N-RasG12D expanded the multi-potential progenitor (MPP) compartment by 8 fold. Allelic expression of Cbfbeta-SMMHC increased the MPPs and short-term hematopoietic stem cells (ST-HSCs) by 2 to 4 fold both alone and in combination with N-RasG12D expression. In addition, allelic expression of oncogenic N-RasG12D and Cbfbeta-SMMHC increases survival of pre-leukemic stem and progenitor cells. Differential analysis of bone marrow cells determined that Cbfb+/MYH11 and Nras+/G12D; vii Cbfb+/MYH11 cells included increased number of blasts, myeloblasts and promyelocytes and a reduction in immature granulocytes, suggesting that expression of N-RasG12D cannot bypass Cbfbeta-SMMHC driven differentiation block.
N-RasG12D and Cbfbeta-SMMHC synergized in leukemia, in which Nras+/G12D; Cbfb+/MYH11 mice have a shorter median latency than Cbfb+/MYH11 mice. In addition, the synergy in leukemogenesis was cell autonomous. Notably, leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC showed higher (over 100 fold) leukemia-initiating cell activity in vivo than leukemic cells expressing Cbfbeta-SMMHC (L-IC activity of 1/4,000 and 1/528,334, respectively).
Short term culture and biochemical assays revealed that pre-leukemic and leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC have reduced levels of pro-apoptotic protein Bim compared to control. The Nras+/G12D; CbfbMYH11 pre-leukemic and leukemic cells were sensitive to pharmacologic inhibition of MEK/ERK signaling pathway with increasing apoptosis and Bim protein levels but not sensitive to PI3K inhibitors. In addition, knock-down of Bcl2l11 (Bim) expression in Cbfbeta-SMMHC pre-leukemic progenitors decreased their apoptosis levels.
In collaboration with Dr. John Bushweller’s and other research laboratories, we recently developed a CBFbeta-SMMHC inhibitor named AI-10-49, which specifically binds to CBFbeta-SMMHC, prevents its binding to RUNX proteins and restores CBF function. Biochemical analysis in human leukemic cells showed that AI-10-49 has significant specificity in reducing the viability of leukemic cells expressing CBFbeta-SMMHC (IC50= 0.83μM), and negligible toxicity in normal cells. Likewise, mouse Nras+/G12D; viii Cbfb+/MYH11 leukemic cells were sensitive to AI-10-49 (IC50= 0.93μM). By using the NrasLSL-G12D; Cbfb56M mouse model, we also show that AI-10-49 significantly prolongs the survival of mice bearing the leukemic cells. Preliminary mechanistic analysis of AI-10-49 activity has shown that AI-10-49 increased BCL2L11 transcript levels in a dose and time dependent manner in murine and human leukemic cells, suggesting that the viability through BIM-mediated apoptosis may be targeted by both oncogenic signals.
My thesis study demonstrates that Cbfbeta-SMMHC and N-RasG12D promote the survival of pre-leukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define NrasLSL-G12D; Cbfb56M mice as a valuable genetic model for the study of inv(16) AML targeted therapies. For instance, the novel CBFbeta-SMMHC inhibitor AI-10-49 shows a significant efficacy in this mouse model. This small molecule will serve as a promising first generation drug for targeted therapy of inv(16) leukemia and also a very useful tool to understand mechanisms of leukemogenesis driving by CBFbeta-SMMHC.
Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.
Clinical and Financial Impact of Hospital Readmissions Following Colorectal Resection: Predictors, Outcomes, and Costs: A Thesis
Background: Following passage of the Affordable Care Act in 2010, 30-day hospital readmissions have come under greater scrutiny. Excess readmissions for certain medical conditions and procedures now result in penalizations on all Medicare reimbursements. We examined the risk factors, outcomes, and costs of 30-day readmissions after colorectal surgery (CRS).
Methods: The University HealthSystem Consortium database was queried for adults (≥ 18 years) who underwent colorectal resection for cancer, diverticular disease, inflammatory bowel disease, or benign tumors between January 2008 and December 2011. Our outcomes of interest were readmission within 30-days of the patient’s index discharge, hospital readmission outcomes, and total direct hospital costs.
Results: A total of 70,484 patients survived the index hospitalization after CRS during the years under study, 13.7% (9,632) of which were readmitted within 30 days of discharge. The strongest independent predictors of readmission were: LOS ≥4 days (OR 1.44; 95% CI 1.32-1.57), stoma (OR 1.53; 95% CI 1.45-1.61), and discharge to skilled nursing (OR 1.63; 95% CI 1.49-1.76) or rehabilitation facility (OR 2.93; 95% CI 2.54-3.40). Of those readmitted, half occurred within 7 days of the index admission, 13% required ICU care, 6% had a reoperation, and 2% died during the readmission stay. The median combined total direct hospital cost was over twice as high ($26,917 v. $13,817) for readmitted than for nonreadmitted patients.
Conclusions: Readmissions following colorectal resection occur frequently and incur a significant financial burden on the healthcare system. Future studies aimed at targeted interventions for high-risk patients may reduce readmissions and curb escalating healthcare costs.
Categorization: Outcomes research; Cost analysis; Colon and Rectal Surgery
The Cellular Consequences of FUS/TLS Depletion: A Loss of Function Model for Amyotrophic Lateral Sclerosis: A Dissertation
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons, generally leading to paralysis and death within 3-5 years of onset. Over 50 different mutations in the gene encoding FUS/TLS (or FUS) will result in ALS, accounting for ~4% of all inherited cases. FUS is a multifunctional protein with important functions in DNA/RNA processing and stress response. How these mutations affect the structure or function of FUS protein and ultimately cause ALS is not known. The fact that mutations cause the protein to mislocalize from the nucleus to the cytoplasm of cells suggests that ALS pathogenesis may occur through a loss of nuclear function, gain of toxic cytoplasmic function, or both. Several FUS knockout animal models have been utilized for investigating a loss of function hypothesis and show phenotypes such as early lethality, reduced lifespan, and locomotor defects.
To uncover cellular pathways affected by loss of FUS function, I have characterized the knockdown of FUS in a motor neuron-like cell line, NSC-34. In NSC-34 cells, the depletion of FUS severely impacts cellular proliferation and potentially causes increased levels of DNA damage. A quantitative proteomics analysis performed on cells undergoing various degrees of FUS knockdown revealed protein expression changes for known RNA targets of FUS, consistent with a loss of FUS function with respect to RNA processing. Proteins that changed in expression as a function of FUS knockdown were associated with vii multiple processes, some of which influence cell proliferation including cell-cycle regulation, cytoskeletal organization, oxidative stress and energy homeostasis. Importantly, cellular proliferation could be rescued by the re-expression of FUS and by treatment with the small-molecule, rolipram, indicative of potential therapeutic approaches.
Collectively, the work presented in this dissertation demonstrates the importance of FUS for cell health and homeostasis, is suggestive of a role for FUS in DNA damage repair and identifies additional cellular pathways influenced by FUS depletion. Overall, this work provides mechanistic insight into ALS pathogenesis through loss of FUS/TLS function.
Comparative Effectiveness of Lithium and Valproate for Suicide Prevention and Associations With Nonsuicide Mortality: A Dissertation
Background: The mood stabilizer lithium has long been reported to be associated with reduced suicide risks, but many studies reporting associations between lithium and reduced suicide risks also have been nonrandomized and lacked adjustment for many potential confounders, active controls, uniform follow-up, or intent-to-treat samples. Concerns also have been raised that medications being considered as potential suicide preventative might increase risks of nonsuicide mortality while reducing risks of suicide.
Methods: Three studies of Veterans Health Administration (VHA) patients were conducted combining high-dimensional propensity score matching with intent-to-treat analyses to examine the associations between lithium and valproate and one-year suicide and nonsuicide mortality outcomes.
Results: In intention-to-treat analyses, initiation of lithium, compared to valproate, was associated with increased suicide mortality over 0-365 days among patients with bipolar disorder (Hazard Ratio (HR) 1.50 [95% Confidence Interval 1.05, 2.15]) Nonsuicide mortality among VHA patients with or without bipolar disorder was not significantly associated with the initiation of lithium compared to valproate ( HR 0.92 [0.82-1.04]). Rates of treatment discontinuation, however, were very high (≈ 92%). Longitudinal analyses revealed that the increased suicide risks associated with initiating lithium among patients with bipolar disorder occurred exclusively after discontinuation of lithium vii treatment. In secondary analyses restricted to patients still receiving their initial treatment, there was no difference in suicide risk between the initiation of lithium or valproate.
Conclusions: Significantly increased risks of suicide were observed at one year among VHA patients with bipolar disorder initiating lithium compared to valproate, related to risks observed after the discontinuation of lithium treatment Since these studies are nonrandomized, confounding may account for some or all of our findings, including the risks observed after lithium discontinuation. Nevertheless, these results suggest that health systems and providers consider steps to minimize any potential lithium discontinuation-associated risk. Approaches might include educating patients about possible risks associated with discontinuation and closely monitoring patients after discontinuation if feasible. Given the obvious importance of any substantive difference between lithium and valproate in suicide or nonsuicide mortality risk, our studies also suggest that further research is needed, especially research that can further minimize the potential for confounding.
Preclinical models of lupus indicate that T cell-B cell collaboration drives antinuclear antibody (ANA) production and sustains T cell activation. Autoreactive B lymphocytes are present in the normal repertoire but persist as ignorant or anergic cells. Mechanisms that normally limit T cell activation of autoreactive B cells remain incompletely resolved, but potentially include the absence of autoreactive effector T cell subsets and/or the presence of autoAgspecific regulatory T cells (Tregs). Several studies have addressed this issue by using experimental systems dependent on transgenic autoreactive B cells, but much less is known about the activation of autoreactive B cells present in a polyclonal repertoire. In the second chapter of this thesis, I have explored the role of effector T cells and Tregs using mice that express an inducible pseudoautoAg expressed on B cells and other antigen presenting cells (APCs). In this system, activated Th2 cells, but not naïve T cells, elicit the production of ANAs, but ANA production is severely limited by autoAg-specific Tregs. Bone marrow chimera experiments further demonstrated that this B cell activation is constrained by radioresistant autoantigen-expressing APCs (rAPC) present in the thymus as well as by non-hematopoietic stromal cells located in peripheral lymphoid tissue. Importantly, peripheral rAPC expression of autoAg induced the expansion of a highly effective subset of CD62L+CD69+ Tregs. The third chapter of this thesis focuses on the contribution of CD8+ T cells to fibrosis resulting from sterile lung injury. Type 2 effector production of IL-13 is v a demonstrated requirement in several models of fibrosis, and is routinely ascribed to CD4+ Th2 cells. However, we now demonstrate a major role for pulmonary CD8+ T cells, which mediate an exaggerated wound healing response and fibrosis through robust differentiation into IL-13-producing pro-fibrotic type 2 effectors (Tc2). Remarkably, differentiation of these Tc2 cells in the lung requires IL-21. We further show that the combination of IL-4 and IL-21 skews naïve CD8+ T cells to produce IL-21, which in turn acts in an autocrine manner to support robust IL-13 production. TGF-β negatively regulates production of IL-13 by suppressing CD8+ T cell responsiveness to IL-21. Our data illuminate a novel pathway involved in the onset and regulation of pulmonary fibrosis, and identify Tc2 cells as key mediators of fibrogenesis.
Blood lipids and the incidence of atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis and the Framingham Heart Study.
BACKGROUND: Dyslipidemia is a major contributor to the development of atherosclerosis and coronary disease. Its role in the etiology of atrial fibrillation (AF) is uncertain.
METHODS AND RESULTS: We studied 7142 men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study who did not have prevalent AF at baseline and were not on lipid-lowering medications. Total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were measured using standard procedures. Incident AF during follow-up was identified from hospital discharge codes; review of medical charts; study electrocardiograms; and, in MESA only, Medicare claims. Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of AF by clinical categories of blood lipids in each cohort. Study-specific results were meta-analyzed using inverse of variance weighting. During 9.6 years of mean follow-up, 480 AF cases were identified. In a combined analysis of multivariable-adjusted results from both cohorts, high levels of high-density lipoprotein cholesterol were associated with lower AF risk (hazard ratio 0.64, 95% CI 0.48 to 0.87 in those with levels > /=60 mg/dL versus < 40 mg/dL), whereas high triglycerides were associated with higher risk of AF (hazard ratio 1.60, 95% CI 1.25 to 2.05 in those with levels > /=200 mg/dL versus < 150 mg/dL). Total cholesterol and low-density lipoprotein cholesterol were not associated with the risk of AF.
CONCLUSION: In these 2 community-based cohorts, high-density lipoprotein cholesterol and triglycerides but not low-density lipoprotein cholesterol or total cholesterol were associated with the risk of AF, accounting for other cardiometabolic risk factors.